Cdj Delangen

CONCENTRATION-DEPENDENT PROTECTION BY CAPTOPRIL AGAINST MYOCARDIAL DAMAGE DURING ISCHEMIA AND REPERFUSION IN A CLOSED CHEST PIG MODEL

We previously reported concentration-dependent protection of captopril against ischemia-reperfusion injury in the isolated rat heart. In order to study these effects in vivo, we developed a closed-chest pig model. Reversible occlusion of the left coronary artery was achieved with a PTCA catheter during one hour. Captopril (C) i.v. was given in two different concentrations (0.6 mg/kg/10min + 0.3 mg/kg/2 hr and 6 mg/kg/10 min + 3.0 mg/kg/2 hr) timing the experiments to II and 10 pigs. respectively, versus 12 controls, who received only saline. Due to malignant ventricular arrhythmias, nine pigs died during ischemia. At the end of the reperfusion period of two hours, eight pigs were alive in each group. In the entreated pigs, maximum creatine kinase after two hours of reperfusion was significantly lowered to 6.337 ± 709 U/L in the high dose group versus 8.285 ± 851 U/L in the low dose group and 9.635 ± 1,115 U/L in the saline group. A reduction of local inosine overflow in the coronary sinus was seen. Maximum noradrenaline overtlow after 5 min reperfusion diminished dose-dependently to 695 ± 284 and 3,129 ± 1.728 pg/ml in the C treated groups versus 4.693 ± 2,277 pg/ml in the saline group. Mean arterial blood pressure and cardiac output decreased significantly during ischemia and reperfusion, but no significant differences occurred between the treated and untreated groups. Reperfusion arrhythmias, mainly accelerated idioventricular rhythm disturbances, were comparable among the three groups. We conclude that in vivo administration of C reduces myocardial damage upon reperfusion after one hour of ischemia in a dose-dependent way. It is suggested that direct myocardial effects play an important role in the underlying mechanism.

CAPTOPRIL-INDUCED INCREASE IN CORONARY FLOW - AN SH-DEPENDENT EFFECT ON ARACHIDONIC-ACID METABOLISM

The effect of captopril (80 μg/ml) on coronary flow in the isolated rat heart was compared with the effects of a nonsuflhydryl-converting enzyme inhibitor, ramipril (15 μg/ml), and of a sulfhydryl-containing compound with no converting enzyme-inhibiting properties. glutathione (112 μg/ml). Drug concentrations were equipotent in their effect on angiotensin I pressor response and equimolar with respect to the sulfydryl group. Cyclo-oxygenase products or their stable metabolites (TXB:2 6-keto-PGF1α and PGF.2) were measured in the coronary effluent. Furthermore, the effect of mepacrin (1 μM), in-domethacin (1 μM), and FPL 55712 (10 μM) on the changes in coronary flow induced by captopril was studied. Both captopril- and glutathionc-treated hearts showed a significant increase in coronary flow already after 5 min treatment. After 60 min treatment, coronary flow was further increased to 185 ± 9% for captopril-treated hearts and to 210 ± 11% for glutathione-treatcd hearts when compared to saline treatment. Ramipril treatment resulted in a slower increase in coronary flow, which was significant after 20 min treatment. After 60 min treatment, this increase was 122 ± 3% when compared to saline-treated hearts. This effect of ramipril was associated with a significant increase in 6-keto-PGF1α overflow when compared to saline-treated hearts. Captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products. The effect of captopril and glutathione on coronary flow appeared to be dose dependent in an equimolar range. Simultaneous mepacrin treatment diminished the effect of captopril on coronary flow; indomcthacin had no effect, and FPL 55712 potentiated the effect of captopril. It is suggested that ramipril increases coronary flow by reducing bradykinin breakdown and subsequently increasing PGF synthesis. Apart from this effect, captopril interferes by a more potent mechanism with arachidonic acid metabolism. This effect probably depends on the presence of the sulfhydryl group, and an effect on the lipoxygenase pathway is discussed.

EFFECTS OF ANGIOTENSIN-II AND CAPTOPRIL ON INDUCIBLE SUSTAINED VENTRICULAR-TACHYCARDIA 2 WEEKS AFTER MYOCARDIAL-INFARCTION IN THE PIG

The effects of angiotensin II (AII) and captopril (C) on the inducibility of ventricular tachyarrhythmias were investigated 14 days after infarction in pigs. In 27 pigs, ischemia was induced by 60-min occlusion of the left coronary artery. Four pigs died of ventricular fibrillation during ischemia, and six others died within 24 h due to pump failure. Of the 17 survivors, eight pigs developed a sustained (>30 s) monomorphic ventricular tachycardia (sVT) after programmed electrical stimulation. In nine noninducible pigs, an AII infusion (0.6 μg/kg/min) caused inducible sVT in three animals and nonsustained VT in two animals (>10 reentrant beats). In two of the remaining four animals, spontaneous premature ventricular beats appeared during the infusion. In a group of five healthy pigs, the electrophysiological effects of AII were evaluated. Infusion of AII caused a rapid and sustained increase in arterial blood pressure to 161 ± 6.4% (p < 0.001). The sinus cycle length decreased to 74 ± 5.2% (p < 0.02). The effective refractory period of the right ventricle decreased significantly to 82 ± 5.5% (p < 0.05). These results show that modulation of the renin-angiotensin system after myocardial infarction influences the inducibility of malignant ventricular tachyarrhythmias, as shown by the increased inducibility of sustained ventricular tachycardia. This may be related to a decreased ventricular refractoriness. Therefore, it is suggested that C can reduce malignant ventricular tachycardia late after myocardial infarction by preventing the deleterious arrhythmogenic effects of AII.

The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent electrophysiologic stability in the pig

SummaryThe effects of oral zofenopril pretreatment were investigated in a chronic closed-chest pig model of ischemia and reperfusion. Pigs (25–35 kg) were pretreated orally with zofenopril (15 mg/day) on the 2 days prior to ischemia, which was evoked by the inflation of a catheter balloon in the left anterior descending coronary artery over 45 minutes. The catheter was then removed and the myocardium was reperfused. After 2 weeks, infarct properties were assessed by signal averaging of the body surface electrocardiogram and the inducibility of malignant ventricular tachyarrhythmias was tested with a programmed electrical stimulation protocol.A significant increase in the pressure-rate product (43±11%, mean±SEM), indicating the oxygen demand of the heart, was prevented by zofenopril (19±8%, p<0.05). Zofenopril reduced the peak efflux of adrenaline (1302±213 vs. 3201±760 pg/ml; p<0.05), noradrenaline (402±54 vs. 902±282 pg/ml; p<0.05), and of the adenosine catabolites inosine and hypoxanthine (56±4 vs. 78±9, pg/ml; p<0.05) in the coronary venous effluent. The efflux of the cytoplasmatic enzyme creatine phosphokinase was not significantly reduced after zofenopril (p=0.08). No difference in plasma renin levels between the groups were found. After 2 weeks, late potentials were found only in the surviving animals from the untreated group, i.e., the voltage vector magnitude was more reduced, and a prolongation of the QRS duration and of the terminal low-amplitude part of the high-frequency QRS were found. Moreover, zofenopril had caused a significant reduction of the inducibility of sustained ventricular tachyarrhythmias.These findings support the view that catecholamine and purine efflux, and an adverse increase in the oxygen demand during early reperfusion are reduced by zofenopril pretreatment, leading to a higher electrophysiologic stability of the subsequently developed infarct after 2 weeks.

SUSTAINED PROTECTION BY ILOPROST OF THE PORCINE HEART IN THE ACUTE AND CHRONIC PHASES OF MYOCARDIAL-INFARCTION

Summary: The effects of iloprost (ZK 36 374) on myocardial ischemia and infarction were studied in three groups of four anesthetized and heparinized pigs. Coronary microembolization was evoked by the injection of microspheres (50 μM) into the left coronary artery. A dose of 12 million beads/kg was followed by ventricular fibrillation and death after 11 ± 5 min (group A). In group B, ischemia was evident at 15 min after the injection of 6 million beads/kg from an ST segment elevation in the precordial electrocardiogram (2.9 ± 1.1 mV; p < 0.05) and from an arterial-coronary venous difference in inosine concentration of −8.5 ± 0.3 μM (p < 0.05). However, in the presence of iloprost—an infusion of 0.18 μg/kg/min started 30 min before embolization—no ST segment elevation (0.45 ± 0.23 mV; NS) or inosine release (−1.5 ± 1.0 μM) was detected after the injection of 12 million beads/kg (group C). After 7 days, the animals from group B had more frequent spontaneous ventricular arrhythmias than those from group C. Programmed electrical stimulation induced intraventricular reentry in some animals of both groups (3 of 4 in B and 2 of 4 in C). Ventricular tachycardia was induced in two animals from group B. Postmortem examination revealed small myocardial infarcts in all group B animals; however, in group C no infarcts were detected. These data corroborate the view that prostacyclin-mimetic compounds are beneficial in the acute and in the chronic phases of myocardial infarction.

In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig.

In this study, the effect of brady kinn on saline infusion during isehemia and reperfusion on electrical stability 2 weejs after nt icarcra, infaction, was assessed Acute mvocardial infarction was increced in 23 Pigs by at transiummal occlusion of the left coronary artery with of catheter balloon, intlated for 48 min. Bradskinn was administered by a 30 min infustion that started after 30 min of coronary occlusion adn was continued and 15 min after reperfusion. Although creatine kinase levels in bradykinn-treated annuals were signticantly lower (p 0.001) 2 week survival was not different between groups In survivors the filtered QRS ventricular deflection ducation detected asing signal-ever aged electrocardiographys was significantly prolonged in Saline-treated pags. whereas in bradskinn- treated pigs this prolongasion was prevented. The terminal voltage of the QRS complex was significantly lower in dline-treated pigs than in bradvkinin treated pigs. These two parameters signify an improved electrical stability after bradykinin treatment. Refractory periods in Sahne-treated hearts were longer than in bradskimn-treated hearts (106 ± 10) vs 95 ± 13% (p 0.05) Also. current thresholds in the intaret border zones showed a greater varianc e in saline-treated hearts (p 0.001) pointing toward mor tissue beterogeneity of the infared border zone. Programmed electrical stimulation showed a trend toward reduced inducibility of sustained ventricular tachycardia in bradykinin treated hearts. Therefore, bradvkinin improves electrical stability 2 weeks after expermental myocardial infarction.

Differential inhibition of plasma versus tissue ACE by utibapril : Biochemical and functional evidence for inhibition of vascular ACE activity

Utibapril is an angiotensin-converting enzyme (ACE) inhibitor with a proposed tissue-specific inhibitory profile. This implies that at a certain dose, utibapril should be able to inhibit tissue ACE activity without affecting plasma ACE. Moreover, if tissue ACE activity is rate limiting, functional conversion of angiotensin I should be decreased. Accordingly, we studied the dose-dependent effect of long-term treatment with utibapril on plasma and tissue ACE. Normal Wistar rats were randomly allocated to oral treatment with different doses of utibapril (0, 2, 10, 50, or 250 micrograms/kg/day) for 30 days. Tissue inhibition of ACE was assessed biochemically, whereas functional conversion of angiotensin I was determined in the isolated organ. Utibapril significantly inhibited plasma, renal, and vascular ACE but not ventricular ACE activity. Notably, however, only treatment with the highest dose of utibapril resulted in a significant inhibition of plasma ACE, whereas vascular ACE activity was already significantly inhibited after treatment with a lower dose of utibapril. In accordance, utibapril dose-dependently inhibited the contraction of isolated aortic rings to angiotensin I. Furthermore, angiotensin I-induced decreases in coronary flow in the isolated heart were significantly inhibited after treatment with the higher doses of utibapril. These data suggest the preferential inhibition of vascular ACE by utibapril in normal rats. Furthermore, the dose-dependent inhibition of the functional conversion of angiotensin I indicates that the tissue ACE activity may be rate limiting in vascular beds in rats.

EFFECTS OF EARLY ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN A PIG MODEL OF MYOCARDIAL-ISCHEMIA AND REPERFUSION

Summary: In a blind, randomized study, the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were compared with those of placebo in a closed-chest pig model of myocardial infarction. In anesthetized pigs, myocardial ischemia and reperfusion were induced by inflation and deflation of a catheter balloon in the left anterior descending coronary artery (LAD), respectively. Thirty minutes after induction of ischemia and 15 min before reperfusion, a bolus injection of 0.06 mg/kg perindoprilat (n = 12), the active compound of perindopril, or placebo (n = 12) was administered in the pulmonary artery of these animals. After the acute phase of myocardial infarction, treatment with 12 mg/day perindopril or placebo was continued orally for 2 weeks. During the entire treatment period, 7 of 12 animals died in the placebo group versus 2 of 12 animals in the perindopril group (Fishers exact test p < 0.04). This beneficial effect of perindopril on mortality could not be attributed to salvage of myocardial tissue because the increases in creatine phosphokinase and coronary venous purine levels were similar in perindopriland placebo-treated animals. Neither were there any significant between-treatment differences in the hemodynamic and (neuro)humoral parameters during the acute phase of myocardial infarction. The difference in mortality was observed within 24 h after myocardial infarction. Prevention of acute pump failure and, especially, life-threatening ventricular arrhythmias may explain this improvement in survival by perindopril. Retrospectively, logistic regression analysis showed that, irrespective of treatment, survival was inversely correlated to plasma renin activity (PRA) before induction of ischemia (r = −0.33; p < 0.02). High initial PRA levels most likely reflected increased angiotensin II (ANGII) activity, which might have been beneficially influenced by perindopril. In addition, during the acute phase of myocardial infarction, prostaglandin E2 (PGE2) levels were significantly higher in animals that survived than in animals that died, but to establish the role of these humoral parameters to mortality in myocardial infarction definitively prospective studies are needed.

Improved recovery of cardiac function after 24 h of hypothermic arrest in the isolated rat heart: comparison of a prostacyclin analogue (ZK 36 374) and a calcium entry blocker (diltiazem)

Summary: The effects of a stable prostacyclin analogue (ZK 36 374; 4 nM) and a calcium entry blocker (diltiazem; 50 nM) on the recovery of cardiac function after 24 h of hypothermic (10°C) cardiac arrest were studied in the isolated rat heart. Recovery of the pressure – rate index of treated hearts was significantly better [59 ± 10% for diltiazem (p < 0.05) and 51 ± 7% for ZK 36 374 (p < 0.05)] than in untreated hearts (27 ± 9%). Untreated hearts had second- and higher-degree atrioventricular block, with an average ventricular rate of 60 ± 6% of control. All drugtreated hearts, however, were in sinus rhythm at their initial frequency without a significant alteration in PQ interval. Moreover, the incidence of severe arrhythmias was significantly reduced by ZK 36 374 (p < 0.02) and diltiazem (p < 0.01). ZK 36 374 reduced total purine overflow upon reperfusion (503 ± 51 vs. 223 ± 22 nmol min−1 g dry weight−1; p < 0.0005). The delayed overflow of adenosine, a proposed marker of reperfusion damage, was not affected by ZK 36 374 treatment. In contrast, diltiazem had no effect on total purine overflow upon reperfusion, but nearly abolished delayed adenosine overflow. It is concluded from these results that both ZK 36 374 and diltiazem improve myocardial recovery after 24 h of hypothermic cardiac arrest.

Effects of Bradykinin on Inducible Sustained Ventricular Tachycardia Two Weeks After Myocardial Infarction in Pigs

Summary: We studied the in vivo effect of bradykinin infusion on inducible sustained ventricular tachycardia (VT) 2 weeks after myocardial infarction in pigs, based on the assumption that the antiarrhythmic effect of angiotensin-converting enzyme (ACE) inhibitors may, apart from their angiotensin-II lowering effect, also be due to elevation of endogenous bradykinin levels. Of the six pigs with inducible VT in the control state, four were noninducible during subsequent bradykinin infusion (p < 0.05). The ventricular effective refractory period (VERP) did not change during bradykinin infusion (from 237 × 37 to 239 × 42 ms), nor did intraventricular conduction change (filtered QRS duration was 45 × 17 ms before and 43 × 19 ms during infusion). Bradykinin caused both a significant systolic blood pressure (SBP) decrease (from 79 × 14 to 49 × 4 mm Hg, p < 0.001) and diastolic BP (DBP) decrease (from 41 × 10 to 27 × 4 mm Hg, p < 0.01). In conclusion, exogenous bradykinin reduced the inducibility of sustained VT 2 weeks after myocardial infarction. Because refractory periods or conduction velocity were not affected, the mechanism of action might be associated with the BP decrease, which can decrease wall stress. The previously reported antiarrhythmic effect of ACE inhibitors may he due in part to elevation of endogenous bradykinin levels.