Prostaglandin E1 increases myocardial contractility in ...

Prostaglandin El increases myocardial contractility in the conscious dog' S o Woux, J . G. h,a.rsua,' I?. T H ~ R O UJ.XP. , CLOZEL, !%NI) M.G. BOUKASSA Laboratories of Experirnentab S ~ ~ r g e r~yi n dExpei-imcntal Pnihologjl, Bnsticut dc~c.ar.~liologie.dc Motarri.nl, 5000 Bclangol- St. E . , MotltrLul, QuC.. Cnncrdu H l T IC'H Received March 7, 1984

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by 199.201.121.12 on 06/03/13 For personal use only.

Woux, S . . J .

@. LATOUR.P. T H ~ R O U9X . P. , C1,0z6~.and Ikl. @. BOURASSA.19164. Prostaglanc4in E l increases myocardial contractility in the conscious dog. Can. J . Physiol. Pharmacol. 62: 1505- 8 5 10. 'The systemic and inotropic properties of prostaglandin El (PGEI) werc investigated in 20 unancsthctized dogs. Pdirs of ultrasonic dimension gauges and a micromanometer werc implanted in the subendocardium and the apex of the left ventricle (EV). respectively. Seven to ten days later. increasing doses of l%El were infused into the left atrium. To appreciate the inotropic effects of the agent, the heart rate was maintained constant at 150 beats/min In a subgroup of dogs while preload was modified by bleeding or saline infusion over matched ranges of end-diastolic segmental length (EDL) during placebo and PGEr infusions (0.25 p g - kg ' rnin I). LV function curves (AE: systolic segmental shortening versus EDL) were plotted. Increasing doses of PGE, above 0.03 1 k g . kg - I . m i n ' brought a progressive decrease of left ventricular end-diastolic pressure, EDE, AL, and peak left ventricular systolic pressure. The heart rate increased significantly at dosages from 0.063 to 0.125 p g kg -' min I . and peak positive dP/dt after an initial increase fell at the dose of 0.5 kg * kg ' .min I. The LV function curves invariably showed a shift to the %eftwhen PGEl was administered; as the basal EDL was rcstored during PGEI infusion, AL reached a 33% increase ( p < 0.001). Thus, in addition to its potent vassdilating properties ttaat are nlore prominent on preload than afterload. PGEl increases myocardial contractility in the conscious dog.

Roux, S., J . G. LATOUR.P. 'THEROLX, % .P. CLOLELet M . C;. BOURASSA.1984. Prostaglandin El increases myocardial contractility in the conscious dog. Can. S. Physiol. Pharnlacol. 62: 1505- 1510. On a examine les proprietks systkmiques ct inotropes de la prostaglandine EL(PGE,) chez 20 chiens non [email protected] a implant@des paires de jauges de mesure ultrasor~oresdans le sous-endocarde et un micromano~mittredans la pointe du ventricule gauche (LV). Sept B 10 jours plus tard, on a perfuse des doses croissantes de N E l dans l'oreillette gauche. Pour &valuer les effets inotropes de I'agent, on a maintenu la freyuence cardiaque constante ii 150 &attements/min chez un sous-groupe de chiens alors qu'on modifiait la precharge par une hkmorragie ou m e perfusion saline sur garnrne de diverses longueurs du segment en fin de diastole (EDL) pendant des perfusion de placebo et da: PGEI (4),25 p,g.kg ' -min I ) ) . On a track Bes courbes de foraction du LV (AL: raccourcissemcnt du segment systolique versus EDL). L'administratlon de doses croissantes de PGEl au-dessus de 0,031 p g *kg ' -min provoqua une diminution progressive de la pression ventriculaire gauche en fin de diastole, de I'EDL, du AL et de la pression systolique de cr2te du ventricule gauche. La frkquence cardiaque augnaenta significativernent aux doses comprises cntre 0,063 et 0,125 p g .kg ' rnin I , et la dP/dt positive de crcts augntenta d'abord pour ensuite chuter la dosc de 0-5 y g kg ' rmin I . Les courbes de fonction du 1,V rnontrkrent invariablenrent unc dkviation vers [a gauche avec I'administration de PC;EI; I'EDL basale fut rktablie sous PGE, alors que le AL augmenta de 33% ( p < 0,001). Par consCqeaent, en plus dc ses propriCt@svasodi1atatrica;ts importantes qui sont plus nettes sur la precharge que sur la postcharge, la PGEI augmenta la contractilltk rnyocardique chez le chlen conscient. [Traduit par le journal]

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Introduction Prostaglandin E l (PGE,) has a number sf potent bic~logical actions including direct relaxing effects on vascular and nonvascular smooth muscles with variations from species to species (Dusting et al. 1979; Judgutt et al. 198%;Karrnazyn and Dhalla 1983). PGE, is used pharmacologically in the neonate to maintain the patency of the ductus arteriosus (Cllley 1975) and beneficial effects have been reported in patients with congestive heart failure (Awan et al. 1982). However, the exact mechanism of this beneficial effect remains unknown as the potent vasodilating property of PGE, changes the cardiac loading conditions and can mask an eventual positive inotropic effect. Most of the studies carried out on isolated cardiac tissue preparations indicate that P@EI increases the strength of ventricular contraction (Karrnazyn and Dhalla 19831, but results reported so far in vivo are not as conclusive because of the use of anesthetics whish are known to interfere with myocardial contractility and the autonomic nervous system (Vatner and Braunwald 1975). In the present study, we have investigated 'Supported by grants from the Fonds de recherche de I'institut de cardiologie de Montrkal and the Medical Research Council of Canada (MT-4478). 'Author to whom all correspondence should be addressed.

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the inotropic effect of PGE! in the conscious dog using u8trasonic piezoelectric crystals and found evidence that PGE, increases myocardial contractility.

Materials and methods A total of 20 mongrel dogs with a weight range of 18-27 kg (mean 22.5 2 1 ) were studied. A left thoracotorny and a pericardiotomy were performed under general anesthesia. A high fidelity pressure micromanometer (Konigsberg P7) and a Silastic tluid-filled catheter (2 rnm inner diameter) were inserted into the left ventricle through the apex and secured in posltion with epicardial sutures. Silastic catheters were inserted into the right and the lcft atria. Pacing electrodes were sutured on the right atrium. Four pairs of small ultrasonic piezoelectric crystals (5 NIHz) were implanted in the left ventricular wall perpendicular to the major axis of the left ventricle as previously described by Franklin et al. (1973) and by 'ThCroux et al. ( 1974). Two pairs were implanted in the region of the circumflex artery and two others in the area of the left anterior descending (LAD) coronary artery. Each crystal was spaced apart by I - 1.5 crn from its partner. The pericardium was sutured and the wires and tubes were passed subcutaneously to the back of the animal and brought through the skin between the scapulae. The catheters were flushed daily with 10 mL saline containing sodium-heparin, 2 U/mL. The experinaents were carried out 7- 10 days after surgery. All the animals were active and trained to lie quietly and unrestrained. They

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C A N . J . PHYSIOL. PHARMACOL. VOL. 62. I984


a_

S Y S T LVP

'"7

BASAL SALINE

PEEI . 8 ! B .@3%.Be3 .I25 . 2 5

.5

( p g .kg-'- rrsin-!)

Fac. 1 . Hemodynalsaic effects of intra-atrial infusions of increasing doses of PGE, in eleven unanesthetized dogs. The systolic left ventricular pressure (syst LVP), positive rnaxilnuran dP/dl, and heart rate (HR) were measured in basal conditions after injection sf saline and after six increasing doses of PGEI. Results are given as means 2 standard deviations. were given a single dose of morphine (5 mg, iv) 15 anin before the experiment. The ultrasonic dimension system of Schuessler and Associates (lrlodel 401) was used for the study of the regional wall motion and impulses of 200 V lasting 0.2 ys at 1 kHz repetition rate were sent to one crystal of each pair. The reproducibility of the method in chronically instrumented dogs has been previously tested ('I'h6roux et al. 1976). The physiological signals were monitored oal a Beckman W41 I esscillograph and were recorded simultaneously on a Hewlett Packard magnetic tape (HP3968A) and on a B2-channel high frequency response Elema-Schonander Mingograph recorder. The pressure recorded through the catheter located in the left ventricle was calibrated against a mercury snanometer attached to a Statham P23Db strain gauge transducer. and zero pressanre was set at the midchest level. 'The Konigskrg rnicro~nanometerwas matched to the pressure obtained with the catheter. End-diastc~licsegmental length (EBL) was readily identified on the recording and corresponded with the very initial positive deflection of dP/dt. End-syst~liclength was identified 10 ms before peak negative dP/db. Active segmental shortening was calculated as the difference between these two lengths. 'Fhese values were normalized by dividing EDL and extent of shortening by control ED&, and multiplying by 10. This mletkod, previously described by 'Fheroux et al. (1974), makes the comparison of segments of various lengths more convenient. The first derivative of the left ventricular pressure (dY/dr) was obtained by using an active differentiating circuit with a cutoff set at 700 Hz and calibrated against a triangular wave of a known slope. A stock solution of PGE, (UpJohn Co.) was prepared in absolute ethanol ( I 0 mg/rnL) and was stored at 4°C. Samples were diluted with 0.9% saline at the appropriate concentration and were sterilized on

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BASAL SALINE PGE,

FIG. 2. Effects of intra-atrial infusions of' increasing doses of PGEI in eleven rananesthetized dogs. The left ventricuiar end-diastolic pressure (LVEDP) , segmental end-diastolic length (EDL). and shortening (AL) from ultrasonic crystals were measured In basal conditions, after injection ~f saline and of six increasing doses of Results are given as means 2 standard deviations. 0.22-prn filters. PGEl was infused into the left atrium at increasing doses (saline, 0.00 105, 0.83 B 25, 0.0625, 0.125, 0.25. and 0.5 pg kg-' min- 1 in I I dogs by use of a Harvard syringe pump. Each infusion lasted 1 1 min and the physiologic measurenlents were made over the last min~te.intervals of I8 min between infusions allowed recovery of the basal contml state, and the total volume infused was 50 mL. assess the effects of PGE, on myocardial contractility. independently of preload, blood volume loading conditions were altered over various ranges by bleeding or sal~neanfusron in nine additional d ~ g while s they received 48 h apart in a random order salirae or PGE, (0.25 pg kg ' rnin ). After nleasurement s f the basal parameters, the dogs were bled through the right heart catheter. Measurements were made during steady state after each witiadrawal of 50 inL taken over 1 rnin; systolic blood pressure was not allowed to fa11 by 10% of the base-line values. The blood was then restituted (BOO rnL/min) and 30 rnin later, the dogs were loaded with I .5 L of physiolog~csaline (125 rnL/rnin) through the same catheter. The physiologic parameters were recorded after each infusion of 250 mL. Iluring these experiments, the heart rate was held constant (158 beats/min) by external atrial pacing to keep constant its effect om contractiility and on the other

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SEGMENT LENGTH rim) a -

before PGEl

F ~ G3.. Original tracings, demonstrating LV pressure, LV dP/dt, and LV scglnental length before and after an intra-atrial infusion of PGE, (0.50 p g - kg ' emin '1. 'Fhere was a dramatic decrcasc in eand-diastolic length and systc~licsinortening. Ira contrast, peak systolic LV pressure was only lnodestly decreased, suggesting a rnore irnpc~rtanteffect on preload than on aftcrload. ' h e sinall change in d P / Q t is explained by the reduction in blood pressure.

SEGMENT LENGTH (rnmHg)

14

w

250 mL Saline infusion

PGE 1 0.25 y g . kg-I-min-I + 500 mL Saline infusion

F ~ G4.. Original tracings of the LV pressure, LV dPldt, and LV segmental length obtained during right atrial loading. On the left panel, 250 mh,of saline have been infused without W E , . On the right panel, 500 n-aL have been infused to reach the same EDk despite infusion of PGE, (0.25 pg-kg-'.min I ) . This figure illustrates the striking increase of segme~ftalshortelling induced by PGE, when preload is matched. Kotc that LV systolic pressure was the same in the two conditions and that heart rate was kept constant by atrial pacing. determinants of cardiac function. A linear regression was used to calculate the slope of the function curves (AL versus EDL); the perccnt systolic shortening at an EDI, value of 80 mrn was extrapolated on this regression. Results arc as SD deviation). A scheff6 test (scheff6 1959) was used to the measuren,cnts obtained with saline infusion versus increasing doses of PGE,. Slopes and Ak at EDL of 18 mrn were analyzcd statistically with the Student paired t-test. 'Fhe level of significance wax set at 0.05.

Results Do,se-resgonse study The hernodynamic effects crf PGEl appeared within seconds after the beginning of infusion, reached a steady state after 3 mi", and disappeared completely within 5 min after termination of the infusion. The cardiovascular changes are presented in Fig. 1. The heart rate i m e a s e d ( p < 0.05) with low doses and the peak effect was observed at a dosage of

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Am CONTROL

Frc;. 5. Typical graph describing the changes in systolic shortening (AL) obtained with and without PGE in one dog during acute changes

in preload produced by bleeding and loading with saline. During infusion of' PGEI, AL is higher at all valucs of end-diastolic length (EDL). The p i n t on the curve indicated by basal PGE, describes the physiological status of this dog before beginning the infusion of PGEI; it was very comparable to the status obtained the day before during the control infusion of saline. 0.125 pg - kg ' man ' . At higher doses three dogs presented a bradycardia. Systolic blood pressure increased slightly but not significantly at small doses, and decreased ( p < 0.05) at the high doses of 0.25 and 0.5 b g -kg-! *mila- I . Peak positive dP/dt also showed a biphasic response possibly related to the change in afterload with an initial increase (p < 0.05) followed by a h 1 1 ( p < 0.05) at higher doses (0.25 and 0.5 pg kg - min-' ). The variations of left ventricular enddiastolic pressure (LVEDP) segmental EDL, and AL were much more consistent and dose related (Fig. 2). LVEDP fell gradually from 6 2 2 to 1 + 8.9 mmMg (1 nmHg = 133.322 Pa) ( p < 0.0%).while EDL decreased from I0 to 8.9 mrn with increasing concentrations of PGE, of 0.03 1-0.5 p g mkg-' min-'. AL also decreased with PGE, and the changes became significant only at doses greater than 0.0625 pg kg- ' min- ' . Figure 3 illustrates a typical response. Acute hemorrhage clad volume loading

As much as 200 mL of blood could be withdrawn in control dogs before a 10% decrease in blood pressure was achieved, whereas removal of only 50 anL induced similar changes in PGEl-treated dogs. The parameters returned to base line within 30 mirn after restitution of blood. Figure 4 illustrates the changes observed during this procedure while heart rate was maintained constant, and Fig. 5 shows the results of a single experiment to illustrate the typical response obtained during acute preload modifications with and without PGE, infusion. Figure 6 shows Binear regressions measured in the nine dogs studied. With PGE,, there was a significant shift to the left of the functional ventricular curve at all end-diastolic lengths studied; at a end-diastolic length of 10 rnrn, AL increased with ffiE, from 1.23 zk 0.33 to 1.64 & 0.41, ($3'396; p < 0.001). Furthermore, the slopes of the curves increased from 0.594 k 0.124 in the control state to 0.736 ? 0.074 with PGEi ( p < 0.001). Individual slopes and systolic shortenings for EBL = 10 mm, with and without PGE, treatment are given in Takle 1.

Discussion Hn the present study, PGE, showed a positive instropic effect in the conscious dog, and measurement of segmental short-

FK;. 6 . Relationship of left ventricular segmental shortcniasg (AL) and end-diastolic length (EDLB before and during PGEI infusion in different loading conditions. PGEI infusion reduces EDL and decreases AL as shown by the dotted line and the arrow. '%helow values of EDL were obtained by bleeding and the high values by physiologic saline infusion before and during W E , infusion. At ail values of EDL, the curve is displaced to the left with PGEI.

ening under different loading conditions discriminated between the systemic vasodilator effects and the positive inotropic property of the prostaglandin. Use of in-nplanted piezoelectric crystals in conscious dogs provides accurate and reproducible measurements of the segmental shortening (FrankBin et al. 4973; Thkroux et al. 1976) and their implaratation in the subendocardiral myscardiurn allows direct evaluation of the instantaneous myocardial fiber length. Because several studies have previously shown dose-related biphasic effects of prostaglandins (Emerson et al. 197 % ; Nutter and Crumly 1972; Fitzpatrick et al. 1978: Karmazyn et al. 1979) we have used a wide conce~mtratioslrange of PGEI. The metabolism sf PCEl in vivo being very rapid (Puglisi and Maggi B977), the effects of the prostaglandin were lost 5 min after the infusion was stopped. As we spaced the infusion periods 10 min apart, total recovery of the base-line values was obtained. The systemic effects of increasing doses of PGE, have been previously reported. A decrease in-arterial pressure (Carlson and Oro 1966; Nakano and h/lcCurdy 1967. B 968; Rose et al. 1975) and an increase in cardiac output and coronary blood Wsw have been reported in dogs given PGEI in the left atrium or directly in the left coronary artery (Hollenberg et al. 1968; Bloor et al. 1973; Busting et al. 1979). The effects on arterial blood pressure were present after P-sndrenergic and ganglionic blockade (Carlson and Oro 1966; Kot et al. B975), and the increase in heart rate was suspected to be of baroreflex origin (Nakans and McCurdy 1967). As we observed with high doses of PGE,, some dogs presented a bradycardia as a result of vagal stimulation that was suppressed by atropine. This parasympathetic response has also been reported with prostacyclin administration (Dusting et aB. 1979). In the present study, the doses required to induce vasodilatation were higher than those used in humans (Awan et a%.1981), the prostaglandin interspecies differences being well-known (Berti et a1. 1965; Nutter and Cmmly 1972). Our study with increasing doses of E E I indicates that preload is more sensitive to PGE, than afterload. As a matter of fact, with dosages of 0.31 and 0.63 pgskg-' ernin-', respectively, we found a significant lowering of LVEDP and EDL without modification of the systolic LVP which decreased only with high dosages.

TABLE1 . Individual values sf the slopes of the left ventricular fu'eanctior~ curves and segmental shortening for EIIL of 80 rnm as obtained before and after infusion of W E I (0.25 gag-kg 'srnin ' ) in nine dogs

Scgrnental shortening for S 1ope


Control

EBL PGE ,

Control

=

I 0 mrn

PGE ,

0.530 0.837 0.497 0.658 0.584 0.421 0.407 0.542 0.575 Mean 1 SD

0.59410.828

* p < 0.001, compared with control values

To examine contractility independently of the preload modifications and with shortening adjusted for the changes in diastolic length, we modified the loading condition by bleeding or infusing saline. Segmental functional curves were constructed by plotting EBL and hL as rcpoi-ted elsewhere with col-ssciousdogs (Bishop and Stone 1967; Boettcher et al. 1978) and with ultrasonic dimension gauge systems (Thkroux et al. 1976). If' acute henlorrhage and loading with saline can induce changes in the tone of autonomic nervous system, a condition known to interfere with myocardial contractility (Horwitz and Bishop 1972; Fitzpatrick et al. 19781, it is unlikely that this effect modified our results, since our dogs underwent the sairae loading protocol on two different days in a random order. Furthermore, the two procedures were undertaken 48 h apart so that the base-line values were virtually identical (Fig. 5 ) , thus permitting comparison of the functional curves in the two experimental settings. Because volu~meloading nnay affect the systolic EVP and bring a shift in function curves by increasing afterload (Miller et al. 1982), we excluded all the values exceeding 10% change of basal systolic LVP. and found no statistical changes in systolic LVP between control and treated dogs during loading. When comparing the Frank-Starling curves, we invariably demonstrated an increased contractility when BGE, was administered. This result was expressed by a shift to the left of all the curves under PGE, infusion. The PGEl regression slopes appeared unexpectedly higher than the control slopes. This could be easily explained by the fact that for the same EDL, LVEBP was always lower under PGEl than in control state. Because of this discrepancy, we could not compare ventricular function curves using LVEDP as a preload index, since the Hatter was constantly lower in PGE,-treated dogs as compared with controls. Our observation of this inotropic action of PGEBconfirms previous studies conducted on anesthetized animals or on isolated cardiac tissues. Earlier evaluation of the myocardial contractile force as measured by the Walton Brodie gauge disclosed an increase in this parameter when PCE, was infused directly in the LAD (Nakano and McCurdy 1967, 1968; Wsllenberg et al. 1968). This effect appeared before any systemic vasodilatation effects (Nutter and Cmmly 1972). When PGE, was administered intravenously, a significant increase in maximum dP/dt and myocar.dia1 contracting force has been

observed (Nakano and ,McCurdy 1967, 1968; Hutton et al. 1973; Rose et al. 19751, but in regards to its inotropic effects, PGE, appeared less potent than its preclarsor digarmma linolenic acid (Needleiman and Kaley 1978; Busting et al, 1979). Similar results were reported on isolated mammalian cardiac tissues (Berti et al. 1965), although other data conflict with these studies (Su et al. 1973; Sterin-Borda et a]. 1980; Vadlamudi and McNeili 1981). The mechanism by which PGEl increases contractility of cardiac muscle cells is uncertain, since many biochemical changes result from prostaglandin administration and especia%lyin the sympathetic and parasympathetic systems (Hedquist 1977; Busting et al. 1979; Feuerstein et al. 1982). Norepinephrine stinlulates prostaglandin synthesis and release (Vapaatalo et al. 1978; Wennmalm and Brundin 1978) which in turn inhibit norepinephrine release (Hedqmist 1977). PGE, is known to increase myocyte cyclic 'AMP levels but experimental data does not support the concept that cyclic AMP mediates the positive inotropic effect csf PGE, (Metsa-KeteBa 1981), neither that prostaglandins modulate chronotropic and inotropic effects of' sympathetic nerve stimulation (Chiba and Malik 1981). However, in the present study, pharmacological doses of PGE, have been used and the potential physiologlcal action of PGEl on myocardial homeostasis is hypothetical, its production in situ being modest and its lung clearance very high (Puglisi and Maggi 1977; Needieman and Kaley 1978j. Wowever. its potential therapeutic effects in ischemic heart disease (Awan et al. 1981, 1982) make investigations on the indropic properties of PGEi relevant, and direct intracoronary infusions should allow the use of much lower doses of PGE,. AWAN.N. A . , J . M . B E A ~ I E K ., E. NEEDHAM, M . K. EVENSON,and B. T. MASON.1982. Prostaglandin El in ischemic heart failure:

dernonstration of salutary actions on myocardial energetics and ventricular pump performance. In Prostaglandins in medicine. Cardiovascular and thrombotic disorders. Edited hy K. K. LVu and E. (3. Rossi. Year Book Medical Publishers he., Chicago, IL. pp. 289-293. AWAN,N. A , , M. K . EVENSON, K. E. NEEDHAM, J . M . BEATTIE, E. A. AMSTERDAM, and D. T. MASON.198 1 . CardiwircuHatory and myocardial energetic effects of prostaglandin El in severe left ventricular failure due to chronic coronary heart disease. Am. Heart J. 102: 703-1909. BERTI,F., R . LENTATI.and M. M. USARDI. 1965. The species


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