head to significant declines in renal blood ...... in- hibition in dogs. Circ Res. 1986;58:874-881. 42. Ogawa. N, Ono. H: Different effects of noradren- ahine, angiotensmn. II, and. BAY. K 8644 on the abolition of autoregubation of renal blood flow.
The Effects of Calcium Antagonists On Renal Hemodynamics, Urinary Protein Excretion, And Glomerular Morphology In Diabetic States George
G.L.
L. Bakris1
Bakris,
Orleans, (J. Am.
Ochsner
Medical
Institutions,
New
LA Soc. Nephrol.
1991;
2:521-S29)
ABSTRACT Numerous animal studies have been performed in the early stages of diabetic renal disease documenting beneficial effects of angiotensin converting enzyme inhibitors. Over the past 5 yr. a number of animal and human studies show similar results with certain calcium antagonists. However, the data with calcium antagonists are not as consistent as that with angiotensin converting enzyme inhibitors. This article will review all of the pertinent clinical and laboratory studies involving these classes of agents in the course of diabetic nephropathy. Emphasis is placed on explaining divergent results between animal and human studies with regard to renal hemodynamic, histologic, and antiproteinic effects. Key Words: merular
Diabetes,
filtration
rate,
proteinuria, renal
diabetic
nephropathy,
hemodynamics,
calcium
gbantag-
onists
,
B
etween 1986 and 1988, 32% of all new cases of end-stage renal disease were caused by diabetes melbitus, making it the most common cause (1). The combination if diabetes and hypertension accounted for the largest increase in end-stage renal disease from 1 977 to 1 988 (1 ,2). Blacks have a four-times greater incidence of diabetes-related renal disease when compared with whites (1), and Native Amencans having a twofold increase over blacks. The fact that the combination of diabetes and hypertension is twice as common in the black population (3) could account for their increased susceptibility to developing end-stage renal disease (1-4). Thus, therapeutic agents which attenuate the renal hemodynamic and histologic effects of these two diseases should in‘Correspondence Renal Division.
7703
to Dr. G.L. Bakris, University of Texas Health Science Floyd Curl Drive, San Antonio, TX 78284-7882.
1046-6673/0202-0S21 $030010 Journal of the American Society of Nephroiogy Copyright © 1991 by the American Society of Nephrology
Journal
crease the time needed before dialysis, therefore reducing the costs changed to Medicare for this procedune. A family history of diabetic nephnopathy and the devehopment of microabbuminunia in a diabetic patient appear to be reliable predictors of progression to end-stage renal disease (5- 1 4). Increases in microahbuminunia have ahso been statistically correhated with an increased mortality nate in both type I and type II diabetic subjects (1 2, 1 4). A recent 1 0-yr follow-up study by Parving et at. supports the notion that control of arterial pressure in diabetic subjects is critical for preserving renal function and howening proteinunia, which in turn impede the progression to renah disease ( 1 5). However, a study by Wiegmann et at. demonstrates proteinunia to be concurrent with abnormal renal function and blood pressure rather than a predictor of renal disease ( 1 6). Data from another recent prospective, double-blind study with the converting enzyme inhibitor enalapnih also attempt to show a lack of conrehation between proteinunia and progression of diabetic renal disease (17). That study, however, only points out that enalapnih exacerbates preexisting renal dysfunction, which incidentahly is associated with a lowering of urinary protein excretion. These studies raise an important issue, i.e. is proteinunia a good predictor of progressive renal dysfunction in people with significant preexisting renal insufficiency (gbomeruhar fihtration rate, 8 wk).
diabetes. A summary of these micropuncture studies is presented in Table 1. Six of these studies were performed in the 1 /6 nephrectomy model of renal insufficiency, and all studies used in all three different classes of calcium antagonists. Two of these studies documented a decrease in gbomerular capillary pressure. All studies which reported efferent arteriolar resistance demonstrated a reduction, and all but one showed a decrease in afferent arteriobar resistance. One of these studies evaluated the chronic effects (>8 wk) of verapamib (29). No significant effect was demonstrated on gbomerular capillary pressure or afferent arteriobar resistance. Efferent arteriobar pressure fell, but because mean arterial pressure increased, the dm1cab significance of the data may not be relevant. In a unilaterally nephrectomized deoxycorticosterone (DOCA) salt rat model, nifedipine had no effect
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on efferent arteriolar resistance or gbomerular capillary pressure (34). A 24% reduction in mean arterial pressure and a decrease in afferent arteriolar resistance were seen. Three separate, acute micropuncture studies were performed in normal rats. No change in gbomerular capillary pressure was seen in any of the studies, and only one demonstrated a decrease in efferent arterial resistance. Arterial pressure was only minimably reduced in all three studies. When compared with the effects of ACE inhibitors, significant and persistent lowering of arterial pressure with all but the dihydropyridmne class of calcium antagonists is exceedingly difficult in rat models of hypertension (S. Anderson, personal communication). These studies demonstrate that the effects of calcium antagonists on renal hemodynamics vary depending on the model used for study (22.23,28-37). In general, they all dilate the afferent arteriole but effects on the efferent arteriole and gbomerular capibbary pressure may vary. Factors which may account for these variations include differences among models, such as hemodynamic and hormonal differences, differences in the activation of the renin angiotensmn system (low in Dahl salt-sensitive rats and elevated in diabetic rats), altered renal autoregulatory response by the kidney, and variable baseline values of single nephron gbomerubar filtration rate. The single nephron gbomerubar filtration rate was increased by calcium antagonists in only one study (28), whereas all other studies showed either a decrease or no effect. An increase in this factor is generally seen in models of diabetes and renal ablation. ACE inhibitors increased this parameterin most studies. The results with calcium antagonists may, in part, be related to variable effects on arterial pressure. These variable results may help explain the disparate effects between ACE inhibitors and cabcium antagonists on urinary protein excretion and histologic preservation. Hemodynamic differences between the renal ablation model, the streptozotocin diabetic rat, and the DOCA salt rat include baseline renal blood flows, ghomerubar capillary pressures, and arteriobar pressures. The afferent arteriolar response to calcium antagonists also differs depending on the model studied (38). These variables may have an impact on the comparative renal hemodynamic effects of ACE inhibitors and calcium antagonists. Differences in baseline hormonal profiles are also critically important in assessing the effects of calcium antagonists on renal hemodynamics. Two recent studies evaluate the renal hemodynamic and renin angiotensmn system profiles in the streptozotocm diabetic rat (20,39). One study evaluated the status of the renin angiotensin system in a streptozotodin model of diabetes at 12 days (39). Anderson et at.
Journal
of the American
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of Nephrology
evaluated the renin angiotensmn system at 2 months, as well as the effects of an angiotensmn II peptide antagonist (Dup 753) in the same model (20). These studies report increased messenger RNA for prorenmn as early as 1 2 days after the onset of diabetes (38). The messenger RNA expression for angiotensmnogen shows no increase at 1 2 days, but a significant increase after 8 wk; yet, plasma renin levels were normal. These hemodynamic changes seen with the Dup 753 in this model correlate with histologic changes in human mesangiab cells exposed to elevated extracellular glucose concentrations in the presence of both this compound as well as ACE inhibitors (40). Although this type of analysis has not been studied in other models. it would be predicted that low activation of the renin angiotensmn system would occur with the DOCA salt hypertensive rat, as webb as with some of the other models. Thus, the renin angiotensin system may have a significant influence on the way different calcium antagonists affect renal hemodynamics. Altered renal autoregubatory response may play a significant robe in the ability of the kidney to adapt to pressure changes in some animal models. Two major components of renal autoregulation-tubulogbomerular feedback and alferent arteriolar “myogenic” autoregubatory system-are affected by calcium antagonists. Calcium antagonists block tububogbomerubar feedback, affecting regulation of gbomerubar capillary pressure and afferent arterlohar resistance (39,4 1 -42). A recent study by Epstein et at. has shown an altered afferent arteriobar response to calcium antagonists in a model of diabetes, which has not been shown in other models of hypertension (38). Theoretically, impairment of renal autoregulation by calcium antagonists may affect renal blood flow and gbomerular filtration rate as perfusion pressure varies. Consequently, significant decreases in arterial pressure would head to significant declines in renal blood flow and gbomerubar filtration rate. In some studies, an increase in arterial pressure leads to no change or an increase in renal blood flow and gbomerular filtration rate. In short, alterations in renal autoregulation based on the model studied may help explain the disparate renal effects of ACE inhibitors and calcium antagonists. Atriab natriuretic factor has also been shown to alter renal hemodynamics in rat models of diabetic nephropathy (43). Specifically, levels of atrial natriuretic factor are increased in human studies as well as in animal models of diabetes and reduced renal mass (43-46). This increased hormonal level has been shown to increase both renal blood flow and gbomerubar filtration rate (43). However, recent studies in humans demonstrate that the renal hemodynamic effects of atrlab natriuretic peptide, demonstrated by a blunted vasodilatory response of the afferent arteriole, occur in early diabetes (44.46).
S23
Effects
of Calcium
Antagonists
This finding is consistent with that seen by other investigators with calcium antagonists (38). Atriab natriuretic peptide also has effects on mesangial cell proliferation and will be discussed hater in this report.
TABLE 2. Effects of calcium antagonists protein excretion and progression of glomerulosclerosis#{176} Reference No.
Model/Drug
EFFECTS OF CALCIUM RENAL HISTOLOGY
ANTAGONISTS
S24
Glomerulosclerosis
.
-
ON
More than 1 4 separate studies, which are summarized in Table 2, have investigated the effects of calcium antagonists in various models of renah insufficiency and hypertension (23-27,29,31-33,4750). Three studies were in two separate models of diabetes; seven studies were in a 1 /6 nephrectomy model. Four of the seven studies which evaluated ghomerular histology showed attenuation in the progression of ghomerubosclerosis, whereas three showed no effect. The remaining models included a unilateral nephrectomized DOCA salt rat model, a unilaterally nephrectomized spontaneously hypertensive rat model, and a Dahh salt-sensitive rat model. The DOCA salt rat and spontaneously hypertensive rat models showed attenuation of gbomerubosclerosis. The Dahl salt-sensitive hypertensive model did not show significant long-term attenuation in gbomeruloscherosis. The factors which may affect the variability of results include: an independent effect apart from blood pressure reduction (47); decreases in gbomerubar radius impacting preservation of histology more than reduction in glomerular capillary pressure (Dworkin et at. 23); and better histologic preservation by calcium antagonists over conventional vasodilators (48,49). Four of the 1 1 studies that evaluated glomerular histology failed to show renal protection, and 2 demonstrated actual worsening of glomerulosclerosis (Table 2). The reasons for these disparate effects of calcium antagonists on gbomeruhar preservation are not entirely clear. However, three of the four studies were in a remnant kidney model of renal insufficiency, which lacks renal autoregulatory properties. Also, arteriah pressure was only mildly reduced in these studies as compared with significant reductions seen with ACE inhibitors. These factors, in addition to factors such as the status of the renin angiotensmn system, may play a role in accounting for the differential effects between these classes of drugs. In vitro studies with either rat and human mesangiab cell cultures with all groups of calcium antagonists and ACE inhibitors have demonstrated an attenuated mitogenic response to various growth factors, including angiotensin I! and insulin (40-51). These studies show a hess-pronounced effect on cell growth at very high extracellular glucose concentrations (30 mM) when insulin is present (unpublished observations). Because mesangial cell and matrix proliferation are the hallmarks of the renal lesion in diabetic nephropathy, attenuation of this prohifera,
.
Proteinuria
on urinary
RA Verapamil Harrisetal.’ Yoshioka et a!. Pelayo et a!. Brunner et 01. Nisoldipine Eliahou et 01. Nifedipine Dworkinetal. Felodipine Jackson and Johnston DOCA Salt Nifedipine Dworkineta/. DahI salt-sensitive TA-3090 Tolins and Raij /o
47
0
31 29 27
j -
1
1
48 23,33 24
-p
34
25
1 (long
term) -,
SHR Nifedipine Dworkin et a!. Cohen diabetic rat Nisoldipine Rosenthal et a!. /6 RA/STZ rat Verapamil Jackson et al. Sato et al. 0
mild decrease;
neously
tozotocin b Chronic
hypertensive
36
50
0
26 49
0 0
-
0. not measured; rat;
(short term) (long term)
% PA,
1/o
-p.
renal
unchanged; ablation
model;
SHP. spontaSTZ. strep-
diabetic rat. studies (>8 wk).
tion would be beneficial to diabetic subjects. No pubhished studies to date have investigated the effects of these agents on proliferation of mesangiah matrix, a major histopathohogic process in diabetes. Atrial natriuretic peptide has also been shown to attenuate mesangial cell proliferation (52,53) and the mitogenic response to insulin and fetal calf serum but not to argmnine vasopressin (unpublished observations). Therefore, it may have effects on gbomerubar mesangium that surpass its renal hemodynamic alterations. Gbomerubar size and charge selectivity are also altered in diabetic states. ACE inhibitors have been shown to restore charge but not size selectivity in proteinuric, nondiabetic humans (54), whereas studies in diabetic humans clearly show altered charge selectivity (55). ACE inhibitors, by lowering ghomer-
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ular capillary pressure, Influence gbomerular permselectivity to macromolecules, consequently altering urinary protein excretion. Theoretically, certain cabcium antagonists should have the same benefit but these effects have not yet been assessed.
210
-
f GFR
180
-
150
-
120
-
(mI/mm)
PROTEINURIA Eleven studies have evaluated the relative antiproteinuric effects of calcium antagonists in various animal models of both diabetes and renal ablation (22-26,31 .33,34,48,49). In models of streptozotocininduced diabetes, calcium antagonists were found to reduce proteinuria when compared with hydrabazine (48,49). However, other studies do not show a dramatic reduction in urinary protein excretion (26). The disparate effects of calcium antagonists and ACE inhibitors on blood pressure may account for this lack of reduction in proteinuria. Furthermore, in the studies by Jackson et at. creatinine clearance was significantly reduced in the ACE inhibitor group, which would contribute to a reduction of proteinuria (24,26). A dramatic reduction in blood pressure was not seen in the calcium antagonist-treated group, but a small reduction in proteinuria was still noted. Two mechanisms have been postulated for reducing proteinuria in the previously mentioned models: one is the reduction in gbomerular capillary pressure, and the other is altered charge selectivity to various proteins (55,56-58). Only one study has evaluated the effects of permselectivity with verapamib (31). These investigators clearly showed an improved gbmerular permselectivity after 2 wk of therapy in a renal ablation model. However, formal studies to evaluate the effects of calcium antagonists on charge selectivity, gbomerubar capillary pressure, and proteinuria in diabetic animal models have not been published.
_____________________________
660-
600
RPF (ml / mm)
540
480-
420
,
HUMAN
of the
American
100
MAP (mmHg) 90
80
Baseline
Lisiropril
Figure 2. The effects of lisinopril on renal hemodynamics in normotensive incipient diabetic human subjects. GFR, gbmerular filtration rate; RPF, renal plasma flow; MAP, mean arterial pressure; ‘P< 0.05 different from baseline.
150
U
STUDIES
A number of studies have evaluated the beneficial effects of ACE inhibitors on proteinuria in diabetic humans (2 1). We recently evaluated the effects of ACE inhibitors in eight normotensive, noninsubindependent diabetic subjects and controls (Figures 2 and 3). This small pilot study demonstrated a significant reduction in gbomerubar hyperfihtration and normalization of microalbuminuria in two of the four patients receiving bismnoprib. This is a contradistinction to a control group that received alpha-methyldopa, which demonstrated no significant reduction in proteinuria after 1 yr of therapy (data not shown). No conclusions can be drawn from this small study until the results of barge-scale, ongoing trials evaluating the use of these agents in a normotensive diabetic population are completed.
Journal
110
Society
of Nephrology
protein’’ (.tg/mmn)
50
Baseline
Lisinopril
Figure 3. The effects of lisinopril on renal hemodynamics and urinary protein excretion in normotensive incipient diabetic human subject. FF, filtration fraction. p< 0.05 different from baseline.
S25
Effects
of Calcium
Antagonists
There are at beast 1 3 published reports on the effects of calcium antagonists on proteinuria. Eleven of these are in diabetic subjects (59-7 1). These chinicah studies generally demonstrate that calcium antagonists either lower or do not affect proteinuria. The notable exception is the dihydropyridine compound, nifedipine, in which three separate clinical studies have documented significant increases in both type I and type II diabetic subjects, regardless of the initial level of protemnuria (Figure 4) (59-61). These increases in protemnuria occurred in spite of adequate blood pressure control, equal to that of an ACE inhibitor (59,6 1). Only four of these studies are hong term (greater than 8 wk). These long-term studies document sustained antiprotemnuric effects of the calcium antagonists. verapamib and dibtiazem, while noting variable results with nifedipine. Three studies
Initial
Washout
Crossover
jflfl [1ii
120
Hg)
1
1
1
I
*
U protein
V
iE11fl fl [Ii 100
(m?5in)
Figure 4. The effects of diltiazem (sustained release) or nifedipine XL (long-acting preparation) on mean arterial pressure (MAP) and renal function in humans. Open bars, baseline; dashed bars, nifedipine; cross-hatched bars, diltiazem. ‘P< 0.05 different from baseline. Reprinted by permission of Elsevier Science Publishing Co. Inc. from ‘The renal hemodynamic and histologic effects of calcium antagonists in models of renal insufficiency and diabetes,’ by George 1. Bakris, American Journal of Hypertension, Vol. 4, 4875-4935, copyright 1991 by the American Journal of Hypertension, Inc. ,
S26
,
I
document a persistent increase in protemnuria with nifedipine (Figure 4) (6 1 .64,65). Two other hong-term studies ( 1 yr) report no change in urinary albumin excretion (70,7 1 ). Interestingly, three of these four studies report an exacerbation of preexisting renal insufficiency with nifedipine, a process that was reversible with discontinuation of the drug (59,61.71). Other short-term studies in diabetic subjects with the calcium antagonist nicardipine also demonstrate reductions in urinary protein excretion; however longterm data are not available in these studies (66,69). No double-blind, placebo-controlled trial of the attenuating effects of these agents on protemnuria or progression of diabetic nephropathy has been performed in humans. Carmines and Navar recently demonstrated that addition of a calcium antagonist to an isolated perfused kidney pretreated with an ACE inhibitor potentiates dilation of the efferent arteriole (72). We used this concept to evaluate the potential benefits of combining a calcium antagonist and an ACE inhibitor in treating proteinuria in diabetic subjects (65). This study demonstrates that the combination of verapamil with lisinoprib yielded an additional 26% reduction in protemnuria over either calcium antagonists or ACE inhibitors alone. There was no significant difference in gbomerubar filtration rate or renal blood flow, and blood pressure was equably well controlled in all groups. This suggests that other factors, in addition to renal hemodynamics, play a robe in this antiprotemnuric effect.
SUMMARY One possible explanation for the similar effects of calcium antagonists and ACE inhibitors on the kidney is their similar renal hemodynamic effects on inhibition of angiotensin II (73,74). However, future studies in diabetes should attempt to select an animal model that more closely resembles the natural history of diabetic nephropathy in humans (75). In addition, intervention should occur after a period of time, not immediately, as previous studies demonstrate. This type of intervention will provide more clinically rebevant data regarding the renal effects of these classes of antihypertensive agents in advanced nephropathy. With the available data, it is unclear whether calcium antagonists are clearly superior or equal to the renal “protective” effects of ACE inhibitors when administered during the very early stages of diabetes for management of hypertension. However, on the basis of both clinical and animal hemodynamic studies, calcium antagonists offer greater beneficial effects over conventional vasodilators, such as hydrabazine, for preservation of gbomerular histology and reducing proteinuria. Until further studies are performed in humans to assess the effects of calcium
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antagonists on the ropathy, appropriate, guide their use.
natural history of diabetic clinical judgment will
nephhave to
ACKNOWLEDGMENT We
thank
Mrs.
Peggy
1 7.
1 8. Bourque
for
her
excellent
secretarial
contri-
button.
1 9.
REFERENCES 1 . United Report. 27. 2.
3.
4.
5. 6. 7.
8.
9.
10.
1 1.
12.
1 3. 14.
15.
16.
Journal
Teutsch
States Renal Am J Kidney
Data Dis
System 1 990;
1 990 1 6(suppl
Annual 2):2220.
S, Newman
J, Eggers
P: The problem
of diabetic renal failure in the United States: An overview. Am J Kidney Dis 1989;13:1 1-13. Bud D, Teutsch SM: The control of hypertension in persons with diabetes: A public health approach. Public Health Rep 1 987; 102:522-529. Jarrett RJ: Hypertension in diabetic patients and differences between insulin-dependent diabetes mebbitus and non-insulin-dependent diabetes melhitus. Am J Kidney Dis 1 989; 13:14-16. Mogensen CE: Prevention and treatment of renal disease in insulin-dependent diabetes melbitus. Semin Nephrob 1990;10:260-273. Nelson RG, Pettitt DJ, Carraher MJ, et at.: Effect of proteinuria on mortality in NIDDM. Diabetes 1988:37:1499-1504. Krolewski AS, Canessa M, Warram JH, et at.: Predisposition to hypertension and susceptibibity to renal disease in insulin dependent diabetes mellitus. N Engb J Med 1988:318:140-145. Kaysen GA, Myers BD, Couser WG, Rabkin R, Felts JM: Mechanisms and consequences of proteinurla. Lab Invest 1986:54:479-498. Noth RH, Krolewski AS, Kaysen GA, Meyer TW, Schambelan M: Diabetic nephropathy: Hemodynamic basis and implications for disease management. Ann Intern Med 1 989; 110:795813. Hawthorne VM: Consensus statement: Proceedings from the International Workshop on Preventing the Kidney Disease of Diabetes Mebbitus. Public Health Perspective. Am J Kidney Dis 1989; 13: 1-6. Viberti GC, Hill RD, Jarrett RJ, et at.: Microabbuminuria as a predictor of clinical nephropathy in insulin-dependent meblitus. Lancet 1982; 1: 1430-1432. Mogensen CE: Microalbuminuria predicts clinicab proteinuria and early mortality in maturityonset diabetes. N Engb J Med 1984:310:356360. Tuttle KR, Stein JH, DeFronzo RA: The natural history of diabetic nephropathy. Semin Nephrol 1990:10:184-193. Schmltz A, Vaeth M: Microabbuminuria: A major risk factor in non-insulin-dependent diabetes. A 10-year follow-up study of 503 patients. Diabetic Med 1988:5:126-134. Parving HI!, Smidt UN, Mathiesen ER, Hommel E: Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy [Abstract]. J Am Soc Nephrob 1990;! :294. Wiegmann TB, MacDougall M, Chonko A, Moore W: Risk factors for abbuminurla in pa-
of the American
Society
of Nephrology
2 1.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
tients with type II diabetes mebhitus. Am J Kidney Dis 199!, in press. Reams GP, Bauer JH. Decrease in protemnuria with ACE inhibition does not predict attenuation of progression of renal disease [Abstract]. Chin Res 1991;39:247. Zatz R, Dunn BR, Meyer TW, Anderson 5, Rennke HG, Brenner BM: Prevention of diabetic glomerubopathy by pharmacological amelioration of gbomerular capillary hypertension. J Clin Invest 1986;77: 1925-1930. Anderson 5, Rennke HG, Garcia DL, et at.: Short and long term effects of antihypertensive therapy in the diabetic rat. Kidney Int 1989; 36:526-536. Anderson 5, Bouyounes B, Clarey LE, Ingelfinger JR: Intrarenal renin-angiotensin system (RAS) in experimental diabetes [Abstract]. J Am Soc Nephrob 1990;l:62!. Keane WF, Anderson 5, Aurell M, et at.: Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Ann Intern Med 1989;! 11:503-516. Brunner FP, Hermie M, Thiel G: Verapamib (V) in contrast to enalaprib (E) aggravates hyperfibtration despite lowered blood pressure in rats with reduced renal mass [Abstract]. Abstr Xth Int Congress Nephrol 1987:10:497. Dworkin LD, Parker M, Tolbert E, Feiner H: Nifedipmne and enabaprib decrease gbomerular injury in rats with remnant kidneys by different mechanisms [Abstracti. J Am Soc Nephrob 1990; 1:627. Jackson B, Johnston CI: The contribution of systemic hypertension to progression of chronic renal failure in the rat remnant kidney: Effect of treatment with an angiotensmn converting inhibitor or a calcium inhibitor. J Hypertens !988;6:495-501. Tolins JP, Raij L: Comparison of converting enzyme inhibitor and calcium channel blocker in hypertensive gbomerular injury. Hypertension 1990:16:452-46!. Jackson B, Cubela R, Debrevi L, Whitty M, Johnston CI: Disparate effects of angiotensmn converting enzyme inhibitor and calcium blocker treatment on the preservation of renal structure and function following subtotal nephrectomy or streptozotocin-induced diabetes in the rat. J Cardiovasc Pharmacol 1 987; 1 0(suppl 10):S167-S! 69. Brunner FP, Thiel G, Hermie M, et at.: Longterm enahaprib and verapamib in rats with reduced renal mass. Kidney mt 1989;36:969-977. Ichikawa I, Miele JF, Brenner BM: Reversal of renal cortical actions of angiotensmn II by verapamil and manganese. Kidney Int 1 979; 16:137147. Pelayo JC, Harris DC, Shanley PF, et at.: Gbmerubar hemodynamic adaptations in remnant nephrons: Effects of verapamih. Am J Physiol 1 988;254:F425-F43 1. Pelayo JC: Modulation of renal adrenergic effector mechanisms by calcium blockers. Am J Physiol 1 987;252:F6 1 3-F620. Yoshioka T, Shiraga H, Yoshida Y, et at.: “Intact Nephrons:” as the primary origin of proteinuria in chronic renal disease. Study in the rat model of submotab nephrectomy. J Chin Invest 1988; 82:1614-1623.
S27
Effects
32.
34.
35.
36.
37.
38.
39.
40.
42.
43.
44.
45.
46.
47.
S28
Antagonists
Anderson S: Renal hemodynamics of calcium antagonists in rats with reduced renal mass. Hypertension 1 99 1 ; 17:288-295. Dworkin LD, Parker M, Feiner HD: Nifedipine decreases gbomerular injury in rats with remnant kidneys by inhibiting gbomerubar hypertrophy [Abstract]. Kidney Int 1989:35:427. Dworkln LD, Levin RI, Benstein JA, et at.: Effects of nifedipine and enalapril on gbomerular injury in rats with deoxycorticosterone-saht hypertenslon. Am J Physiol 1 990;259:F598-F604. Isshiki T, Amodeo C, Messerli FH, Pegram BL, Frohlich ED: Diltiazem maintains renal vasodihation without hyperfiltration in hypertension: Studies in essential hypertensive man and spontaneously hypertensive rat. Cardiovasc Drugs Ther 1 987; 1:359-366. Dworkin LD, Parker M, Feiner D, Berstein JA: Renal protective actions of nifedipmne and enahapril: Averting the hypertrophied, hypertensive gbomerulus [Abstract]. Kidney Int 1 990;37:504. Anderson 5, Rennke HG, Zayas MA, Brenner BM: Chronic calcium channel blockade fails to lower gbomerular pressure and ahbuminuria in diabetic rats [Abstract]. Chin Res 1991 ;39:247. Epstein M, Hayashi K, Forster H, Loutzenhiser R: Impaired myogenic afferent arteriolar (AA) vasoconstriction in genetically diabetic rats [Abstract]. J Am Soc Nephrob 1 990; 1:627. Muller-Suur R, Gutsche HU, Schurek HJ: Acute and reversible inhibition of tububoghomerubar feedback mediated afferent vasoconstriction by the calcium-antagonist verapamib. Curr Probl Clin Biochem 1 976;6:29 1-298. Bakrls GL, Akerstrom V, Re R: Insulin, angiotensin II and endothehin: Effects on human mesangial cells [Abstract]. Hypertension 1990; 16:326A.
33,
41
of Calcium
.
Navar
LG, Champion
WJ,
Thomas
CE: Effects
of calcium channel blockade on renal vascular resistance responses to changes in perfusion pressure and angiotensmn-converting enzyme inhibition in dogs. Circ Res 1986;58:874-881. Ogawa N, Ono H: Different effects of noradrenahine, angiotensmn II, and BAY K 8644 on the abolition of autoregubation of renal blood flow by verapamih. Naunyn-Schmiedeberg’s Arch Pharmacol 1986:333:445-449. Ortola FV, Ballermann BJ, Anderson 5, Mendez RE, Brenner BM: Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. J Clin Invest 1987:80:670-674. Lieberman J, Parra L, Loon N, Myers B: Circuhating ANP and the renal response to water immersion in diabetic nephropathy (Abstract]. J Am Soc Nephrob 1990:1:635. Brandt MA, Fink GD, Chimoskey JE: Plasma atrial natriuretic peptide in conscious rats with reduced renal mass. FASEB J 1989:3:23022307. Shinoda T, Ishihara M, Kurimoto F, et at.: Elevated plasma atriab natriuretic peptide level in early phase of microalbuminuria in patients with noninsulin dependent diabetes meblitus. Chin Nephroh !990;34:202-207. Harris DC, Hammond WS, Burke TJ, et at.: Verapamil protects against progression of experimental chronic renal failure. Kidney Int 1987; 31:41-46.
48.
49.
50.
5 1.
52.
53. 54.
55.
56.
57.
58.
59.
60.
61
62.
63.
.
Eliahou HE, Cohen D, Herzog D, et at.: The control of hypertension and its effect on renal function in rat remnant kidney. Nephrol Dial Transplant 1 988;3:38-44. Sato T, Nara Y, Note 5, Yamori Y: Effect of calcium antagonists on hypertension and diabetes in new hypertensive diabetic models. J Cardiovasc Pharmacol 1 987; 1 0(suppl 1 0):S 192S 194. Rosenthal T, Rosenmann E, Cohen AM: Effects of nisobdipine on hypertension and gbomeruhosclerosis in Cohen diabetic rat with Goldbbatt hypertension [Abstract]. Am J Hypertens 1 990;3:27A. Schultz PJ, Raij L: Inhibition of human mesangial cell proliferation by calcium channel blockers. Hypertension 1 990; 1 5(suppl I): 171180. Johnson A, Lermioglu F, Garg UC, MorganBoyd R, Hassid A: A novel biologic effect of atrial natriuretic hormone: Inhibition of mesangial cell mitogenesis. Biochem Biophys Res Commun 1 98 152:893-897. Appel RG: Growth inhibitory activity of atrial natriuretic factor in rat gbomerular mesangiab cells. FEBS Lett 1988;238:135-138. de Zeeuw D, Heeg JE, de Jong PE: ACE inhibition improves glomerular permsebectivity to proteins, not to dextrans [Abstract]. J Am Soc Nephrol 1990:1:626. Nakamura Y, Myers BD: Charge selectivity of proteinuria in diabetic glomeruhopathy. Diabetes 1988:37:1202-1211. Zatz R, Anderson 5, Meyer TW, et at.: Lowering of arterial blood pressure limits gbomerular scherosis in rats with renal ablation and in experimental diabetes. Kidney Int !987;31(suppl 20):S123-S129. Remuzzi A, Puntorieri S, Battaglia C, Bertani T, Remuzzi G: Angiotensmn converting enzyme inhibition ameliorates gbomerubar filtration of macromolecules and water and lessens glomeruhar injury in the rat. J Chin Invest 1 990;85:54 1549. Myers BD, Meyer TW: Angiotensmn-converting enzyme inhibitors in the prevention of experimental diabetic glomerubopathy. Am J Kidney Dis 1989:13:20-24. Mickisch 0, Schmid M, Mann JF, et at.: Calcium antagonists in chronic renal failure. Undesirable effects on gbomerubar hemodynamics? Dtsch Med Wochenschr 1988:113:1546-1548. Miniran A, Insua A, Rthstein J, Monnier L, Bringer J, Mirouze J: Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. J Hypertens 1988:6:919-923. Demarie BK, Bakris GL: Effects of different classes of calcium antagonists on proteinuria associated with diabetic meblitus. Ann Intern Med 1990;! 13:987-988. Jungmann E, Schumm-Draeger PM, Nickelsen T, Haak T, Scheuermann EG, Schofifing K: Long-term effects of febodipine in hypertensive patients with insulin-dependent diabetes mebbitus [Abstract]. Am J Hypertens 1990:3:28A. Capewell 5, Collier A, Matthews D, et at.: A trial of the calcium antagonist. felodipine. hypertensive type 2 diabetic patients. Diabetic Med 1989:6:809-812.
Volume
2
‘
Number
Supplement
1’
1991
Bakris
64.
65.
66.
67.
68.
69.
Journal
Bakris GL: Effects of dibtiazem on massive proteinuria associated with diabetes mellitus. Ann Intern Med 1990;! 12:707-708. Barnhill B, Bakris GL: The combined effects of verapamil and bisinopril on urinary protein cxcretion in diabetic nephropathy [Abstract]. J Am Soc Nephrob 1990;1:362. Baba T, Murabayashi 5, Takebe K: Comparison of the renal effects of angiotensin converting enzyme inhibitor and calcium antagonist in hypertensive type 2 (non-insulin-dependent) diabetic patients with microalbuminuria: A randomized controlled trial. Diabetobogia 1989; 32:40-44. Cruickshank JK, Anderson NM, Wadsworth J, et at.: Treating hypertension in black compared with white non-insulin dependent diabetics: A double-blind trial of verapamib and metoprobol. Br Med J l988;297:1 155-1159. Gotz R, Heidbreder E, Heidland A: Different effects of ACE-inhibitor and calcium channel blocker on proteinuria in histologically proven gbomerubonephritis [Abstract]. Am J Hypertens 1 990:3:70A. Stornello M, Valvo EV, Scapellato L: Hemodynamic, renal and humoral effects of the calcium entry blocker nicardipine and converting en-
of the American
Society
of Nephrology
70.
7 1.
72.
73.
74.
75.
zyme inhibitor captoprib in hypertensive type 2 diabetic patients with nephropathy. J Cardiovasc Pharmacol 1989:14:851-855. Melbourne Diabetic Nephropathy Study Group. Comparison between perindoprib and nifedipine in hypertensive and normotensive diabetic patients with macroalbuminuria. Br Med J 1991:302:210-216. Ferder L, Daccordi HA, Martello M, Marisa P, Inserra F: ACE inhibitors versus calcium antagonists in the treatment of diabetic hypertensive patients [Abstract]. Hypertension 1 991 ; 17:453. Carmines PK, Navar LG: Disparate effects of Ca channel blockade on afferent and efferent arteriohar responses to ANG II. Am J Physiol 1989:256:F1015-F1020. Magometschnigg D, Hortnagl H, Rameis H: Dm1tiazem and verapamil: Functional antagonism of exogenous noradrenahine and angiotensmn II in man. Eur J Cbin Pharmacob 1984:26:303-307. MIllar JA, McLean K, Reid JL: Calcium antagonists decrease adrenal and vascular responsiveness to angiotensmn II in normal man. Chin Sd 198! ;6 1 :65s-68s. Velasquez MT. Kimmel PL, Michaelis OE N: Animal models of spontaneous diabetic kidney disease. FASEB J 1990:4:2850-2859.
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