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European Journal of Pharmacology, 73 (1981) 85--89 85 Elsevier/North-Holland Biomedical Press

Short communication

EFFECTS OF ON CORONARY ARTERY THROMBOSIS AND MYOCARDIAL ISCHEMIA IN ACUTE CANINE EXPERIMENTS

VOLKER B. FIEDLER Department of Pharmacology, The University of Michigan Medical School, M 6322 Medical Science Building I, Ann Arbor, MI 48109, U.S.A.

Received 12 May 1981, accepted 18 May 1981

V.B. FIEDLER, Effects of moisidomine on coronary artery thrombosis and myocardial ischemia in acute canine experiments, European J. Pharmacol. 73 (1981) 85--89. Antithrombotic and hemodynamic properties of molsidomine (0.10 mg/kg i.v.) were evaluated in an in-vivo model of coronary artery thrombosis initiated by electrical stimulation for 6 h. Molsidomine prolonged time to vessel occlusion and prevented rate and end-diastolic pressure increase and contractility decrease. Infarct size was smaller after drug treatment related either to left ventricle (P < 0.02) or to vessel area-at-risk (P < 0.01). It is suggested that molsidomine has antithrombotic effects which might prevent acute coronary infarction.

Coronary thrombosis Molsidomine Myocardial infarct size

I. Introduction of molsidmone on protection of the acutely ischemic canine myocardium and on in-vivo Molsidomine is a new agent platelet reactivity. with effects on (Fiedler and Scholtholt, 1978) and on the venous side of the circulation (Holtz et al., 1978). In patients, 2. Materials and methods the drug has been shown to be effective in the treatment of pectoris by a nitroglyce- 14 adult mongrel dogs of either sex weighing rin-like mode of action but of substantially between 18 to 26 kg were randomly assigned longer duration (Majid et al., 1980). Recent to groups receiving either molsidomine (8 studies (Slany et al., 1981) in patients with dogs) or saline (6 dogs), anesthetized with i.v. suggested that molsi- pentobarbital sodium (30 mg/kg), incubated domine might decrease platelet reactivity as and placed on positive pressure respiration assessed by in-vitro aggregometry. The drug (Harvard respirator, model 607) using room also produced a dilatation of large coronary air. Body temperature was regulated at 37 +- vessels in the isolated blood perfused canine 1°C by a heating pad. Aortic heart (Schaper, unpublished observations) was measured by a cannula positioned in the which might serve as an important mechanism descending aorta via the right femoral artery for improving coronary flow to an ischemic using a Statham pressure transducer (model region of the myocardium via collateral ves- P 23 Db). A peripheral vein was catheterized sels. The potential of molsidomine in this for compound administration. Left ventricular respect would be enhanced if the drug pre- systolic and end

0014-2999/81/0000--0000/$02.50 © Elsevier/North-Holland Biomedical Press 86 V.B. FIEDLER carotid artery. Heart rate was obtained from 2.2. Quantification of infarct size and throm- the electrocardiogram (limb II). Contrac- bus weight tility was obtained by continuous computer differentiation of left ventricular pressure as Following final recordings at completion of clP/dt. The sum of ST~egment elevations was the 6 h stimulation, the animal was sacrificed obtained from 5 sLngle measurements at the by an overdosage of anesthetic, the heart was determination times. A thoracotomy was per- electrically fibrillated and rapidly removed for formed at the fifth left intercostal space, the post-mortem quantification of infarct size lungs retracted and the heart was suspended (Romson et al., 1980a). To this end, cannulae in a pericardial cradle. A calibrated flow were inserted into the vessel distal to the site probe was positioned around the left circum- of LCX occlusion and into the aortic root flex coronary artery (LCX) distal to the above the coronary ostia. The LCX coronary atrial branch and proximal to its first descend- bed was perfused with 1.5% triphenyltetrazo- ing branch for measurement of phasic and liumchloride (TTC) in 20 mM potassium phos- mean LCX flow by a flowmeter (Carolina phate buffer. The aorta was perfused in a Instr.). Coronary vascular resistance was ob- retrograde manner with 0.5% Evans blue. tained by dividing mean aortic pressure by Both solutions were perfused at a constant mean LCX flow. A silk snare was placed pressure of 100 mmHg for 20 min. The heart around the vessel distal to the probe. To aid was then sliced into 1.0-cm thick sections. in the insertion of the LCX stimulating elec- The area of the left ventricle at risk was trode, the tip of a 25-gauge hypodermic demarcated by lack of reddish staining of needle was secured to the leading end of a the tissue when perfused with TTC. The area- 28-gauge teflon coated silver wire (Romson at-risk, in addition to the regions of infracted et al., 1980b). This electrode was inserted myocardium were excised from the left ven- through the wall of the LCX so that the tip tricle and weighed. Thus, the extent of infarc- of the electrode (2--3 mm) was in contact tion was expressed as a percentage of both with the intimal lining of the vessel. The total left ventricle and the area of myocardi- circuit was completed by suturing a disc um at risk. The previously occluded LCX was electrode to a subcutaneous region of the dissected free of surrounding tissue and chest wall. Hemodynamic variables were opened lengthwise. Adhering thrombotic ma- recorded on a Grass model 7 polygraph. terial was removed from the intimal surface of the LCX to determine thrombus wet 2.1. Experimental design weight.

After basal hemodynamic measurements 2.3. Statistical analysis were recorded either molsidomine (0.10 mg/ kg) or saline were intravenously administered. Statistical analysis of results on hemo- 15 to 20 min later (Holtz et al., 1978) electri- dynamics was made by use of Student's t-test cal stimulation of the LCX was initiated at for paired samples and analysis of variance 150 gA via the implanted silver wire electrode. followed by Dunnett's modification of the Stimulation was continued for 6 h using a t-test. Infarct sizes were compared by use of 250 000 ~2 potentiometer, a 9 V nickel-- the two-by-two chi square analysis. All data cadmium battery, and a digital ammeter. are expressed as mean -+ standard error of the Recordings were done every 15 min at 25 mean (S.E.M.). Differences between control mm/sec. and drug-treated values were considered signi- ficant when P < 0.05. MOLSIDOMINE ON CORONARY THROMBOSIS AND INFARCT SIZE 87

3. Results pressure decreased in both groups. In the saline group, heart rate and end

TABLE 1 Effects of molsidomine on myocardial hemodynamics.

Parameter Compound Control 30 min 3 h 4 h 6 h

Mean aortic pressure M 121 81 118 97 118 (mmHg) + 5 b -- 4 C --+ 5 + 4 c + 4 NaC1 118 117 119 93 116 -+3 -+5 -+4 +6 c -+3 Hear rate (rain -1 ) M 124 127 122 131 120 •+8 -+10 +8 -+9 -+11 NaC1 131 130 129 169 126 •+9 -+9 -+7 +7 -+9 Left ventricular M 6.8 3.2 3.8 6.5 7.2 end-diastolic pressure + 1.2 -+ 0.7 c + 0.8 c -+ 1.1 -+ 1.2 (mmHg) NaCl 5.4 6.2 5.8 13.7 11.2 -+ 0.9 -+ 0.5 -+ 0.7 -+ 1.2 c + 0.8 c DP/dtmax M 2 180 2 240 2 016 2 007 1 970 (mmHg/sec) -+ 201 -+ 199 -+ 167 -+ 137 -+ 211 NaCl 2 431 2 601 2 379 1 421 1 640 + 186 -+ 201 -+ 154 -+ 141 c + 134 c ST-segment elevation M 34 31 35 40 37 (mV) -+ 6 + 4 -+ 9 -+ 5 -+ 8 NaC1 42 40 52 88 83 •+3 -+6 -+4 c +4 d -+6 c Mean coronary blood M 48.1 36.2 44.3 11.8 0 flow (ml/min) -+ 3.2 -+ 4.1 c -+ 2.2 -+ 1.5 d -+ 3.2 d NaC1 40.0 42.6 39.6 0 0 •+4.1 -+3.0 -+3.2 -+1.1 d -+0 d Coronary resistance M 2.5 2.2 2.7 -- -- (mmHg × rain x m1-1) -+ 1.0 -+ 0.8 + 0.7 NaCl 3.0 2.8 3.0 -- -- + 0.6 + 0.8 -+ 0.8 a Minutes or hours after 0.10 mg/kg molsidomine (M) and saline (NaCI) administration. b Values are given as mean + S.E.M. of 8 experiments in the molsidomine and of 6 experiments in the saline group. e Significantly different vs. control with P < 0.05. d Significantly different vs. control with P < 0.01. 88 V.B. FIEDLER

TABLE 2 Although coronary blood flow decreased Effects of molsidomine on thrombus formation, after administration of molsidomine conco- infarct size, and thrombus weight. Data are given as mitant to the fall in perfusion pressure, an the mean -+ S.E.M. of 8 experiments in the molsido- improvement of coronary blood supply to mine group and 6 experiments in the saline group. jeopardized tissues can be assumed from the LCX = left circumflex coronary artery. smaller ultimate ischemic regions. Parameter . Saline Molsidomine In recent experiments (Schaper, unpublished results) with canine perfused at constant Thrombus formation aortic pressure large epicardial coronary (hours, after compound arteries dilated. Such an event may not administration) 3.1 -+ 0.4 3.8 -+ 0.3 a increase coronary blood flow in the unaffected Infarct size : area of the coronary bed but it may serve as (1) %left centricular mass 28 -+ 2.0 14 + 3.0 b an important mechanism for improving (2) % LCXarea-at-risk 58 + 14 18 + 3.0 c coronary flow to an ischemic region of the LCX thrombus mass myocardium probably via collaterals. At the (rag, wet weight) 32 -+ 4.0 14 -+ 0.8 a same time there is a dose