Control of the renal microvasculature by ... - The FASEB Journal

Control

of the renal

vasoactive PAMELA

K.

tDepartmen: Microcirculatory

CARMINES*.2

AND

JOHN

Tulane University

T

angiozerisin

New

University of Louisville Research, Louisville, Kenlucky 40292, USA of Physiology

and

Biophysics,

final urine. -CARMINE5, P. K.; FLEMING,J. T. Control of the renal microvasculature by vasoactive peptides. FASEBJ. 4: 3300-3309; 1990.

Words:

FLEMING1

School of Medicine,

Abstract In recent years, numerous techniques have been developed to study renal microcirculation. These technical advances have provided new insight regarding the specificity of action of vasoconstrictor peptides (angiotensin II, arginine vasopressin, endothelin) and vasodilator peptides (bradykinin, atrial natriuretic peptide) at discrete sites within the renal vascular bed. Differential signal transduction mechanisms, particularly those related to calcium regulation, appear to mediate the renal vascular actions of these compounds, both in a segment-specific and agonistspecific manner. These observations substantiate the concept that regulation of intrarenal and intraglomerular dynamics is accomplished by selective changes in pre- and postglomerular resistance induced by different endogenous peptides. This microvascular selectivity allows precise regulation of glomerular and peritubular capillary function, and ultimately exerts great influence on the volume and composition of the

Key

by

peptides1

of Physiology,

and tDepartment

microvasculature

II

nalriuretic peptide#{149} bradykinin

arginine vasopressin calcium . endothelin

Orleans,

Louisiana

School of Medicine,

70112,

USA;

and Center for Applied

tides have been the subject of considerable scrutiny, primarily because of their potent influences on salt and water excretion. These peptides gain access to the renal vasculature either by delivery in the bloodstream (angiotensin II, arginine vasopressin, atrial natriuretic peptide, bradykinin) or as a result of intrarenal synthesis (angiotensin II, endothelin, bradykinin) to subsequently exert their effects at preglomerular and/or postglomerular arteriolar sites. As the arteriolar segments of the renal vasculature are not accessible for direct study in vivo, the microvascular actions of these com-

pounds were initially inferred from ventional clearance and micropuncture cently,

however,

investigation

studies using techniques.

of the renal

conRe-

hemodynamic

actions of these agents has been facilitated by the development of innovative techniques for direct study of renal microvascular function, both in vivo and in vitro (1). In compiling this review, our goals are twofold: to summarize current knowledge concerning the renal microvascular actions of the most prominent vasoactive peptides, and to integrate this information with contemporary concepts regarding receptor localization, signal transduction, and calcium activation processes involved in determining vascular tone.

atrial renal

ANGIOTENSIN

II

microcirculation

The strong influence renal hemodynamics ability to elicit sodium PERHAPS

MORE

THAN

WITH ANY other

organ,

renal

func-

tion depends critically on the microvasculature in terms of its structure, capillary exchange characteristics, and smooth muscle function. These factors determine the nature and rate of glomerular filtrate formation and peritubular capillary uptake of tubular absorbate, ultimately influencing the composition of the final urine. A number of exquisitely complex and powerful mechanisms control glomerular and tubular function through influences on the preglomerular and postglomerular microvasculature. These systems regulate, either separately

or interactively,

the

hemodynamic

status

of the

entire nephrovascular unit. Among the many factors that influence renal hemodynamic function, several endogenous vasoactive pep-

3300

of angiotensin II (ANGII)3 on contributes substantially to its and volume retention during

Control of the Renal Microvasculature by Vasoby The American Physiological Society at the 74th Annual Meeting of the Federation of American Societies for Experimental Biology, Washington, D.C., April 3, 1990. Chaired by P. K. Carinines and J. T. Fleming. 2To whom correspondence should be addressed, at: Department of Physiology Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112, USA. 3Abbreviations: ANGII, angiotensin II; ANP, atrial natriuretic peptide; AVP, arginine vasopressin; BK, bradykinin; DG, diacylglycerol; ET, endothelin; GFR, glomerular filtration rate; 1P3, inositol trisphosphate; K, glomerular ultrafiltration coefficient; PG, prostaglandin; RBF, renal blood flow; ROC, receptor-operated channels; VGC, voltage-gated Ca2’ channels; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate. ‘From the Symposium

active Peptides presented

0892-6638/90/0004-3300/$01

.50. © FASEB

tablish an effect of ANGII on gbomerular dimensions in vivo. Rather, the peptide appears to alter intraglomerubar flow in a manner that shunts flow to fewer capillaries (6). In addition to this emerging scenario of ANGIIinduced alterations in glomerular perfusion pattern, it is likely that the reduction in Kf reflects in part a decline in capillary hydraulic conductivity (6, 7). Pregbomerular and glomerular ANGII receptors appear to be heterogeneous with regard to the potency with which selected analogs inhibit ANGII binding (5). Furthermore, in contrast to the behavior of the gbomerular ANGII receptor population (4), pregbomerular ANGII receptor density is not modulated by circulating peptide levels (5). The presence of ANGII receptors on the pregbomerular vessels of rabbit kidney implies a physiological function related presumably to contraction, although the behavior of interlobular and afferent arterioles isolated from this species has failed to support this contention (8). Interlobar arteries isolated from dog kidney are also unresponsive to ANGII (9). In contrast, except for one report (10), all studies directly assessing microvascular ANGII responsiveness in rodents have revealed actions of the peptide at both preglomerular and efferent arteriolar sites, although the relative

periods of reduced effective blood volume. In a variety of species, i.v. administration of exogenous ANGII decreases renal blood flow (RBF), and to a lesser extent, reduces glomerular filtration rate (GFR) so that filtration fraction is elevated. Such observations have led many investigators to hypothesize that ANGII elicits its renal hemodynamic action primarily or exclusively through efferent arteriolar vasoconstriction. The putative preferential efferent arteriolar action of ANGII represents a controversial issue that has initiated extensive experimental pursuit. The reader is referred to previous reviews (2, 3) for a detailed discussion of this issue. We will limit out treatment of this topic to evidence provided by experimental techniques that allow direct access to the renal microvasculature. ANGII receptors are located in abundance on gbmeruli,

vasa

recta

bundles,

and

in lesser

density,

on

preglomerular vessels (4, 5). Efferent arteriolar ANGII receptors have not been revealed by autoradiographic binding studies, but their presence is implied by the efferent vasoconstriction elicited by the peptide, an effect that is readily reversed by ANGII receptor antagonists. The presence of ANGII receptors in glomeruli is consistent with numerous observations that exogenous ANGII decreases the glomerular ultrafiltration coefficient

(Kf).

A physiological

role

for endogenous

potency

ANGII-

dependent modulation of the ultrafiltration barrier is evidenced by a reduction in Kf during stimulation of the endogenous renin-angiotensin system. Because of the inability to quantify changes in capillary hydraulic conductance in vivo, considerable attention has focused on the potential action of ANGII to reduce Kf through a reduction in capillary surface area. Cultured mesangial cells contract when exposed to ANGII, which has led many investigators to postulate that mesangial contraction represents the means whereby this peptide might reduce gbomerular capillary surface area. Indeed, the peptide contracts isolated gbomeruli in proportion to peptide concentration and receptor binding (4). Despite the contractile behavior of glomeruli in vitro, direct videometric observations have failed to es-

TABLE

1. Microvascular

localization of ANGII-induced

at these sites varies. Table

Technique

Rabbit

Isolated

Hamster

Renal

Rat

Isolated

used to gain vascular arterioles

allografts arterioles with with

[ANGII]

Arcuate artery

Interlobular artery

(1)

1 pmola

(11)

1 nM

Afferent arteriole

Efferent arteriole

%

Afferent

%

Efferent

- 53%

0.00

-40%

-63%

0.63

-51%

-89%

0.57

18%

- 11%

1.64

- 24%

20% -34%

1.20 1.03

0

nephrons:

albumin-containing homologous blood

Hydronephrotic kidney: Perfused in vitro with

in diameter

0

1 nM

cheek pouch

In vitro juxtamedullary Perfused Perfused

access (Ret)

(8) into

seg-

renal vasoconstriction Change

Species

1 summarizes

mental vascular responsiveness to ANGII, as ascertained by techniques that provide direct microvascular access. In addition to its direct, receptor-mediated effects on the vasculature, the renal vasoconstriction induced by ANGII in vivo depends in part on the systemic effects of the peptide. Elevations in circulating ANGII levels associated with marked increases in total peripheral resistance elicit an enhanced pregbomerular constrictor response to ANGII. This intensified preglomerular vasoconstriction reflects an autoregulatory response to the elevation in systemic arterial pressure (14). In accord with its noninvolvement in autoregulatory resistance adjustments, efferent arteriolar responsiveness to ANGII is unaffected by the systemic pressor effect of the peptide.

saline (12)

(10)

100 nM 0.1 nM

0 -20%

-

0.3 nM5 IOOnM

-25%

-39%

0 13%

-

albumin-containing

Krebs-Ringer-bicarbonate

solution

(13)

Invivo(14) Amount of ANGII pipetted aside vessel. topically at the concentrations indicated.

5Concentration

PEPTIDE INFLUENCES ON THE RENAL MICROVASCULATURE

of ANGII

in perfusate

solution.

-35%

AU other data represent

response

to ANGII

applied

3301

Stimulation of vasodilator prostaglandin (PG) synthesis also modulates the renal vasoconstrictor response to ANGII. Micropuncture analysis of superficial nephron function

in vivo

indicates

that

inhibition

of endogenous

PG synthesis enhances the afferent and efferent resistance effects of ANGII in the rat equally (15), whereas it selectively augments pregbomerular responses in the dog (16). ANGII-induced stimulation of PG synthesis has been documented in pregbomerular microvessels isolated from both dog and rabbit kidneys (17, 18), and the vasodilatory effect of these compounds may be responsible for failure to observe ANGII-induced contractile events in isolated pregbomerular vessels from these species (8, 9). Direct microscopic observation of the microvascubature of rat kidney, however, has not provided convincing support of PG-induced attenuation of the constrictor response to ANGII. Cycbooxygenase inhibition does not alter ANGII sensitivity of either isolated rat afferent arterioles (11) or the pre- and postgbomerular vascubature rendered accessible by inducing hydronephrosis in the rat (Fig. 1). Basal PG synthesis largely determines the effect of cycbooxygenase inhibition on renal hemodynamics and microvascular reactivity. To circumvent this problem, Inscho and co-workers (19) studied the influence of exogenous prostanoids

on ANGII-induced

contractile

blood-perfused juxtamedublary oxygenase inhibition. Under PGE2 nor PGI2 attenuated vasoconstriction elicited by

responses

in

nephrons during cyclothese conditions, neither the afferent arteriolar ANGII. In fact, PGE2

1 00-

w Iw

AFFERENT 80-

60

a LU z -J LU U)

Li

40

1001 EFFERENT

80-

0 z

60-

uJ 0

40

LU 0 0

I

i

0

ANC Figure

II BATH

L6

I_7

10

10

CONCENTRATION

3302

of cyclooxygenase

10

(M)

inhibition on renal arteriolar hydronephrotic rat kidney. Arteriolar inside diameters were measured using videometric microscopy. Data from a single afferent arteriole (, A) and efferent arteriole (0, #{149}) are shown. The tissue was exposed to increasing bath concentrations of ANGII under control conditions (t, 0) and after addition of 2.8 x 10 M indomethacin to the bath (A, ).

ANGII

1. Influence

-g

10

responsiveness

Vol. 4

in the in vivo

December

1990

enhanced the constrictor response to ANGII in this ex perimental setting. These observations suggest a previously unappreciated complexity of ANGII-PG interfl actions in determining renal arteriolar tone in the rat. Experimental delineation of these interactions will likely require consideration of the possible involvement of interspecies variations and interzonal heterogeneities in determining ANGII responsiveness in the kidney. In vascular smooth muscle cells of nonrenal origin, ANGII binding to its receptors initiates a G proteindependent cascade that leads to activation of phosphobipase C in the cell membrane and subsequent hydrolysis of membrane inositol phosphobipids to form inositol trisphosphate (1P3) and diacyiglycerol (DG) (20). 1P3 induces the release of Ca2’ from nonmitochondrial stores (likely the sarcoplasmic reticulum) to initiate contraction via phosphorylation of myosin by myosin light chain kinase. The ANGII-induced increase in DG may terminate the rapid mobilization of intracellular Ca2. DG also sustains influx of extracellular Ca2’ and maintains prolonged contraction, a process that is likely mediated by activation of protein kinase C (21). In addition, ANGII inhibits adenylate cyclase (22) and activates an amiboride-sensitive Na/H exchange (20), events also thought to contribute to the contractile response. Stimulation of PG synthesis results from activation of phospholipase A2 to release arachidonic acid from tissue phospholipids. The signaling mechanisms triggered by ANGII in the renal microvasculature are less well-defined. The influence of ANGII on cultured mesangial cells has received considerable experimental scrutiny (23), but it is not known whether the behavior of these cells reflects that of afferent and/or efferent arteriolar vascular smooth muscle. The increase in renal vascular resistance elicited by ANGII requires extracellular Ca2, yet it is only partially inhibited by antagonists of voltagegated channels (24), which suggests a role for receptoroperated channels in the renal vasoconstriction (25). Indeed, microvascular studies indicate that afferent arteriolar responses to ANGII require Ca2 access through voltage-gated channels, whereas the efferent arteriolar responses appear to be relatively independent of this process (13, 26, 27). These observations suggest that pre- and postglomerubar vascular responses to ANGII may not use identical signal transduction and C a2’ access pathways. ANGII-induced depolarization of smooth muscle cells (28), resulting from activation of a chloride channel (29), may contribute to opening of voltage-gated Ca2 channels, and ultimately to the afferent arteriolar contractile response; however, no information is available concerning efferent arteriolar signaling events evoked by ANGII stimulation. ARGININE

VASOPRESSIN

The potent antidiuretic peptide, arginine vasopressin (AVP), exerts a vasoconstrictor influence on many vascular beds. However, AVP infusion alters neither RBF nor GFR, whereas antagonists of the vascular response

The FASEB Journal

CARMINES AND FLEMING

i

to this

tion

peptide

elicit

systemic,

in water-deprived

sensitivity

animals.

to the vasoconstrictor

but not renal, The relative

vasodilarenal in-

effect of AVP is likely

observations suggest that an efferent arteriolar striction could contribute to the V1-mediated in vasa

recta

blood

flow

induced

by AVP.

vasoconreduction In

contrast,

due to intrarenal formation of a vasodilatory PG, as cyclooxygenase inhibition unmasks the renal vascular effects of AVP and AVP antagonists (30). The ability of AVP to induce both renal vasoconstriction and PG production has been documented in studies using the isolated perfused rat kidney (31). AVP has also been reported to decrease Kf (32), a response thought to reflect mesangial cell contraction (23). AVP interacts with two distinct receptor subtypes. The V1 receptor is characteristically located in vascular and hepatic target tissues, whereas V2 receptors mediate the antidiuretic action of the peptide on the collecting duct. Although the presence of functional V1 recep-

in vivo micropuncture studies performed with the rat have not detected a significant influence of the peptide on preglomerular or efferent arteriolar resistances (32). The arteriolar effects of AVP could have been masked by vasodilator PG production under the experimental conditions associated with the micropuncture study, however, thereby leaving the segmental vascular responsiveness to this peptide incompletely characterized. The cellular mechanism through which interaction of AVP with its V1 receptor elicits contraction has been extensively investigated using cultured mesangial cells,

tors

Ca2’ and influx of Ca2’ from the extracellular

has

been

documented

in cultured

mesangial

cells

(33), at least one recent autoradiographic study (34) suggests that this receptor population is not expressed in a detectable quantity in situ. These investigators suggested that some of the in vivo glomerular actions ascribed to AVP may result instead from stimulation of oxytocin receptors. Specific and dense [3HJAVP binding has also been observed in both medullopapillary and cortical portions of the rat kidney (34).

In concert papillary

with localization

tissue,

on the water

as well

permeability

as the

of AVP binding

sites in

influence

of this

peptide

ducts,

physio-

of collecting

logical concentrations of AVP decrease papillary vasa recta blood flow without altering whole-kidney GFR or

plasma

flow. The effect of AVP on vasa recta blood flow

appears to be indirectly influenced by the antidiuretic (V2) action of the peptide, reflecting a reduction in capillary uptake of reabsorbed volume originating in the collecting ducts (35). In addition, V1 receptor antagonists substantially attenuate the vasa recta blood flow response to AVP, while not interfering with concentrating ability (36). This observation indicates that there is also a V1-mediated component of the AVPinduced reduction in vasa recta blood flow, although this effect is not essential to the antidiuretic response. The V1-mediated influence on vasa recta blood flow may reflect a direct action of the peptide on the myoepithelial

elements

of pericytes

associated

with

prox-

imal segments of descending vasa recta. Alternatively, the reduction in vasa recta blood flow may occur secondarily to vasoconstriction of arterioles associated with juxtamedullary glomeruli. Differentiation between these two possible sites of V1-mediated influences on papillary perfusion awaits direct experimental evaluation.

In only one study were direct techniques

used to ex-

plore the effects of AVP on the resistance segments of the renal microvasculature. Edwards and co-workers (37) reported the ability of AVP to elicit a concentrationdependent constriction of isolated efferent arterioles from the mid-to-outer cortex of the rabbit kidney, whereas afferent arterioles were unresponsive. The efferent vasoconstriction was inhibited by V1-selective antagonists, but was not influenced by V2 blockade. Although these investigators were unable to isolate and study arterioles from juxtamedullary nephrons, their

PEPTIDE INFLUENCES

ON THE RENAL MICROVASCULATURE

and ment

involves (23).

both It

1P3-mediated

is assumed

release that

the

mediates AVP-induced contraction smooth muscle. The few studies that address this the behavior

issue have of cultured

revealed

some

of intracellular same

compartmechanism

of renal vascular have attempted to divergence

from

mesangial cells. AVP induces depolarization of afferent arteriolar vascular smooth muscle cells (28), which suggests that activation of voltage-gated ion channels might be involved in the vascular smooth muscle response to this peptide. In accordance with this observation, a substantial component of the V1-mediated vasoconstriction requires Ca2’ influx through voltage-gated channels, with a less prominent Ca2’ release component (31). Furthermore, the renal vasoconstrictor response may be independent of calmodulin. The AVP-induced increase in PG synthesis appears to occur primarily through intracellular Ca2’ mobilization, with subsequent Ca2’-calmodulin interaction resulting in activation of phospholipase A2 (31). This observation is in contrast with reports that AVP-stimulated PGE2 production by rat mesangial cells is blocked by verapamil, nifedipine, or exposure to Ca2-free solutions (38). Evidence from cultured aortic and mesenteric vascular smooth muscle cells indicates that a component of AVP- and ANGII-induced vasoconstriction entails movement of Ca2’ through receptoroperated channels, and that a phospholipase C or A2 metabolite is involved in the opening of these channels (25). However, the renal vasoconstrictor response to AVP is insensitive to phospholipase inhibition (30), thus leaving uncertain the role of receptor-operated Ca2 channels in eliciting the renal vascular response to this

peptide.

ENDOTHELIN

Endothelin (ET), a recently identified peptide derived from vascular endothelium, has received considerable attention with regard to its vasoconstrictor activity. The constrictor response to ET is particularly potent in the renal, mesenteric, and pulmonary vascular beds (39). Intravenous administration of ET increases systemic arterial pressure and decreases both RBF and GFR, effects that are attenuated by stimulation of PG production. The renal vasoconstrictor effect of ET is sustained

3303

for several hours, leading most investigators to consider a physiological regulatory role of the peptide unlikely. Rather, interest in ET-induced vasoconstrictor events stems primarily from its potential involvement in many pathological states. In vitro autoradiographic localization of intrarenal ‘251-labeled ET binding has disclosed very high-density binding overlying glomeruli and inner medullary structures (40, 41). The glomerular binding sites have been further characterized to include both high-affinity, lowdensity and low-affinity, high-density sites, the latter being implicated in most of the mesangial responses to ET (42). High-density binding sites are also located in vasa recta bundles of the outer medulla and in resistance vessels as small as 20 sm in diameter (40, 41). Despite the clear demonstration of macroand microvascular ET binding sites within the kidney, studies probing the influence of ET on renal microvascular function have failed to provide consistent data with regard to the relative influence of the peptide on the various segents of the vasculature. Micropuncture studies of the rat indicate that ET elicits both preglomerular and efferent arteriolar vasoconstriction. However, the peptide has been reported to exert a greater influence on preglomerular resistance (43), a relatively greater efferent effect (44), or equivalent alterations in preglomerular and efferent resistances (45). Because these variable segmental resistance effects are associated either with no change or with a reduction in Kf, a consistent influence of ET on single-nephron GFR has not emerged from these investigations. Studies directly assessing microvascular responsiveness have not resolved the dilemma. Isolated rat efferent arterioles are considerably more sensitive to ET than are afferent arterioles (46), whereas the isolated perfused hydronephrotic kidney

exhibits

a more

potent

afferent

arteriolar

effect

of

the peptide (47). Other direct investigations in this field are required to provide a definitive characterization of the segmental arteriolar actions of this peptide. In the short time since its discovery, considerable information has accrued detailing the cellular events involved in the actions of ET. Among the myriad of cell types found within the kidney, the cultured mesangial cell has proved particularly amenable to studies of transmembrane signaling events evoked by ET. Progress in this area, which was recently reviewed by Simonson and Dunn (39), has revealed that ET receptor activation elicits alterations in mesangial cell function through a complex chain of events. Intracellular [Ca2’] is elevated in two distinct kinetic patterns: a rapid transient IP3-dependent release of Ca2’ from intracellular storage sites, and a slow, sustained Ca2’ influx from the extracellular compartment through a mechanism that is insensitive to voltage-gated channel blockade. In addition to these effects on cytosolic [Ca2’], ET stimulates Na’/W

exchange

to

alkalinize

mesangial

cells,

and

stimulates phospholipase A2 with resulting PG synthesis (39). Whether ET evokes identical processes to elicit effects on afferent and/or efferent arteriolar vascular smooth muscle is unknown. Attempts to address this question in vivo have provided conflicting results with

3304

Vol. 4

December

1990

regard to the requirement for Ca2’ entry through voltage-gated channels (48, 49). This discrepancy may arise, in part, from a segmental variation in the signaling mechanism (or mechanisms) evoked by this peptide. Loutzenhiser and co-workers (47) observed that the vasoconstrictive effect of ET on afferent arterioles was completely reversed by nifedipine, whereas this agent had no effect on the modest efferent arteriolar action of the peptide. These data can best be explained on the basis of a vital role of voltage-gated Ca2’ channels in the ET-stimulated signal transduction processes that result in preglomerular vasoconstriction, whereas other mechanisms predominate in the efferent arteriole. ATRIAL

NATRIURETIC

PEPTIDE

Although the potent natriuretic and diuretic effect of atrial natriuretic peptide (ANP) is not absolutely dependent on its renal hemodynamic actions, it is clear that the influence of this peptide on glomerular and renal microvascular function can ultimately affect the magnitude of the excretory response. Under most conditions, infusion of ANP or one of its structurally related peptides elicits a sustained increase in GFR, whereas its influence on RBF is variable. Indeed, although ANP appears to vasodilate the kidney more effectively than other vascular beds, the peptide is also capable of increasing GFR without altering RBF. This realization has spurred substantial interest in elucidating the complex influences of this peptide on glomerular and hemodynamic function. In vitro autoradiography has localized specific highdensity [‘25I]ANP binding concentrated over glomeruli, the arterial vasculature, and afferent and efferent arterioles (50, 51). Moderate density binding has also been reported to overlie vasa recta bundles (51). Most of the ANP binding sites within the kidney represent clearance receptors that contribute to the short half-life of the circulating peptide. The relative intrarenal distribution of ANP clearance receptors and biologically active ANP receptors remains incompletely characterized, although recent observations indicate that only biologically active receptors are expressed in rat papilla, whereas two-thirds of the glomerular binding sites represent clearance receptors (52). In concert with identification of vasa recta binding sites for ANP, several reports suggest that the peptide may exert its renal hemodynamic actions through a preferential effect on medullary blood flow. ANP elicits an increase in inner medullary blood flow whereas outer cortical perfusion remains either unaffected or only modestly increased, resulting in significant natriuresis without sustained alterations in whole-kidney GFR or RBF. Such observations suggest that ANPinduced diuresis occurs through a blood flow redistribution to deep nephrons and subsequent medullary washout; however, the increase in papillary blood flow occurs after initiation of the natriuresis and diuresis, and thus probably does not directly mediate the excretory response (53, 54). Nevertheless, the papillary hyperemia can be expected to impede fluid reabsorp-

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CARMINES

AND

FLEMING

tion and contribute to the natriuretic and diuretic response to the peptide. In addition to the effects of ANP on the medullary vasculature, an elevation in GFR likely contributes to the magnitude of the natriuretic response by increasing the sodium and volume load presented to the transporting segments of the nephron. The hemodynamic mechanisms responsible for eliciting this hyperfiltration have been studied extensively at the single-nephron and microvascular levels. Micropuncture studies have revealed the ability of ANP infusion to increase singlenephron GFR, although it does not significantly alter glomerular plasma flow. Studies using isolated glomeruli indicate that an increase in Kf contributes to the ANP-induced elevation in GFR (55); however, the hyperfiltration elicited by exogenous ANP infusion in vivo can be attributed generally to preglomerular vasodilation and efferent arteriolar constriction, thus resulting in an increase in glomerular capillary pressure. The preglomerular vasodilatory response to ANP has been substantiated by direct microvascular access studies of isolated afferent arterioles from dog (56) but not rabbit kidney (57), in vitro blood-perfused juxtamedullary nephrons from rat kidney (58), and the in vivo hydronephrotic rat kidney (59). These reports document afferent arteriolar vasodilation at ANP concentrations as low as 100-300 pM (56, 58). An ANP-induced efferent arteriolar vasoconstriction has also been observed, but only in response to peptide concentrations in the 100- to 500-nM range (55, 59). Circulating ANP concentration in normal humans is approximately 3-25 pM, and pathophysiologic conditions such as congestive heart failure may raise the level only as high as 150 pM (60). Therefore, the physiological and pathophysiological significance of the efferent vasoconstrictor response to ANP appears limited. The cellular mechanism involved in eliciting the vasodilatory response to ANP uses cGMP as its second messenger. The biologically active ANP receptor acts as a membrane-bound guanylate cyclase, allowing direct generation of the second messenger upon ANP binding. The cGMP thus formed activates a protein kinase, which in turn induces vasodilation. The ability of ANP to increase cGMP formation has been demonstrated in renal vascular smooth muscle cells (61) and isolated glomeruli (57). Furthermore, the afferent arteriolar dilatory response to ANP is potentiated by cGMP phosphodiesterase inhibition (56). The mechanism by which cGMP elicits renal vasodilation has not been fully elucidated. The relaxant effect of ANP on renal arcuate arteries is not associated with any change in membrane potential or 22Na efflux (62), thus ruling out a hyperpolarization-dependent vasodilation. Rather, the response appears to involve attenuation of agonistinduced rises in intracellular [Ca24] and/or prevention of myosin light-chain phosphorylation (60) via phosphorylation of various regulatory proteins by cGMPdependent kinases. These vasodilatory effects are similar to the actions of nitrovasodilators, which also use

cGMP ANP

as a second elicits

efferent

PEPTIDE INFLUENCES

messenger. arteriolar

ON

THE RENAL

The

constriction

means

whereby

has not been

MICROVASCULATURE

addressed. The recent report that ANP differentially modulates T- and L-type voltage-gated calcium channels in adrenal glomerulosa cells, stimulating L current and inhibiting T current (63), may provide one mechanism by which the contrasting effects of this peptide on pre- and postglomerular vasculature could develop. BRADYKININ Activation of plasma or glandular kallikrein initiates a cascade leading to kallidin formation and subsequent generation of kinins, of which bradykinin (BK) is the most noted. The ability of vasodilator kinins to modulate renal function via tubular and vascular actions has been extensively investigated. Acute administration of exogenous BK increases RBF without altering GFR, yielding a decline in filtration fraction. This effect may involve a reduction in Kf, which would attenuate the influence of kinin-induced vasodilation on glomerular filtration. Although the renal hyperemia usually does not persist throughout the period of acute BK administration, chronic infusion of the peptide induces a longterm elevation in RBF. Despite the reported effects of exogenous kinin infusion, it is unlikely that circulating kinins normally exert a potent influence on the renal vasculature, as these peptides are rapidly inactivated by kininases localized on the endothelial cell membrane. It is more likely that intrarenally produced kinins are involved in renal hemodynamic control. The necessary components of the kallikrein-kinin system are all present within the kidney (64). Kallikrein concentrations in canine kidney decrease from outer to inner cortex. Although kallikrein is present in the medulla and papilla, its concentration is significantly less than in the cortical regions. Because kallikrein and kininogen are localized predominantly in renal tubular compartments (64, 65), the ability of locally produced kinins to influence vascular elements has been questioned. However, kallikrein released from the basolateral aspect of distal tubular cells could form kinins in the interstitial compartment, subsequently influencing the smooth muscle cells of nearby arterioles. This postulate is strengthened by the recent demonstration that the distal connecting tubule cells containing kallikrein consistently establish a close anatomical relationship with the afferent arteriole in the region of the juxtaglomerular apparatus (66). Kinins reaching the vascular elements of the nephron may interact with two major types of membrane receptors - designated and B2 both of which appear to be involved in the vasodilator response to BK (67). Support for the contention that locally formed kinins can influence RBF is provided by the demonstration that kinin receptor antagonists reduce RBF (without altering systemic arterial pressure or GFR) when administered under conditions known to enhance the activity of the renal kallikrein-kinin system (68). Endogenous kinin production also appears to modulate intrarenal blood flow distribution, as kinin receptor blockade reduces papillary blood flow without altering outer cortical flow or GFR (69). Conversely, inhibition of kinin -

3305

degradation substantially elevates papillary blood flow. The renal kallikrein-kinin system has been proposed to function as a modulator of PG synthesis and reninangiotensin activity. Basal PG production by the kidney may be regulated by the activity of the kallikreinkinin system. Indeed, renal PG synthesis is stimulated by BK infusion (70), a process that is mediated by B2 kinin receptors (67). Furthermore, PGs may mediate in part the dilator and natriuretic effects of BK within the kidney, although these findings are controversial. The reader is referred to Nasjletti and Malik (71) for a more extensive review of this topic. The failure of acute BK administration to sustain an elevation in RBF appears to be due to activation of the renin-angiotensin system and resultant ANGII-induced vasoconstriction. Indeed, BK stimulates renin release both in vivo and in vitro (70, 72); however, as kinin receptor antagonists stimulate rather than inhibit renin release (68), the influence of endogenous kinins on renin release under normal conditions remains uncertain. On the other hand, ANGII can stimulate the release of kallikrein

and

subsequent

kinin

formation.

The

mutual

stimulatory effect of the kallikrein-kinin and reninangiotensin systems, which exert opposite effects on renal vascular tone, may be physiologically relevant during alterations in salt intake. In this regard, both BK and ANGII participate in control of renal vascular resistance in animals fed a low sodium diet, whereas neither peptide appears critically involved in renal vascular control during periods of high sodium intake. The kallikrein-kinin and renin-angiotensin systems are also linked by a common enzymatic pathway: kininase II degrades and inactivates BK, and is identical to angiotensin-converting enzyme, which converts angiotensin I to the vasoactive ANGII. Hence, the vasodilatory action of converting enzyme inhibitors presumably involves both a reduction in ANGII formation and an accumulation of BK, although the relative contribution of each component is controversial. Little information is available regarding the renal microvascular effects of kinins. BK infusions decrease preglomerular resistance in vivo substantially, with an accompanying tendency for efferent vasodilation. Recent data based on direct observation of the rat hydronephrotic kidney microvasculature indicate that BK elicits dilation of both the pre- and postglomerular arterioles T Fleming, unpublished observations). However, isolated arterioles from rabbit kidney exhibit an efferent, but not afferent or interlobular, vasodilation in response to BK (73). Thus, the precise renal microvascular actions of BK have not been clearly established. The cellular actions of BK, like the constrictor effects of other peptides, appear to involve an alteration in phosphoinositol metabolism. In cultured renal tubular cells, BK increases phosphatidylinositol turnover in a way that correlates temporally with Ca2’ mobilization (74). Similarly, BK elevates IP3 formation by isolated glomeruli, an effect inhibited by protein kinase C activation (75). Because BK elicits vasodilation rather than contraction, the effector enzymes triggered by this pep-

U-

2(

/I

A

iO0i

Tt,.r.

rcn

tide must differ from those activated by vasoconstricto peptides that similarly stimulate phospholipid metabolism. It is possible that the vasodilator action of this peptide may involve a cGMP-dependent mechanism (76), as is common for other dilator substances. Furthermore, an endothelium-dependent process may contribute to the renal vasodilation elicited by BK. BK stimulation of PG synthesis likely results from the hydrolysis of DG through processes similar to those elicited by ANGII and AVP, although some investigators support the contention that BK enhances renal PG synthesis by stimulating a lipase that does not require Ca2’ and calmodulin (24).

Ca2 AND PEPTIDE ACTION: IS THERE SEGMENTAL DIVERGENCE IN RENAL MICROVASCULAR Ca2 REGULATORY MECHANISMS?

A

Organic Ca2’ entry antagonists, acting primarily by interfering with Ca2’ movement through voltage-gated channels, substantially increase both RBF and GFR. This effect implies a renal microvascular selectivity not characteristic of other potent vasodilators (i.e., papaverin acetylcholine), which tend to increase RBF to a greater extent than GFR and thereby reduce filtration fraction. Recent evidence, derived from experimental settings that provide direct microvascular access, supports the idea that organic Ca2 entry antagonists dilate preglomerular arterioles significantly more than efferent arterioles (26, 77). Conversely, the Ca2 channel agonist BAY K 8655 constricts the same preglomerular vascular sites that are dilated by dihydropyridine Ca2 channel antagonists (78). Furthermore, KC1-induced depolarization weakly constricts efferent arterioles of the isolated perfused hydronephrotic kidney compared with the marked response of afferent arterioles (79). Taken together, these findings suggest a fundamental difference in the Ca2 regulatory processes of pre- vs. postglomerular vessels. Voltage-gated Ca2’ channels seem to predominate on preglomerular arterioles such that their basal tone, but not that of efferent arterioles, is largely dependent on Ca2’ entry through these channels. The recent observation that i.v. infusion of Mn2’, which interferes with both voltage-gated Ca2’ channels and other Ca2’ entry pathways, exerts selective preglomerular vasodilation (80) suggests that basal efferent arteriolar tone may be independent of the extracellular Ca2 pool, relying instead on intracellular events for maintaining sustained contractile activation. Videomicroscopic observations substantiate the concept that the constriction of preglomerular vessels in response to peptides is also mediated by Ca2 access mechanisms different from those used by efferent arterioles (Fig. 2). In various microvascular preparations, organic Ca2’ entry blockers either prevent, reverse, or attenuate preglomerular constrictor responses to ANGII and ET, whereas the efferent arteriolar responses are generally unaffected (13, 26, 27, 47). In contrast, ANGII-induced contraction of both preCAD&AIMCC

AM

ci

CkAtMt

ci

VASOCONSTRIOTOR PEPTIDE

REFERENCES

ct

1. Navar, L. G., Gilmore, J. P., Joyner, W. L., Steinhausen, M., Edwards, R. M., Casellas, D., Carmines, P. K., Zimmerhackl, L. B., and Yokota, S. D. (1986) Direct assessment of renal microcirculatory dynamics. Federation Proc. 45, 2851-2861 2. Hall,J. E. (1986) Control of sodium excretion by angiotensin II: intrarenal mechanisms and blood pressure regulation. Am. J. Physiol. 250, F960-F972

3. Navar, L. G., and Rosivall, L. (1984) Contribution of the reninangiotensin system to the control of intrarenal hemodynamics. Kidney mt. 25, 857-868

PRIMARY MECHANISMS IN AFFERENT ARIERIOLAR SMOOTH MUSCLE

PRIMARY MECHANISMS IN EFFERENT ARTERIOLAR SMOOTH MUSCLE

Figure

2. Working hypothesis depicting signaling events involved in elevating cytosolic [Ca2l in response to vasoconstrictor peptides, patterned primarily on ANGII-stimulated events. Although all events depicted may be involved in eliciting pre- and postglomerular vasoconstriction, receptor-operated channels (ROC) and release of Ca2 from the sarcoplasmic reticulum may predominate in the efferent arteriole, whereas opening of voltage-gated Ca2 channels

(VGC) appears crucial for eliciting afferent arteriolar vasoconstriction. PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate.

and postglomerular vessels is abated by Cd2’, a nonspecific Ca antagonist (81). Hence, potential-dependent dihydropyridine-sensitive Ca2 channels appear to mediate the activation of preglomerular smooth muscle by vasoconstrictor peptides, although other pathways for Ca2’ entry seem to predominate at the efferent arteriole. In light of emerging evidence that diverse mechanisms mediate contraction at pre- and postglomerular vascular sites, it seems inappropriate to use cultured mesangial cells as all-encompassing models for delineating the cellular mechanisms involved in renal microvascular control. One direction for future research in this field is the development of methods for study of renal arteriolar smooth muscle cells originating from discrete pre- and postglomerular sites. Because the functional distinction between cells from these two intrarenal sites may be subtle, particular emphasis must be placed on ensuring that their behavior in vitro reflects that expressed in vivo. Study of renal arteriolar smooth muscle signal transduction processes remains the crucial next step in advancing our understanding of how vasoactive peptides exert their control of glomerular dynamics through precise alterations in pre- and postglomerular resistance.

E!]

4. Mendelsohn, F. A. 0., Dunbar, M., Allen, A., Chou, S. T., Millan, M. A., Aguilera, G., and Catt, K. J. (1986) Angiotensin II receptors in the kidney. Federation Proc. 45, 1420-1425 5. Brown, G. P., and Venuto, R. C. (1988) Angiotensin II receptors in rabbit renal preglomerular vessels. Am. J. Physiol. 255, E16-E22 6. Zimmerhackl, B., Parekh, N., Kucherer, H., and Steinhausen, M. (1985) Influence of systemically applied angiotensin II on the microcirculation of glomerular capillaries in the rat. Kidney let. 27, 17-24 7. Wiegmann, T. B., MacDougall, M. L., and Savin, V. J. (1990) Glomerular effects of angiotensin II require intrarenal factors. Am. j Physiol. 258, F717-F721 8. Edwards, R. M. (1983) Segmental effects of norepinephrine and angiotensin II on isolated renal microvessels. Am. j PhysioL

244, F526-F534 9. Strandhoy, J. W., Cronnelly, R., Long, J. P., and Williamson, H. (1972) Effects of vasoactive agents and diuretics on isolated superfused interlobar renal arteries. Proc. Soc. Exp. Biol. Med. 141, 336-339 10. Sanchez-Ferrer, C. F, Roman, R. J., and Harder, D. R. (1989) Pressure-dependent contraction of rat juxtamedullary afferent arterioles. Circ. Res. 64, 790-798 11. Yuan, B. H., Robinette, J. B., and Conger, J. D. (1990) Effect of angiotensin II and norepinephrine on isolated rat afferent and efferent arterioles. Am. J. Physiol. 258, F741-F750 12. Carmines, P. K., Morrison, T K., and Navar, L. G. (1986) Angiotensin II effects on microvascular diameters of in vitro blood-perfused juxtamedullary nephrons. Am. j Physiol. 251, F610-F619 13. Loutzenhiser, R., Hayashi, K., and Epstein, M. (1988) Calcium antagonists augment glomerular filtration rate of angiotensin Il-vasoconstricted isolated perfused rat kidneys by dilating afferent but not efferent arterioles. j Cardiovasc. Pharmacol. 12 (Suppl. 6), S149 (abstr.) 14. Steinhausen, M., Sterzel, R. B., Fleming, J. T., Kuhn, R., and Weis, 5. (1987) Acute and chronic effects of angiotensin II on the vessels of the split hydronephrotic kidney. Kidney let. 31 (Suppl. 20), 564-S73 15. Baylis, C., and Brenner, B. M. (1978) Modulation by prostaglandin synthesis inhibitors of the action of exogenous angiotensin II on glomerular ultrafiltration in the rat. Circ. Res. 43, 889-898 16. Heller, J., and Horacek, V. (1986) Angiotensin II: preferential efferent constriction? Renal Physiol. (Base!) 9, 357-365 17. Hura, C. E., and Kunau, R. T. (1988) Angiotensin IIstimulated prostaglandin production by canine renal afferent arterioles. Am. j PhysioL 254, F734-F738 18. Chaudhari, A., and Kirschenbaum, M. A. (1988) A rapid method for isolating rabbit renal microvessels. Am. j P/zysiol. 254, F291-F296

19. Inscho, Work on this topic in the authors’ laboratories was supported by grants from the National Institutes of Health (DK39202, HL18426,

and HL06790), ate,

and

the American Heart Association/Kentucky the Boehringer Ingelheim Research Foundation.

and J. T F. are recipients Awards. P. K. C. is an Heart Association.

PEPTIDE INFLUENCES

of National Institutes Established Investigator

AffiliP. K. C.

of Health FIRST of the American

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P. K.,

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3, A1386 (abstr.) 28. B#{252}hrle, C. P., Nobiling, R., and Taugner, R. (1985) Intracellular recordings from renin-positive cells of the afferent glomerular arteriole. Am. j Physiol. 249, F272-F281 29. Kremer, S. G., Breuer, W. V., and Skorecki, K. L. (1989) Vasoconstrictor hormones depolarize renal glomerular mesangial cells by activating chloride channels. j Cell. PhysioL 138, 97-105 30. Yared, A., Kon, V., and Ichikawa, I. (1985) Mechanism of preservation of glomerular perfusion and filtration during acute extracellular fluid volume depletion: importance of intrarenal vasopressin-prostaglandin interaction for protecting kidneys from contraction action of vasopressin.] Cue. Invest. 75, 14771487 31. Cooper, C. L., and Malik, K. U. (1984) Mechanism of action of vasopressin on prostaglandin synthesis and vascular function in the isolated rat kidney: effect of calcium antagonists and calmodulin inhibitors. j Pharmacol. Exp. Ther. 229, 139-147 32. Schor, N., Ichikawa, I., and Brenner, B. M. (1981) Mechanism of action of various hormones and vasoactive substances on glomerular ultrafiltration in the rat. Kidney let. 20, 442-451 33. Jard, S., Lombard, C., Marie, J., and Devilliers, G. (1987)

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