Effects of prostaglandin A1 on cardiovascular dynamics and myocardial metabolism

JOURR‘.4L

OF

SURGICAL

EWECTS

H.

B. BARNER,

RESEARCII,

12,

168-172 (1972)

OF PROSTAGLANDIN A1 ON CARDIOVASCULAR AND MYOCARDIAL METABOLISM M.D.,

G. C. KAISER, J. B. LEE,

M.D., M.D.,

J. W. AND

HAHN, V.

M. JELLINEK,

PH.D.,

H. AMAKO,

M.D.

M.D.

Experimental preparation. Nine normal dogs were anesthetized with pentobarbital (30 mg./kg., intravenously) supplemented with intravenous succinylcholine and prepared for right-heart, bypass. The trachea was intubated with a cuffed tube for positive-pressure ventilation. The chesl was opened by median sternotomy. The azygos vein was divided, and the vena cavae were cannulated after intravenous administration of heparin 3 mg./kg. Heparin, 1 mg./kg., was added every 60 minutes, and homologous blood for prime and replacement was freshly drawn into heparin (20 mg./500 ml.). Systemic venous return passed through an extracorporeal circuit (Fig. l), which consisted of a reservoir, a bubble oxygenator, a heat exchanger, a roller pump, and an electromagnetic flow probe (Caroline Medical Electronics, Inc., Winston-Salem, NC) for recording flow through the circuit. Arterial return was to the pulmonary artery. With the vena cavae snared and the pulmonary artery ligated over the cannula, the right heart chambers were isolated. A catheter in the right ventricle returned total coronary venous flow, minus left ventricular sinusoid flow, through an electromagnet,ic flow probe to the reservoir. Strain gauges (Statham P23 Db, Statham Instruments, Inc., Oxnard, CA) were used to measure systemic pressure by cannulation of the left, carot,id art.ery and to measure left ventricular systolic and diastolic pressure with a Y-shaped cannula in the apical dimple. The maximum rate of rise of the left ventricular

From Unit II Surgery, John Cochran VAH and the Department of Surgery, St. Louis University, St. Lollis, Missouri. Read hefore t,he 5th annual meeting of t,he Association for Academic Surgery, Philadelphia, Nov. 19. 1971. Supported by Grant HE 06312 of the US Public Health Service and the John A. Hartford Foundation, Inc. Submitted for publication Nov. 24, 1971. 168 Q 1972 by Academic Press, Inc.

WILLMAN,

METHOD

THE PROSTAGLANDIN A (PGA) COMPOUNDS are relatively specific for the cardiovascular system and are not metabolized by the lungs as arc other Prostaglandins [8]. In the anesthetized dog intraarterial PGAl increases blood flow in the carotid, renal, mesenteric, and femoral arterial beds but only small increases were observed in coronary flow [7, lo]. Intravenous PGAl in the anest’hetized dog results in a fall in syst,emic pressure and peripheral resistance and a slight increase in cardiac output [9, 111. Alore recent data from the conscious dog indicate profound changes in cardiac output and coronary tlow in response to intravenous PGAl [4]. The lesser responses to PGAl observed by others were thought to be related to the effects of anesthesia and operative manipulat,ion in causing coronary vasodilatation and alteration of the response to vasoactive drugs. To provide further information on the effects of PGA, we have compared its vasodilator action to that of a standard vasodilator, papaverine, in the right-heart bypass preparation. Myocardial metabolism has also been evaluated in an attempt to determine any direct or indirect effects of PGA1.

Copyright

D.V.M., L.

DYNAMICS

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EFFECTS

pressure (dp/dt) was obtained with an RC electronic differentiator. Pulmonary artery pressure was measured via a centrally directed catheter placed in a peripheral branch of the pulmonary artery. Heart rate was controlled by electrical pacing of the right ventricle after induction of heart block, which was achieved by placing a suture ligature around the bundle of His. The standard electrocardiogram was recorded. Data were recorded on the multichannel direct-writing oscillograph (Offner II dynagraph, Beckman Instruments, Inc., Fullerton, C,4). Coronary sinus blood was sampled by a catheter inserted through the right atriotomy into the coronary sinus to the left border of the heart. Arterial blood was sampled by a catheter placed in the right internal mammary artery with the tip in the subclavian artery. Arterial and venous oxygen, lactate, and pyruvate were continuously measured by means of an automated system [5, 63 that consumed 1.23 ml. of blood per minute. The metabolic data were recorded on a multipoint recorder (Esterline Angus Div., Esterline Corp., Indianapolis, IN) so that a point was recorded for each substrate every 15 seconds. Arterial pH was measured intermittently, and the pH was adjusted by the addition of sodium bicarbonate to the venous reservoir. Rectal temperature was continuously measured and maintained at 37.5 -C 1” C. ExpeGnentnl protocol. Bolus injections of 1, 2, and 5 pg./kg. of freshly prepared PGA,” (a crystalline preparation which was diluted with sterile, distilled water prior to each experiment) and 0.2 mg./kg. of papaverine were made into the pulmonary artery cannula while cardiac out’put and heart rate were held constant. Data were recorded for 10 minutes after each injection and an additional lo-minute recovery period was allowed before proceeding to a larger dose. Papaverine was administered after the three injections of PGA,. At the end of each experiment the heart was excised and weighed. The atria and right vent,ricle were trimmed away so that weight of the *Provided by Dr. Natoo Company, Kalamazoo. MI.

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Fig. 1. Right-heart bypass preparation. TCF, electromagnetic flow probe for total voronary flow. RES, rcnow reservoir. 02, bubble oxygenator. Pump, roller pump. CO. electromagnetic flow probe to measure flow through circuit (cardiac output). Pace, right ventricular electrodes. PR, peripheral resistance clamp (fully opened). Analyzer, blood substrate autoanalyzer, SG, strain gauge (SGI, s~slr~mic pressure. SG2. left ventricular systolic pressure. SG3, left ventricular diastolic pressure).

left ventricle (LV), including intraventricular septum, could be obtained. Calculation. Coronary mean vascular resistance (mm. Hg/ml./lOO grams LV/min.) was calculated as the quotient of the mean arterial pressure and mean coronary flow (ml./100 grams LV/min.) . Data were combined for 13 I-pg., 12 2-pg., and 10 5pg. injections of PGAl and 11 papaverine injections. The total coronary flow (TCF) curve and each substrate consumption curve were normalizedt by the reference to the mean of the control level (Fig. 2). Myocardial oxygen consumption (MVOZ) and TCF are expressed as ml./100 grams LV/min. and lactate and pyruvatc are expressed as mg./100 grams LV/min. t The control values (al. b1. cl. . .) WPW averaged (g), and all subsequent points (a?. a:,. ah. b,. b:,. b.,. *. .) xere related to that mean proportionately with reference to their own starting lwcls [(a2/nl) X Q1 .(a3/al) X 7J, (a4/al) X ?J . ..I.

170

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RESEARCH,

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+

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Fig. d. Mean changes (2 SE) at time of maximal fall in arterial pressure produced by three doses of PGA, and papaverine are shown by solid lines (Column 2, Table 1). Broken lines and triangles indicate maximal coronary flow.

RESULTS The hemodynamic data are summarized in Fig. 2. Systemic circulation. Mean arterial pressure fell 16.6 * 4.5% (p < .005), 20.4 -t 3.2% (p < .OOl), and 20.8 * 4.3% (p < .OOl) with increasing doses of PGAl while papaverine resulted in a 26.7 * 1.5% (p < .OOl) fall. Maximal fall of arterial pressure occurred in 30 to 60 seconds with return to control in 1 to 6 minutes. Coronary ciwulation. Total coronary flow

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did not increase with PGAl but declined progressively 12.6 f 1.7% (p < .OOl), 14.8 + 2.3% (p < .OOl), and 14.4 2 2.8% (p < .OOl) with increasing doses of PGAl and then returned to control (Fig. 2). The maximal fall in coronary flow occurred 30 to 60 seconds after infusion of PGAl and coincided with the maximal fall in arterial pressures. Papaverine resulted in a triphasic response with a 48.6 * 9.4% (p < .OOl) increase in coronary flow in 15 seconds after infusion, a fall to control 15 to 45 seconds later, and then a rise to 14.6 f 2.7% (p < .OOl) above control 2 minutes after infusion before gradually returning to control (Fig. 3). Coronary vascular resistance fell 0.7 i: 0.9% (p > .4), 1.0 * 1.2% (p > .4), and 3.3 -C 1.3% (p < .025) 15 seconds after injection of the three boluses of PGAl but coronary flow did not increase (Fig. 1). Coronary resistance continued to decline to a maximum of 4.6 * 1.7% (p = .02), 6.7 * 1.4% (p < .OOl), and 9.0 +- 2.2% (p < .005). After papaverine coronary vascular resistance immediately fell 39.6 + 2.2% (p < .OOl) and had risen to 22.9 -C 2.7% (p < .OOl) below control at the time of maximal fall in systemic pressure (Fig. 2). dp/dt. After the three boluses of PGAl dp/ dt fell 5.6 2 1.3% (p < .OOl), 8.1 -C 1.5% (p < .OOl), and 8.6 * 1.9% (p < .OOl) in 15 to 60 seconds. After Papaverine dp/dt declined 6.9 I+ 2.4% (p < .02). There was then a return of dp/dt to control during 1 to 4 minutes and in some instances

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0 2 4 6 t Papaverlne

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MINUTES

Fig. 3. Substrate utilization curves for oxygen, lactate, and pyruvate curves are sho\$-n at t,he bottom.

are shown for eight dogs. Coronary flow

BARNER

ET

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EFFECTS

dl~/dt exceeded control. After three boluses of PGA1, the maximal rise in dp/dt above control was 1.7 2 .97% (p > .l), 0.4 * 1.32% (p > .7), and 1.4 k 1.39% (p > .3). After papaverine the maximal increase in dp/dt was 13.0 * 4.1;; Ip < .Ol). P~clmonary circulation. Pulmonary artery pressure fell 5.0 2 2.9% (p = .l), 4.6 -C 3.0% (p > .l), and 3.3 2 1.2% (p < .02) with increasing doses of PGAl while it fell 10.3 * 2.7~~ (p < .005) with papaverine. end diastolic pressure Left ventricular (LI’EDP) . The LVEDP (mean 9.1 -C 0.3 cm water) declined 6.3 * 2.2% (p < .Ol), 5.4 r+ 2.8% (p > .05), and 4.9 I+ 2.9% (p > .l) after the three boluses of PGA, and 10.5 + 1.1% (p < .OOl) after papaverine. Ilyocardial metabolism. The substrate consumption curves for oxygen, lactate, and pyruvate are shown in Fig. 3 as well as the total coronary flow curves. Myocardial oxygen consumption (MV02) fell 9.7 * 1.3% (p < .OOl), 12.0 -t 1.9% (p < .OOl), and 12.0 f 2.2% (p < .OOl) after PGAl and then returned to control after papaverine MV02 rose 46.0 -I- 9% (p < .OOl) and then fell 5.6 * 1.1% (p < .OOl) below control before returning to control. Lactate consumption rose 12.3 f 2.1% (p < ,001). declined to 2.8 +- 0.4% (p < .OOl) above control, and then rose to 10.4 * 2.1% (p < ,001) above control before returning to control aft’er PGAl 1 pg/kg. Lactate consumption after the two larger doses of PGAl declined 11.7 & 2.1% (p < .OOl) and 9.8 t 2.3% (p < .0011 followed by a return to control. After papaverine lactate consumption increased 59.6 i 18.1% (p < .Ol) and then returned to control after minor changes. Pyruvate consumption fell 10.6 * 2.4% (p < .OOl’r, 10.6 * 2.1% (p < .OOl), and 9.9 -t 1.6? ip < .OOl) after PGA1. After papaverine pyrurate consumption rose 43.2 -C 10.6% (p < .005) and then returned to cont’rol after minor fluctuations. DISCUSSION In this study, PGA, caused a statistically significant fall in systemic arterial pressure and an associated fall in coronary flow. These ob.zerrations are similar to those of others

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under similar conditions [9, lo]. Higgins and associates [4] found a marked increase in coronary flow after PGAl in the conscious dog and attributed this significant coronary response to t,he absence of the effects of anesthesia and thoracotomy. In the present study there was a significant response of the coronary arterial bed to a relatively small injection of papaverine and a fall in arterial pressure similar to that obtained with PGA,. Our observations ~oulcl indicate that although the coronary arterial bctl may be relatively dilated under these experimental conditions, it is responsive to vasoactire drugs. Our experimental observations are very similar to those in anesthetized pat,ients undergoing coronary vein bypass grafting in whom the coronary arterial bed was relatively unresponsive to PGA, but highly responsive to papaverine [2]. Coronary vascular resistance falls after PGAil but the greater response of other vascular beds to PG,J, lowers systemic pressure so that t’he net efYect i:: one of a fall in coronary flop. Myocnrdial contractility. aa measured by dp ‘clt, declined with the fall in arterial pressure to a similar degree after PC;z41 and papaverine. The dp/dt’ then returned to control after PGA,. but rose significantly above control after paparerine. Although dp,‘dt is not ideal for assessment of the contractile state of the myocardium, it, does provide helpful data when heart rate, cardiac output: nfterload, and preload arc constant [3]. Afterload and preload had usually returned t)o control levels when dp/‘rlt was maximal. Therefore, our observations are at variance with tho.;e of others indicating that PGAil has a positive inot’ropic action [4]. On the contrary, it would appear that paparerine is more inotropic than PGA,. The fall in pulmonary artery pressure was significant only after the largest close of PGA,. Papaverine resulted in a significantly greater (p < .05) fall in pulmonary pressure. Mporardial uptake of each substrate was inhibited by PGA, and enhanced by papaverine (Fig. 2’). Both drugs are thought, to cause vasodilatation by a direct relaxing effect on vascular smooth muscle [12, 33, 151. Because coronary flow increased with papnrerine but not, with PGAkl, the changes in substrate metabolism wollld appear t,o be a flow-dependent

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phenomenon. We are unable to find data from others bearing on this point, probably because these events are very transient and without serial metabolic analysis they would not be observed. The primary determinants [14] of R/IV02 declined with drug infusion. Thus, the diminished MVO, after PGAl is not unexpected. The enhanced MVOa with papaverine vasodilatation can be explained on the basis of an improved vascular-cellular gradient during high flow states so that the middle and distal capillary bed is perfused with blood of greater oxygen content. Coronary venous pO2 was elevated during this high flow state. This “forced feeding” apparently results in greater R/IV02 as cellular stores of oxygen are temporarily enhanced. It is of interest to speculate that this increased uptake of oxygen may be related to the subsequent positive inotropy. The drug-induced changes in lactate metabolism can be explained on the same basis as the changes in MVOn. The response to PGAl 1 pg./kg. is at variance with the other metabolic observations and cannot be readily explained. Pyruvate-utilization curves approximated the oxygen-consumption curves which has been previously commented on [l]. SUMMARY The effect of PGAl, (1, 2, and 5 pg./kg.) and papaverine (0.2 mg./kg.) on coronary flow, coronary vascular resistance, arterial pressure, pulmonary artery pressure, dp/dt, and myocardial metabolism (oxygen, lact’ate, and pyruvate) was studied in nine normal dogs on right-heart bypass in which heart rate and cardiac output were constant. After PGAl systemic vascular resistance fell more than coronary vascular resistance so that coronary flow declined as well as pulmonary artery pressure and dp/dt. Papaverine lowered systemic vascular resistance more than PGA, but coronary vascular resistance fell to a greater degree -so that coronary flow increased. Pulmonary artery pressure and dp/dt also declined. Myocardial uptake of each substrate was depressed by PGAl and enhanced by papaverine. A late increase of dp/dt above control occurred after papaverine but not after PGA,.

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REFERENCES 1. Barrier, H. B., Kaiser, G. C., Jellinek, M., Taira, H., and Willman, V. L. Myocardial metabolism in acute regional ischemia. J. Thorac. Cardiov. Surg. 60 :694,1970. 2. Barner, H. B.. Kaiser, G. C., and Lee, J. B. Effect of prostaglandin A1 on several vascular beds in man. Circulation (submitted). 3. Braunwald, E., Ross, J., Jr., Gault, J. H., Mason, D. T., Mills, C., Gabe, I. T., and Epstein, S. E. Assessment of cardiac function. Ann. Intern. Med. 70: 369, 1969. 4. Higgins, C. B., Vatner, S. F., Franklin, T. P., and Braunwald, E. Effects of prostaglandin A1 on the systemic and coronary circulations in the conscious dog. Circ. Res. 29:638, 1971. 5. Jellinek, M., Barner, H. B., and Kaiser, G. C. A continuous blood oxygen analyzer. J. App2. Physiol. 29 :398, 1970. 6. Jellinek, M., Barner, H. B., Kaiser, G. C., and Hanlon, C. R. Continuous in vivo blood analysis using a mobile autoanalyzer. In Advances in Automated Analysis, p. 171. White Plains, NY: Mediad, 1970. 7. Lee. J. B. Cardiovascular implications of the renal Symposium of prostaglandins. In Prostaglandin the Worchester Foundation for Experimental Biology (P. W. Ramwell and J. E. Shaw, eds.), pp. 131-146. New York: Interscience, 1968. 8. McGiff, J. C., Terragno, N. A., Strand, J. C., Lee, J. B., and Lonigro, A. J. Selective passage of prostaglandins across the lung. Nature (London) 223 :742, 1969. 9. Murphy, G. P., Hesse, V. E., Evers, J. L., Hobika, G., Mostert, J. W., Szolnoky, A., Schooness, R., Abramczyk, J., and Grace, J. T., Jr. The renal and cardiodynamic effects of prostaglandins (PGE, PGA1) in renal ischemia. J. Surg. Res. 10:533, 1970. 10. Nakano, J. Effects of prostaglandins El, A1 and Fsa in the coronary and peripheral circulations. Proc. Sot. Exp. Biol. Med. 127:1160,1968. 11. Nakano, J., and McCurdy, J. R. Hemodynamic effects of prostaglandins E,, 41 and F2* in dogs. Proc. Sot. Exp. Biol. Med. 128:39, 1968. 12. Reynolds, A. K., and Randall, L. 0. Morphine and of Allied Drugs, pp. 196. Toronto: University Toronto Press, 1957. 13. Smith, E. R., McMorrow, J. V., Jr., Covino, B. G., and Lee, J. B. Studies on the vasodilator action of prostaglandin E,. In Prostaglandin Symposium of the Worchester Foundation for Experimental Biology (P. W. Ramwell and J. E. Shaw, eds.), pp. 259-266. New York: Interscience, 1968. 14. Sonnenblick, E. H., Ross, J., Jr., and Braunwold, E. Oxygen consumption of the heart. Amer. J. Cardiol.

22 :328,1968.

15. Strong, C. G., and Bohr, D. F. Effects of prostaglandin E1, E,, A1 and F1a on isolated vascular smooth muscle. Amer. J. Physiol. 213:725, 1967.