Search

The P-glycoprotein (P-gp) substrate MC225, at concentrations ≤10 nM, is a valuable radiotracer for positron emission tomography imaging of P-gp function in rats and mice. The aim of this study was to evaluate its potential toxic hazard toward the cardiovascular system through an in-depth analysis of its effects on rat aorta rings, on CaV1.2 channel current (ICa1.2) of A7r5 cells and on Langendorff-perfused rat heart. In aortic rings, MC225 relaxed phenylephrine-induced contraction in a concentration-dependent and endothelium-independent manner, with an IC50 value of about 1 μM. At concentrations ≥3 μM, it antagonized the response to cumulative concentrations of K. MC225, 1 and 10 μM, inhibited ICa1.2 by 15% and 31%, respectively, without affecting either current activation or inactivation kinetics. In Langendorff-perfused rat hearts, only 10 μM MC225 significantly decreased left ventricular pressure and increased coronary perfusion pressure while reducing heart rate and prolonging the cardiac cycle length as well as the atrioventricular conduction time (PQ interval) on the electrocardiogram. Lower concentrations of the drug were ineffective. These findings demonstrate that MC225-induced cardiovascular effects took place at concentrations that are at least 2 orders of magnitude higher than those allowing in vivo measurement of P-gp function. Therefore, MC225 represents a promising positron emission tomography tool for in vivo straightforward P-gp quantification.

Celiprolol is a selective beta(1)-adrenoceptor antagonist with antihypertensive actions, which causes renal vasodilation by increasing tissue nitric oxide (NO) levels. The authors tested whether celiprolol increases coronary blood flow (CBF) by increasing cardiac NO release in the ischemic heart in vivo. In open-chest dogs, coronary perfusion pressure of the left anterior descending coronary artery was reduced so that CBF decreased to 60% of control levels, and thereafter, coronary perfusion pressure was maintained constant. Ten minutes after the reduction of coronary perfusion pressure, we infused celiprolol into the left anterior descending coronary artery and measured fractional shortening and lactate extraction ratio as indices of regional myocardial contractility and metabolism. CBF significantly increased from 51.5 mL/100 g/min +/- 1.9 to 67.0 mL/100 g/min +/- 5.1 20 minutes after celiprolol infusion without changes in coronary perfusion pressure, while fractional shortening and lactate extraction ratio increased. Celiprolol also increased cardiac NO release. The L omega-nitroarginine methyl ester, the inhibitor of NO synthase, attenuated the increases in CBF, fractional shortening, lactate extraction ratio, and cardiac NO release due to celiprolol. ICI 118551, a beta(2)-adrenoceptor antagonist, did not blunt the effects of celiprolol and a nonselective beta-adrenoceptor antagonist, propranolol, increased neither CBF nor cardiac NO release, indicating that the effect of celiprolol is independent of beta-adrenoceptor blockade. It was concluded that celiprolol mediates coronary vasodilation and improves myocardial ischemia through NO-dependent mechanisms.

Platelet activation in heart disease is important owing to the effects of platelet-derived compounds on myocardial perfusion and cardiac electrophysiology. Diadenosine polyphosphates are secreted from platelets and present in the myocardium, but their electrophysiologic and vasomotor effects are incompletely understood. We used isolated guinea-pig hearts to study the effects of diadenosine triphosphate (Ap3A), tetraphosphate (Ap4A), pentaphosphate (Ap5A), and hexaphosphate (Ap6A) (10 pM-0.1 mM), comparing their actions to those of adenosine, adenosine triphosphate, and non-hydrolyzable Ap4A and Ap5A analogs. Diadenosine polyphosphates (0.1 nM-0.1 microM) transiently reduced coronary perfusion pressure, which recovered during the continued presence of the compounds. At concentrations greater than 0.1 microM effects were maximal and sustained (perfusion pressure decreased from 36.5+/-3.4 to 18.6+/-2.5 mm Hg, p < 0.001, with 1 microM Ap4A). The changes in action potential duration and refractory period developed slowly but were maintained (0.1 nM-1 microM). With 1 nM Ap4A, action potential duration increased from 170.6+/-2.6 to 187.3+/-3.8 ms, p < 0.05, and refractory period increased from 138.5+/-1.6 to 147.9+/-2.0 ms, p < 0.05. Ap4A and its analog reduced QRS duration (from 24.7+/-1.1 to 13.9+/-1.6 ms with 1 microM Ap4A, p < 0.05). P2-purinergic (adenosine triphosphate) receptor antagonism (suramin) reduced perfusion pressure but was without electrophysiologic effect. Other changes in coronary perfusion pressure and electrophysiologic variables associated with Ap4A were not seen in the presence of suramin. P1-(adenosine) antagonism (8-[p-sulfophenyl]theophylline) attenuated the electrophysiologic effects only. Diadenosine polyphosphates have potent cardiac electrophysiologic and coronary vasomotor effects via purinergic receptors, suggesting an important role during platelet activation in acute coronary syndromes.

To examine the responses of coronary conduit and resistance arteries to the continuous i.v. administration of nitroglycerin in 15 patients with atypical chest pain, we measured coronary blood flow velocity in the left anterior descending coronary artery using a Doppler guide wire and the lumen diameter and cross-sectional area by quantitative coronary angiography. Systolic flow, diastolic flow, total coronary flow, and coronary vascular resistance were calculated. Stepwise increases in dose of nitroglycerin resulted in significant dose-dependent decrease in mean aortic pressure (p < 0.01) and increase in lumen diameter (p < 0.05). After nitroglycerin administration of 0.5 microg/kg/min, systolic flow decreased significantly by 89.9+/-15.7% (p < 0.01), and diastolic flow increased significantly by 74.2+/-37.1% (p < 0.05). Total coronary flow did not change significantly with the various doses of nitroglycerin. However, coronary vascular resistance decreased significantly at concentrations greater than 0.5 microg/kg/min nitroglycerin. Continuous nitroglycerin infusion did not reduce either diastolic or total coronary blood flow despite a significant reduction in coronary perfusion pressure. These results indicate that subendocardial blood flow might be maintained during continuous i.v. infusion of nitroglycerin within the clinical dose range.

Summary: Coronary dysfunctions identified in the presence of chronic heart failure are an important pathophysiologic abnormality that influences the prognosis of the disease. Because the endothelin pathway plays a significant role in the increased peripheral vascular tone associated with heart failure, we hypothesized that the endothelin pathway may be involved in the abnormal coronary vasomotion associated with this pathologic condition. Experiments were carried out in failing hearts (UM-X7.1 cardiomyopathic hamsters, aged 225-250 days) and normal hearts (Syrian LVG hamsters, also aged 225-250 days). Isolated hearts were perfused at constant flow and exposed to the blocker of the generation of endothelin-1 (ET-1), phosphoramidon (10 μM infusion), as well as to the selective ETA-receptor antagonist BQ 123 (10 μM infusion) and to a selective ETB-receptor antagonist BQ 788 (1 μM infusion). Coronary and cardiac effects of exogenous ET-1 (0.01-100 pmol) were also studied. Phosphoramidon, BQ 788, and BQ 123 did not altered coronary perfusion pressure either in normal or in failing hearts, whereas cardiac contractility was significantly impaired in the presence of phosphoramidon and BQ 123. Coronary sensitivity to exogenous ET-1 did not demonstrate a significant difference between normal and failing hearts [median effective concentration (EC50), 7 pmol in failing hearts vs. 12 pmol in normal hearts; p = NS]. In the presence of exogenous ET-1, cardiac contractility was significantly increased in both groups. In normal hearts, the exogenous ET-1-induced increase in coronary perfusion pressure was completely antagonized by BQ 123, whereas combined administration of BQ 788 and BQ 123 was necessary to induce complete inhibition in failing hearts. The positive inotropic effect elicited by exogenous ET-1 (EC50) was completely abolished in the presence of BQ 123, whereas BQ 788 had no significant effect. Results indicate that the endothelin pathway does not play a significant role in the altered coronary vasomotion observed in this model of chronic heart failure. On the contrary, the endothelin pathway appears to participate in the maintenance of myocardial contractility. According to these observations, administration of an inhibitor of ET-1 synthesis, as well as the use of an ETA-receptor antagonist, may be contraindicated in the presence of poor left ventricular function because the endothelin pathway contributes significantly to the maintenance of cardiac contractility.

To determine whether the vasoconstrictor response to endothelin-1 (ET-1) is altered in coronary vessels of hypertensive hearts and the role of ETA and ETB receptors in these responses to ET-1, the vasoconstrictor response to ET-1 in coronary vessels was measured with or without ETA and ETB receptor antagonists. In isolated hearts of spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat, the coronary perfusion pressure was measured on a Langendorff apparatus with constant pressure (75 mm Hg). Coronary perfusion resistance (CPR) (mm Hg/ml/min/g) was calculated. ET-1 elicited dose-dependent increases of CPR in both normotensive and SHR rat hearts. However, the responses were significantly greater in SHR than those of WKY. Pretreatment with the ETA antagonist FR139317 and the ETB antagonist BQ788 inhibited CPR increases with ET-1 infusion. However, vasoconstrictor responses to ET-1 were still greater in SHR than in WKY after FR139317 or BQ788 infusion. These findings suggest that the augmented vasoconstrictor response of coronary artery to ET-1 is mediated by both ETA and ETB receptors. These changes may contribute to the impaired coronary circulation in hypertension.

We investigated the effects of human calcitonin gene-related peptide (CGRP) on isolated rabbit hearts to evaluate the mechanisms responsible for the vasodilatory action of the peptide on the coronary district, monitoring contemporaneously the effects on left ventricular pressure (LVP) and heart rate (HR). We also evaluated the reactivity of the human internal mammary artery (IMA) to excitatory drugs acting with different mechanisms and the inhibitory response to CGRP in comparison with the commonly used vasodilatory agents. The peptide induced a slight inhibitory effect on the basal coronary perfusion pressure (CPP), whereas it was ineffective on the inotropism and chronotropism. A more detectable coronary vasodilation was evident when CPP was increased by spasmogenic agents [vasopressin, methoxamine, Bay K 8644, and prostaglandin F2 alpha (PGF2 alpha)]. This inhibitory effect was dose dependent (10(-11)-10(-8) M) and apparently not specific, occurring to the same extent on different stimuli. Forskolin (10(-8) M), an adenylate-cyclase activator, and indomethacin (1.4 x 10(-5) M), a cyclooxygenase inhibitor, did not modify the spasmolytic activity of CGRP on precontracted coronary smooth muscle. The experiments performed on the segments of IMA, used for myocardial revascularization of patients affected by coronary diseases, have shown an evident spasmolytic action of CGRP on increased vascular tone induced by KCl (90 mM), noradrenaline (10(-5) M), serotonin (10(-6) M), and angiotensin II (10(-6) M). These inhibitory responses of CGRP on the spasmogenic compounds disappeared when the endothelial function of IMA, validated by the acetylcholine test, was abolished by mechanical ablation. A series of IMA segments was incubated (30 min) with N(G)-monomethil-L-arginine (L-NMMA), which inhibits nitric oxide (NO) synthase. In these experiments, the peptide failed to induce the vasodilation, suggesting that its action may be related to synthesis of NO. All these results show that CGRP is able to induce a potent vasodilatory action on different vessels of humans (internal mammary artery) and animals (rabbit coronary arteries). In particular the data obtained from IMA demonstrated that the vasorelaxant effect was related to synthesis of NO, one of the most studied endothelium-derived relaxing factors (EDRFs).

OBJECTIVE: To compare the energy required for defibrillation and postshock outcomes after the administration of dronedarone, amiodarone, and placebo in a porcine model of cardiac arrest. METHODS: Forty-two pigs were randomized to amiodarone, dronedarone, or control treatments. After induction of ventricular fibrillation, compressions and ventilations were performed for 3 minutes and treatment was administered over 30 seconds. If defibrillation was unsuccessful, cardiopulmonary resuscitation continued and repeated shocks were administered every 2 minutes with continual hemodynamic monitoring for a total duration of 30 minutes. RESULTS: The cumulative energy required for defibrillation was 570 ± 422 J for dronedarone, 441 ± 365 J for amiodarone, and 347 ± 281 J for control (P = not significant). Survival at 30 minutes was 1 (7.1%) for dronedarone compared with 11 (78.6%) for control (P = 0.001). Mortality in the dronedarone group was because of refibrillation in 3 (21.4%) cases, atrioventricular block in 1 (7.1%) case, and hypotension not because of bradycardia in 9 (64.3%) cases. Two minutes after successful defibrillation, systolic aortic pressure was lower in dronedarone versus control (86.6 ± 26.9 vs. 110 ± 15.1 mm Hg; P = 0.035). CONCLUSIONS: The administration of dronedarone resulted in a significant reduction in survival and both systolic aortic and coronary perfusion pressure compared with control.

We examined the influence of the new angiotensin-converting enzyme inhibitor (ACEI) fosinopril on function and perfusion of the diabetic rat heart. Streptozotocin-diabetic rats (60 mg/kg body weight) were treated with fosinopril (10 mg/kg body weight/day) for 4 months. Cardiac performance was analyzed in the isolated heart perfused at constant volume. Epicardial perfusion was determined by measuring epicardial fluorescence changes after injection of FITC-dextrane (3 kDa) as described previously. As compared with controls, fosinopril prevented or diminished the increase in end-diastolic pressure (EDP), coronary perfusion pressure (CPP), and vascular resistance in diabetes. The intravascular volume strongly reduced in diabetes was increased, and the epicardial perfusion rate was accelerated in hearts of diabetic rats treated with fosinopril. The vascular exchange diminished in hearts of untreated diabetic rats was enhanced, and the transcapillary permeability was slightly accelerated at low flow rates. These data indicate that treatment of streptozotocin-diabetic rats with fosinopril prevents severe disturbances of coronary autoregulation and at least partly the impairment of cardiac perfusion generally observed in diabetic rats. Together with previously published morphological data demonstrating an inhibition of interstitial and perivascular fibrosis in hearts of diabetic rats with fosinopril, our observations suggest that ACE inhibition by fosinopril is cardioprotective in diabetes.

The effects of endothelin-1 (ET-1) are mediated by two subclasses of the endothelin receptor, ETA and ETB. The Langendorff perfused rat heart was used to determine the endothelin receptor subtype mediating rat coronary vasoconstriction. ET-1 (EC50 = 1.5 x 10(-10) M) and endothelin-3 (ET-3) (10(-11)-3 x 10(-8) M) caused dose-dependent increases in coronary perfusion pressure. BQ-123, a selective antagonist of the ETA-receptor subtype, did not cause a parallel shift in the dose-response curves of ET-1 or ET-3. In the presence of 1-3 x 10(-6) M BQ-123, ET-1 and ET-3 exhibited biphasic dose-response curves, suggesting that vasoconstriction was caused by two receptors. The ETB-selective agonist Suc-[Glu9,Ala11,15]-ET-1(8-21) (IRL 1620) maximally increased perfusion pressure by approximately 50% of the maximal response to ET-1 and was not inhibited by BQ-123. These data suggest that the rat coronary vasoconstrictor effects of ET-1 and ET-3 are mediated by both ETA and ETB receptors.

There are various reasons to assume a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in patients with angina pectoris. Reduction of preload and afterload and a sympatholytic action may diminish myocardial oxygen demand. Local vasodilatory effects on the coronary vasculature may cause a relative increase in myocardial oxygen supply, although this can be nullified by the reduction in coronary perfusion pressure. Despite these potentially beneficial effects, placebo-controlled studies on exercise testing have shown variable results and do not justify the widespread use of these agents in chronic effort-induced angina pectoris. Nevertheless, certain subgroups of anginal patients may be identified in whom further studies are needed, especially patients who have unstable angina pectoris or are in the acute phase of myocardial infarction, patients with left ventricular dysfunction without overt heart failure, and patients with hypertension and left ventricular hypertrophy. Apart from this, ACE inhibitors may potentiate the effects of nitrates and reverse tolerance, especially inhibitors that contain a sulfhydryl group. In additional studies, a low starting dose and a long duration of treatment appear to be essential to optimize tissue penetration in the heart and to minimize negative effects due to the reduction in perfusion pressure.

Inosine is a positive inotropic agent and dilates coronary blood vessels. During ischemia, inosine infusion increases blood flow, resulting in decreased myocardial damage. We wished (a) to determine inosine's effect in isolated rat hearts and (b) to determine if inosine attenuates myocardial dysfunction after transient global ischemia. Developed left ventricular pressure (LVP), LV dP/dt, and coronary perfusion pressure were monitored in hearts receiving Krebs-Henseleit buffer (KHB) (n = 10) or KHB + 2 mM inosine (n = 4). KHB + 2 mM inosine significantly reduced coronary perfusion pressure by 21% but had no effect on developed LVP or LV dP/dt. Hearts receiving KHB (n = 6) or KHB + 2 mM inosine (n = 5) were subjected to 15-min global ischemia followed by 30-min reperfusion with KHB. Recovery of LVP, LV dP/dt, the incidence of arrhythmias, and the time to peak recovery of developed LVP was not different between groups. In two additional hearts, KHB + 2 mM inosine administered during reperfusion had no effect on developed LVP, LV dP/dt, or coronary perfusion pressure. Thus, unlike other preparations, inosine pretreatment did not significantly affect the time course of postischemic functional recovery of rat myocardium.

It has been shown that geranylgeranylacetone (GGA) protects heart against ischemia/reperfusion injury via enhanced heat shock protein 72 (HSP72) expression in rats. In the present study, we investigated the protective effect of GGA on ischemia/reperfusion-induced endothelial dysfunction. Rats were given oral GGA (GGA group) or vehicle (CON group), and 24 hours later their hearts were removed and placed in the Langendorff apparatus for 30-minute low-flow ischemia followed by 30-minute reperfusion. GGA improved the postischemic functional recovery (P < 0.01), which was abolished by N G -nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor). NO production during both ischemia and reperfusion were increased in the GGA group, and the acetylcholine (ACh)-induced (endothelium-dependent) vasodilation, measured as the percentage decrease in coronary perfusion pressure after ischemia/reperfusion (14.9 ′ 1.3%), was preserved as compared with that in the CON group (7.9 ′ 1.4%). LY294002, a phosphatidylinositol 3 (PI3) kinase inhibitor, abolished the protective effects of GGA on endothelial-dependent coronary vasodilation and NO production, whereas Y27632 (Rho kinase inhibitor) increased endothelium-dependent coronary vasodilation and NO production in CON group toward the level seen in GGA group. The amount of adrenomedullin in the coronary effluent at basal condition was lower in the GGA group than in the CON group (P < 0.05), and during both ischemia and reperfusion there was no difference in the amount of adrenomedullin between the GGA and CON groups. In addition, no difference was observed in the amount of endothelin-1 between the GGA and CON groups. These results indicate that GGA attenuates the ischemia/reperfusion-induced coronary endothelial dysfunction, which may contribute to its cardio-protective effect. The PI3 kinase and/or Rho kinase pathways appear to be involved in this process, whereas adrenomedullin and endothelin-1 are not necessary for the GGA-induced cardioprotection.

The purpose of this study is to determine the effect of clonidine on cardiac norepinephrine spillover utilizing an isolated rat heart preparation with attached cardiac sympathetic nerves. Following a 20-minute stabilization period, the sympathetic ganglion for each heart preparation was electrically stimulated with 10V and 2 Hz for 30 seconds (S1: 60 pulses). Heart rate, left ventricular developed pressure, and coronary perfusion pressure was allowed to return to baseline and the perfusate was randomly switched to Krebs buffer containing one of two treatments: placebo or clonidine (1 microM). After 10 minutes of treatment, the sympathetic ganglion was again electrically stimulated with 10V and 2 Hz for 30 seconds (S2: 60 pulses). The perfusate exiting the heart before, during, and after each electrical stimulation was collected for the determination of cardiac norepinephrine spillover. Clonidine administration significantly reduced cardiac norepinephrine spillover by approximately 50% (P < 0.05) and was associated with a 36% reduction in heart rate (P < 0.05). These findings provide evidence that clonidine can directly suppress NE spillover from cardiac sympathetic nerve terminals. Thus, suppression of cardiac NE by clonidine may be due to stimulation of presynaptic alpha2-adrenergic receptors or imidazoline subtype I receptors located on cardiac sympathetic nerve terminals. Results from our study demonstrate a reduction in cardiac NE spillover by clonidine and provide additional evidence that it can directly suppress peripheral sympathetic activity in that our results were obtained utilizing an isolated perfused heart preparation with attached cardiac sympathetic nerves devoid of any CNS input.

Calcium channel blockers (CCBs) have variable efficacy in the treatment of heart failure. We hypothesized that modulation of left ventricular diastolic pressure (LVDP) may play a role in the variable efficacy of CCBs in this condition. Isolated perfused hearts from 200- to 250-day-old UM-X7.1 cardiomyopathic hamsters (failing hearts) and age-matched Syrian hamsters (normal hearts) were studied. After recording of heart rate, coronary flow (CF), LVDP and left ventricular systolic pressure (LVSP), hearts were exposed either to verapamil or diltiazem (1 nM-10 microM), mibefradil (1 nM-1 microM) or clentiazem (1 nM-10 microM). Mechanical increase in CF (+2 to +10 ml/min) was carried out using a roller pump. Mechanically-augmented flow led to an increase in coronary perfusion pressure (+40 to +90 mm Hg), LVSP (+5 to +40 mm Hg) and LVDP (+5 to +25 mm Hg). CCBs-induced increment of coronary flow led to a difference in their cardiac response. In normal hearts, the negative inotropic response was more important with diltiazem and verapamil. Failing hearts did not demonstrate increased inotropic sensitivity to first-generation CCBs. On the contrary, at clinically relevant concentrations, verapamil resulted in the most pronounced impairment of LVDP followed by diltiazem while mibefradil and clentiazem, at clinically relevant concentrations, preserved LVDP. Such findings provide an additional explanation for the variable efficacy of CCBs in heart failure.

The aim of the current study was to assess the ability of amlodipine to dilate the coronary vessels in subjects with angiographically normal coronary arteries and normal left ventricular function. Ten patients, six women and four men (mean age 48 +/- 14 years, range 25-67 years) were enrolled. Coronary flow velocity and coronary perfusion pressure were invasively measured at baseline, during intracoronary adenosine (1-mg bolus) and at 5, 15, and 30 min following IV amlodipine (10 or 20 mg). Quantitative coronary angiography was performed at baseline and at 5, 15, and 30 min after amlodipine. Coronary cross-sectional area and mean coronary flow velocity progressively increased after amlodipine administration, resulting in an average increase in coronary flow at 30 min of 76%. On an individual basis, all patients but one showed a consistent trend toward a progressive coronary vasodilator effect of amlodipine over time. The peak effect of amlodipine on baseline mean coronary flow velocity was 43 +/- 12% that of adenosine. This is the first clinical study demonstrating that the IV administration of amlodipine produces a powerful coronary vasodilatation in subjects with angiographically normal coronary arteries and normal ventricular function, besides its known systemic vasodilating effects. The coronary vasodilating properties of amlodipine are particularly expressed at the microcirculatory level.

The aim of this study was to investigate whether the endothelin-B- (ETB) receptor agonist sarafotoxin 6c (S6c) can protect against ischaemia-induced cardiac arrhythmias. Arrhythmias were induced by a 30 min period of coronary artery occlusion in pentobarbitone-anaesthetized male rats, or in Langendorff-perfused rat hearts. Rats or rat hearts were administered a bolus dose of vehicle or S6c (0.8 nmol/kg i.v. or 10(-8) M into the coronary circulation, respectively) 5 min before the onset of ischaemia. In vivo administration of S6c significantly reduced the incidence of ventricular fibrillation (VF) from 59% to 13% and the number of premature ventricular beats. This effect was associated with a transient fall in mean arterial blood pressure. In isolated hearts, S6c reduced significantly both the incidences of ventricular tachycardia (VT) and VF while having no statistically significant effect on coronary perfusion pressure. This is the first report to show that stimulation of ETB-receptors, with a bolus dose of S6c, has an antiarrhythmic effect on rat hearts both in vivo and in vitro, suggestive of a direct effect on the myocardium.

We investigated the effect of a newly synthesized compound, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid] on Na+/H+ or Na+/Ca2+ exchange activity in rat cardiomyocytes, and on radioligand binding with several channels or receptors in membrane preparations, and ischemia/reperfusion injury in isolated perfused rat hearts. In myocytes, SM-20550 concentration-dependently inhibited the recovery from acidosis induced by an NH4Cl prepulse in HCO3(-)-free solution. Its IC50 was 10(-8) M, which was 10 times lower than that of ethylisopropyl amiloride (EIPA). SM-20550 (10(-6) M) did not affect the Na+-dependent Ca2+ influx (Na+/Ca2+ exchange activity) in cardiomyocytes. In the radioligand binding assay, SM-20550 did not have affinity for K+ channel, beta-adrenoceptor, adenosine, angiotensin, or endothelin receptors, and had low affinity for Na+ and Ca2+ channels and alpha-adrenoceptors, only at the concentrations of 10(-6)-10(-5) M. In perfused hearts exposed to 40 min of global ischemia and 20 min of reperfusion, SM-20550 (10(-8)-10(-7) M) significantly reduced the elevation of left ventricular end-diastolic pressure during reperfusion, improved the postischemic recovery of developed pressure, and prevented coronary perfusion pressure increase after reperfusion. Furthermore, SM-20550 reduced creatine phosphokinase release during reperfusion and prevented the abnormal gain of tissue Na+ and Ca2+ at the end of reperfusion. These results suggest that SM-20550 is a potent, highly specific Na+/H+ exchange inhibitor, which exerts a protective effect against myocardial ischemia/reperfusion injury. In addition, our data strongly support the hypothesis that Na+/H+ exchange plays an important role in the development of postischemic cardiac dysfunction, most likely by inducing Na+ and Ca2+ overload.

By using Langendorff-perfused rat hearts, we compared the relaxant effects of two dihydropyridine calcium antagonists (nifedipine and nisoldipine) on the coronary vasculature. Hearts were perfused at a constant flow rate (13 ml/min), and the coronary perfusion pressure was monitored to assess vasoconstriction and relaxation. Administration of 5 nM endothelin significantly increased the perfusion pressure within 5 min, and it did not decrease during the subsequent 10-min washout period. Washout with 1 nM nisoldipine or 10 nM nifedipine almost completely normalized the perfusion pressure. Administration of a nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (100 microM), elevated the perfusion pressure at 5 min. When 1 nM nifedipine was added to the perfusate, it failed to decrease the pressure, but 10 and 100 nM nifedipine partly decreased it (96.4+/-8.2 and 87.0+/-8.8 mm Hg for 10 and 100 nM, respectively). Nisoldipine alleviated the pressure elevation almost completely at 10 nM (60.0+/-5.2 mm Hg). The vasodilatory effect of nisoldipine was also approximately 10 times more potent than that of nifedipine when coronary vasoconstriction was induced by hypoxia-reoxygenation. These results suggest that nisoldipine has a stronger effect than nifedipine at the organ level, which does not depend on the cause of coronary vasoconstriction.

We studied the effects of sevoflurane on myocardial contractility and systemic and coronary hemodynamics, as compared with the effects of isoflurane in dogs under the same cardiac work conditions. Sixteen mongrel dogs were anesthetized with alpha-chloralose. Heart was paced at 100 beats/min after producing a complete atrioventricular (A-V) block. Controlled hypotension to a mean arterial pressure (MAP) of 60 mm Hg was induced and maintained by inhalation of either anesthetic, lasting for 60 min. Measurements were made at baseline, 15 min (T1), and 60 min (T2) after starting hypotension, and 30 min after discontinuing equihypotension (T3). Although left ventricular systolic segment shortening (%SS) decreased approximately 20% in both groups, cardiac output (CO) decreased only in sevoflurane during equihypotension (-27.6% at T2). Sevoflurane decreased the coronary blood flow (CBF; -34.8% at T2) with no significant change of coronary vascular resistance (CVR), whereas isoflurane produced a significant decrease in CVR resulting in no change of CBF despite of decreased coronary perfusion pressure (-37.4% at T2). These systemic and coronary vascular effects were continued even at T3. In conclusion, myocardial depressant effects were comparable between sevoflurane and isoflurane. Both systemic and coronary vasodilatory effects of isoflurane are greater than those of sevoflurane.

Cardiac beta-adrenergic receptors are the primary driving force for the enhancement of contractility in response to sympathetic stimulation. Angiotensin II influences cardiac function by modulating sympathetic activity and by activating cardiac angiotensin II receptors. The aim of this study was to determine whether activation of cardiac angiotensin II receptors modulates the responsiveness of the heart to beta-adrenergic receptor activation. Male Sprague-Dawley rats were anesthetized and the hearts isolated and perfused with oxygenated Krebs-Henseleit buffer (KHB). Coronary artery perfusion pressure, left ventricular pressure (LVP), left ventricular dP/dtmax, and heart rate (HR) were measured. Bolus administration of the beta-adrenergic receptor agonists, isoproterenol, dobutamine, and salbutamol, produced dose-related increases in LVP, LV dP/dt(max), and HR. Addition of angiotensin-II (10-100 nM) to the KHB slightly increased coronary perfusion pressure but did not alter baseline LVP, LV dP/dt(max), or HR. Angiotensin II reduced the increase in LVP, LV dP/dt(max), and HR elicited by isoproterenol and dobutamine but did not affect responses to salbutamol. The inhibitory effect of angiotensin II was blocked by the AT1-receptor antagonist, losartan, and the protein kinase C inhibitor, calphostin C (50 nM). Activation of protein kinase C with phorbol-12, 13-dibutyrate (PDBu; 10 nM) reduced cardiac responses to all three agonists, although the effects were less on responses elicited by salbutamol. These data suggest that activation of protein kinase C by angiotensin II decreases the responsiveness of the rat heart to beta 1-adrenergic stimulation and that angiotensin II-mediated protein kinase C activation may differ from that activated by phorbol esters.

Perfusion of the isolated rabbit heart with 5 x 10(6) human polymorphonuclear leukocytes (PMNL), under recirculating conditions (50 ml) and challenge with A-23187 (0.5 mu M) increased coronary perfusion pressure (CPP) sixfold, accompanied by increased levels of sulfidopeptide leukotrienes (CY-SLT), which had previously shown to correlate linearly with the increase in CPP. Pretreatment (20 min) of isolated rabbit hearts with the prostacyclin (PGI(2)) analogue iloprost (3 nM) resulted in significant protection against the increase in CPP and in almost complete inhibition of 5-lipoxygenase (5-LO) product synthesis. Similarly, pretreatment of isolated rabbit heart with defibrotide (200 mu g/ml), a polydeoxyribonucleotide derivative known to inhibit PMNL activation and enhance PGI(2) production by heart endothelial cells, produced significant protection against the increase in CPP and almost complete inhibition of 5-LO product synthesis. Neither iloprost nor defibrotide affected the A-23187-induced arachidonic acid (AA) metabolism in isolated PMNL alone. Inhibition of rabbit cyclooxygenase by intravenous (i.v.) administration of lysine-acetylsalicylate (60 mg/kg) 2 h before the animals were killed significantly reduced the protection provided by defibrotide, with a parallel fivefold increase in sulfidopeptide LT levels, returning to values in the range observed in control hearts. Control of endogenous modulators of leukocyte-vascular wall interactions such as PGI(2) results in significant changes in sulfidopeptide LT production in an organ model of transcellular metabolism of LT A(4), suggesting a novel mechanism of action for cardioprotective drugs in myocardial ischemia.

The role of cardiac endothelin-1 (ET-1) was studied by determining endogenous tissue and coronary ET-1 levels in isolated rat hearts. Hearts were perfused in an upside-down position with a colloid-free buffer and immunoreactive ET-1 was determined in timed collections of coronary effluent (E) and interstitial fluid (transudate, T) produced by the ventricles and appearing on their surface. Basal ET-1 concentrations were 0.2 +/- 0.01 pg/ml (T) and 0.03 +/- 0.002 pg/ml (E), i.e., the T:E concentration ratio was 7. Angiotensin II (0.1 mumol/L) or thrombin (5 U/ml) increased coronary perfusion pressure and ET-1 secretion but had no effect on the T:E ET-1 concentration ratio (5 and 9). In two different protocols of ischemia/reperfusion, T and E concentrations increased up to two- and fivefold, respectively. The T:E ratios were approximately 2, and the highest concentrations in either fluid were1 pg/ml. No change in coronary perfusion pressure was observed. In the presence of the ET-1-converting enzyme inhibitor phosphoramidon (1.7 mumol/L), ischemia-induced increases of ET-1 concentrations were attenuated in parallel with a time-dependent rise in coronary perfusion pressure. Therefore, under normoxic conditions and in ischemia/reperfusion, ET-1 is an endogenous vasodilator in the rat heart.

The anti-ischemic action of ITF 296 was evaluated in isovolumic, electrically driven rabbit heart preparations subjected to temporary ischemia and reperfusion. Reduction of perfusion rate from 20 to 0.2 ml/min produced a sharp decrease of peak systolic pressure, left ventricular (LV)-developed pressure, and LV dP/dt, which culminated in complete ventricular arrest within 3-4 min. Thereafter, LV end-diastolic pressure (LVEDP) progressively increased, suggesting a severe ischemic episode. Reperfusion with 20 ml Krebs solution/min after 40 min of low-flow perfusion produced only minimal recovery from the rhythm disturbances associated with cardiac mechanical activity. During reperfusion, loss of myocardial elasticity was associated with a significant increase in coronary vascular resistance, as indicated by the augmentation of coronary perfusion pressure. Injection of ITF 296 (0.3-10 microM) into the perfusion system dose-dependently inhibited the increase in LVEDP that took place during ischemia and progressively improved the recovery of a regular rhythm in the isolated heart. Isosorbide dinitrate (ISDN) at a concentration of 10 microM exerted a protective action on the myocardium similar to that obtained with ITF 296 (3 microM). Treatment with ITF 296 (1 and 10 microM) resulted in a dose-dependent increase in the rate of 6-keto-PGF1 alpha biosynthesis during both the ischemia and the reperfusion period (+157% over basal values). Similar results were obtained when hearts were pretreated with ISDN (10 microM). Infusion of a buffer containing NG-monomethyl-L-arginine (L-NMMA; NO synthase inhibitor at 10 microM) just before reduction of flow, markedly exacerbated the effects of ischemia and reperfusion on the myocardium and increased coronary perfusion pressure. The effects of L-NMMA were clearly antagonized by ITF 296 (10 microM) or L-arginine (100 microM). Mechanical activity and sinus rhythm during reperfusion were rapidly and completely restored, and coronary resistance values were close to the preischemic values. As with ISDN, ITF 296 significantly increased the rate of synthesis of 6-keto-PGF1 alpha both under basal conditions and during reperfusion.

beta-Adrenergic blockade alleviates myocardial ischemia, probably largely through heart rate (HR) reduction. We hypothesized that the negative inotropic effect of beta-blockade, which is believed to be potentially dangerous, is attenuated in underperfused hearts with an acute coronary artery occlusion. We studied the effect of intravenous propranolol (1 mg/kg i.v.) in feline hearts with acute circumflex coronary artery (LCX) occlusion by cross-oriented segments in normally perfused and mildly underperfused left ventricular (LV) anterior wall. A control group (n = 10) was compared with a stenosis group (n = 9) in which the mean coronary perfusion pressure was reduced (91 +/- 4 g vs. 136 +/- 5 mm Hg, p < 0.01). End-systolic pressure-length (ESP-ESL) relations during dynamic afterload increase and preload reduction were calculated to evaluate regional inotropy. HR and LV peak systolic blood pressure (LVSP) decreased in both groups after beta-blockade (p < 0.05). Subendocardial and mid-myocardial blood flow measured by radiolabeled microspheres decreased in the control group (p < 0.05) but was unchanged in the stenosis group. Systolic shortening of circumferential segments also decreased in the control group (p < 0.05) but was unchanged in the stenosis group. ESP-ESL relations of circumferential segments shifted markedly rightward in the control group, whereas a modest rightward shift was noted in the stenosis group. This study in feline heart with acute LCX occlusion showed an attenuated negative inotropic effect of beta-blockade in underperfused LV anterior wall.

Using isolated perfused rabbit heart electrically paced, we assessed the relevance of both nitric oxide (NO) and prostacyclin (PGI2) in regulation of resting coronary perfusion pressure (CPP). In preparations in which NO-synthase was inhibited by NG-monomethyl-L-arginine (L-NMMA, 10 microM), resting CPP increased significantly; this phenomenon was potentiated by indomethacin infusion (3 microM), prevented by L-arginine (100 microM) and significantly reduced by iloprost (55 nM) and defibrotide (200 micrograms/ml). Furthermore, the increase in resting CPP induced by graded doses of endothelin-1 (ET-1 0.6-160 pmol), was further augmented by blocking of prostaglandin biosynthesis with indomethacin (3 microM) and was substantially reduced when the rate of formation of PGI2 was enhanced by defibrotide (200 micrograms/ml). Moreover, the coronary vasoconstriction induced by ET-1 (2, 4, and 8 pmol) was increased in hearts in which NO-synthase was blocked by L-NMMA (10 microM) and this event was abolished in preparations in which PGI2 synthesis was stimulated by defibrotide (200 micrograms/ml). These results further emphasize that rabbit coronary vessels are continuously dilated by NO released from endothelial cells. They also indicate that PGI2 takes part in NO generation in the endothelial-derived relaxing mechanism. Inactivation of this mechanism, owing to decreased formation of NO and PGI2 in rabbit heart, induces hyperreactivity of coronary smooth muscles to ET-1. Finally, an increase in PGI2 production (such as that caused by defibrotide) may counterbalance impaired NO generation and attenuate hyperreactivity of the coronary vasculature.

The mechanism for the endothelin (ET)-induced vasodilatation of the endothelium-intact rat coronary vascular bed was investigated. Continuous infusion (0.1-1 nM) or bolus injection (1-100 pmol) of ET-1 or ET-3 elicited a dose-related transient decrease, followed by a slight sustained increase, in the coronary perfusion pressure (CPP). The decrease in CPP induced by an injection (10 pmol) of ET-1 or ET-3 was not modified by indomethacin (5 microM). However, oxyhemoglobin (5 mM) shortened the duration of the ET-induced decrease in CPP, although it did not affect the magnitude. The ET-induced decrease in CPP was abolished by raising K+ in the perfusing solution from 5.9 to 16.9 mM. These findings suggest that the ET-induced dilatation of the rat coronary vascular beds may not be mediated by cyclooxygenase products. The ET-induced vasorelaxation may be mediated, at least in part, by endothelium-derived relaxing factor and may be related to opening of K+ channels.

The effect of nifedipine (0.5, 1.0, and 2.0 micrograms/kg/min), metoprolol (0.1, 0.5, and 1.0 mg/kg), the beta 1-selective adrenoceptor partial agonist epanolol (10, 50, and 200 micrograms/kg), or equivalent volumes of isotonic saline (n = 6, in each group), on coronary blood flow capacity were studied in anesthetized swine. Intracoronary bolus injections of adenosine (20 micrograms/kg/0.2 ml) were administered without and during three levels of coronary stenosis, prior to and following each dose of drug, to obtain maximal coronary blood flows at different perfusion pressures in the autoregulatory range. Coronary perfusion pressures were varied by partial inflation of a balloon around the left anterior descending coronary artery. Special care was taken that the stenoses not lead to myocardial ischemia. Three indices of coronary blood flow capacity were used: absolute coronary flow reserve (ACFR, the ratio of maximal to resting coronary blood flow), the slope and the extrapolated pressure at zero flow (Pzf) of the pressure-maximal coronary flow (PMCF) relationship, and relative coronary flow reserve (RCFR, the ratio of maximal coronary blood flow with a stenosis to maximal coronary blood flow without a stenosis) at two of the three levels of stenosis. Nifedipine decreased ACFR from 4.5 +/- 1.9 to 1.9 +/- 0.3 (mean +/- SD; p less than 0.05), reflecting in part the increase in resting coronary blood flow. The nifedipine-induced changes in maximal coronary blood flow were not only due to a drop in perfusion pressure, as the slope of the PMCF relationship decreased from 2.27 +/- 0.49 ml/(min.mm Hg) to 1.54 +/- 0.51 ml/(min.mm Hg) (p less than 0.05), and Pzf decreased from 30 +/- 4 mm Hg to 20 +/- 7 mm Hg (p less than 0.05). Consequently, calculated maximal coronary blood flow was attenuated from 114 +/- 31 ml/min to 93 +/- 37 ml/min at 80 mm Hg, but was enhanced from 23 +/- 13 to 37 +/- 24 ml/min at 40 mm Hg coronary perfusion pressure. In concert with the change in the PMCF relationship, RCFR at equivalent severe stenosis increased from 0.33 +/- 0.06 to 0.47 +/- 0.10 (p less than 0.05). No changes were observed with metoprolol, epanolol, or saline. The effect of nifedipine on the PMCF relationship not only provides a mechanism for the drug's antiischemic action, but should also be considered in the interpretation of coronary flow reserve measurements in patients on nifedipine treatment.

Summary: We examined the effects of the vasoconstrictor peptide endothelin-1 in isolated hearts under ischemic and cardioplegic conditions. Isolated isovolumic rat hearts were perfused with Krebs-Henseleit buffer at constant pressure. Cumulative dose-response curves were obtained for endothelin-1 boluses of 0.04-400 pmol in four groups of hearts. Coronary flow decreased with increasing dosages and was almost abolished at 400 pmol in control hearts perfused at a constant pressure of 100 mm Hg. In hearts made ischemic by reducing coronary perfusion pressure to 35 mm Hg, thus reducing coronary flow by 76%, the constrictor effect of endothelin-1 was well preserved. The endothelin-1 dose-response curve was unaltered when hearts were perfused with buffer containing 30 m M KCl to abolish mechanical activity without reducing extracellular Ca2 + concentration. A fourth group of hearts was perfused with Ca2 +-free buffer, thus eliminating the source of extracellular Ca2+ as well as mechanical activity. In this group, the constrictor response to endothelin-1 was largely, but not completely, abolished, with a maximal constrictor effect of only 19% as opposed to 87% in control hearts. We conclude that in isolated rat heart endothelin-1 is a potent coronary constrictor under ischemic perfusion conditions and that absence of mechanical activity does not affect the action of endothelin- 1, for which the presence of extracellular Ca2+ is essential. The small residual constrictor response with Ca2 +-free perfusion is probably due to release of Ca2 + from intracellular stores

This study was designed to test the hypothesis that endogenous adenosine participates in the global coronary functional hyperemia accompanying intracoronary infusions of norepinephrine (NE) and isoproterenol (ISO). Intracoronary adenosine deaminase (ADA) was employed to test the hypothesis in isolated, perfused guinea pig hearts. We measured coronary perfusate flow (CPF) at a constant coronary perfusion pressure. Heart rate (HR), left ventricular pressure, and its rate of development were also measured. Global myocardial oxygen consumption (MVO2) and oxygen extraction were calculated, and blood gases and pH were measured routinely in inflow and outflow perfusate samples. In the absence of ADA, NE and ISO increased HR 67 +/- 6 and 106 +/- 11 beats.min-1, left ventricular pressure development 519 +/- 46 and 375 +/- 35 mm Hg.s-1, MVO2 22 +/- 2 and 28 +/- 3 microliters.min-1.g-1, and CPF 1.6 +/- 0.2 and 2.2 +/- 0.2 ml.min-1.g-1, respectively. With constant infusion of ADA (4.5 U.min-1.g-1, a dose which produces no direct effects on cardiac function) for 4 min, similar increments in HR and left ventricular pressure development were achieved with both catecholamines. Corresponding changes in MVO2 (9 +/- 2 and 6 +/- 3 microliters.min-1.g-1) were significantly less than those seen in the absence of ADA. Moreover, CPF did not increase in response to NE and ISO in the presence of ADA. These findings support an important role for adenosine in catecholamine-induced global coronary functional hyperemia in isolated, perfused guinea pig hearts.

Isolated guinea pig hearts were used as a model to investigate the role of pO 2 , coronary perfusion pressure (CPP), and flow on the release of nitric oxide (NO) into the coronary circulation. The in vitro half-life of NO strongly depends on the pO 2 . Reduction of pO 2 from 700 and 50 mm Hg prolonges the NO half-life by 78%, from 3.6 to 6.4 s. Basal release of guansine-3', 5'-cyclic monophosphate (cyclic GMP) taken as an index of endogenous NO concentration, remained unaltered in isolated hearts perfused at normoxic (100% O 2 ) and hypoxic conditions (30% O 2 ).

The effect of two dihydropyridine derivatives, nifedipine and felodipine, on myocardial blood flow distribution 1 h after ligation of the left anterior descending coronary artery (LAD) was studied in open-chest dogs by means of radioactive microspheres. The myocardium normally perfused from the LAD was first labeled with 125I-labeled microspheres injected directly into the LAD before ligation. Microspheres used for blood flow measurements were given in the left atrium. An intravenous infusion rate of 0.3 nmol/kg/min felodipine slightly depressed mean aortic blood pressure (approximately 5 mm Hg) and decreased coronary vascular resistance in normal myocardium. Nifedipine, at three times the dose of felodipine, had a comparable hypotensive effect, but the decrease in coronary vascular resistance was not statistically significant. The two dihydropyridines were also compared in a dose range that was four times higher. The mean arterial blood pressure reduction (approximately 30% for both drugs) was counterbalanced by inflation of an intraaortic balloon to avoid a drastic decrease in afterload and coronary perfusion pressure. Under these circumstances, felodipine and nifedipine decreased coronary vascular resistance and increased blood flow to nonischemic myocardium comparably. However, in severely ischemic, truly collateral-dependent myocardium without admixture of interdigitating healthy myocardium, the blood flow was unaffected after administration of both felodipine and nifedipine. Although felodipine was three times more potent than nifedipine with regard to vasodilatation in the normal myocardium, the difference in vascular selectivity between the two agents did not influence the effect on the "true" collateral blood flow in acute myocardial ischemia.

The acute effects of doxorubicin on coronary perfusion and left ventricular pressures and intracellular phosphate metabolite levels, the latter obtained by 31P nuclear magnetic resonance, were measured simultaneously in isolated, isovolumic rat hearts (Langendorf preparation) perfused at constant flow. Nineteen experimental hearts were perfused for 70 min with oxygenated HEPES-buffered solution containing 6 mg/L doxorubicin. These were compared with 18 control hearts (C), perfused under identical conditions but without doxorubicin, by repeated measures analysis of variance. In the experimental group, coronary perfusion pressure steadily increased to 226.3 +/- 13.8% (mean +/- SEM) of initial levels (p less than 0.0001 vs. C). Because flow was constant, the increase in coronary perfusion pressure in experimental hearts indicates a greater than twofold increase in coronary resistance. Intracellular phosphocreatine and ATP decreased to 80.3 +/- 3.9% (p less than 0.005 vs. C) and 82.1 +/- 6.4% (p less than 0.05 vs. C), whereas inorganic phosphate increased to 149.7 +/- 19.1% (p less than 0.05 vs. C) of initial levels, respectively. Accompanying these changes, diastolic pressure steadily increased to 521.7 +/- 91.4% of initial levels (p less than 0.0001 vs. C). Developed pressure initially increased to 107.1 +/- 4.5% at 30 min, and thereafter decreased to 76.2 +/- 6.3% at 70 min (p less than 0.05 vs. C). Typical structural alterations in myocyte nuclei were noted. Cellular calcium was not increased in doxorubicin-exposed hearts. Thus, acute doxorubicin cardiotoxicity is characterized by an increase in coronary resistance and is closely correlated with alterations in ventricular function and a decrease in intracellular high-energy phosphate content.(ABSTRACT TRUNCATED AT 250 WORDS)

Ro 40-5967 is a structurally novel calcium antagonist that binds to the verapamil binding site but has very weak negative inotropic effects compared to verapamil. The goals of the present study were to assess the effects of Ro 40-5967 on myocardial function during ischemia, and to compare them to those of verapamil. For this purpose, in anesthetized dogs where the circumflex coronary artery was cannulated and perfused at controlled pressure, myocardial function was measured using piezo electric crystals implanted into the endocardium. Myocardial distribution of coronary blood flow was assessed using radioactive microspheres. Ischemia was produced by lowering perfusion pressure from 100 to 15 mm Hg in steps. During ischemia, Ro 40-5967 partially prevented the decrease of segmental shortening (p less than 0.01) and increased coronary flow, especially in the endocardium (p less than 0.01). In contrast, verapamil did not improve myocardial function during ischemia. The protective effect of Ro 40-5967 could be partially explained by the decrease of arterial pressure and heart rate induced by Ro 40-5967. However, Ro 40-5967 injected directly inside the coronary artery did not induce systemic effects, but still had protective effects (p less than 0.05). Verapamil injected intracoronary produced severe cardiac depression. We conclude that in the present model during ischemia Ro 40-5967 has no negative inotropic effects, and in contrast to verapamil can improve the myocardial function.

Effects of nitroglycerin (3 micrograms/kg/min i.v.) on regional myocardial contractility during acute coronary stenosis were studied in open-chest dogs using a strain-gauge arch. Stenosis-induced stepwise decreases in coronary perfusion pressure (CPP) at less than 40 mm Hg correspondingly reduced contractility in the underperfused area and increased the left ventricular end-diastolic pressure (LVEDP). Nitroglycerin caused significant increases in contractility, along with decreases in arterial and left ventricular pressures; at stenosis-induced CPP less than 30 mm Hg, contractility in the underperfused are fell precipitously below the control, while LVEDP increased. When nitroglycerin infusion under coronary stenosis (CPP of 40 mm Hg) decreased CPP to less than 30 mm Hg, contractility fell. When CPP greater than 30 mm Hg was maintained, contractility increased and LVEDP decreased. In conclusion, at least in the absence of well-developed collateral circulation, the critical level of CPP was 40 mm Hg for contractility and LVEDP without nitroglycerin, which shifted to 30 mm Hg with the addition of nitroglycerin. Nitroglycerin resulted in a significant increase in plasma catecholamines, and the increase in contractility diminished with propranolol, indicating participation of beta-adrenoceptor in the positive inotropic effect of nitroglycerin. However, catecholamines at high concentrations probably further aggravated the impaired cardiac function at CPP less than 30 mm Hg.

The direct actions and the ability to antagonize adenosine of theophylline (1,3-dimethylxanthine) and enprofylline (3-propylxanthine) were examined in isolated guinea pig heart preparations. Enprofylline was approximately six times as potent as theophylline in reducing coronary perfusion pressure, and between three and five times more potent in increasing rate and force of contraction in isolated perfused hearts, spontaneously beating right atrias, and electrically stimulated left atrias. Adenosine reduced the coronary perfusion pressure and had negative inotropic and chronotropic actions. Theophylline (5-75 microM) concentration-dependently antagonized the coronary vasodilation and the negative chronotropic and inotropic actions of adenosine, whereas enprofylline (2.5-75 microM) did not antagonize adenosine. Since adenosine may be a protective autacoid in the heart under select stress conditions, the possibility that adenosine nonblocking xanthines, like enprofylline, may offer therapeutic advantages over theophylline should be investigated.

The effects of equipotent doses in negative inotropic and chronotropic properties of nipradilol [10 micrograms/kg/min intravenously (i.v.)] and propranolol (20 micrograms/kg/min i.v.) on hemodynamics and transmural energy metabolites in ischemic hearts were examined in anesthetized dogs. After 5-min infusion of these agents, coronary perfusion pressure of 30 mm Hg was induced by acute coronary stenosis for 10 min. Coronary blood inflow and myocardial contractile force (MCF) in the control ischemic area decreased to about one-third and two-thirds of the respective starting levels. In the nipradilol group, similar changes were observed, but in the propranolol group the MCF tended to decrease further. Cardiac effort index decreased to about two-thirds in both groups. The left ventricular end-diastolic pressure (LVEDP) increased by 4.3 mm Hg with saline, by 8.8 mm Hg with propranolol, and by 1.3 mm Hg with nipradilol. ATP depletion in the ischemic myocardium (by 29 and 22% in inner and outer layers, respectively) was restored to normal level by either agent. A decrease in creatine phosphate and an accumulation of lactate were significantly alleviated by nipradilol (by 74 and 59----by 39 and 21%, and by 4.9 and 2.3----by 0.7 and 0.2 times, respectively), but not by propranolol. The results indicate that in addition to a decrease in myocardial oxygen consumption caused by the beta-adrenoceptor blocking effects of nipradilol, reductions in preload and afterload caused by the vasodilating property significantly contribute to nipradilol-induced improvement in the ischemic derangement of transmural energy metabolism.

We studied the effects of felodipine [4-(2,3-dichlorophenyl)-1,4-dihydropyridine-2,6-dimethyl 3,5-dicarboxylic 3-ethylester and 5-methylester] on the coronary vascular bed of pig hearts with an ischemic region in the left ventricle following ligation of the left anterior descending coronary artery. At an infusion rate of 0.12 nmol X kg-1 X min-1, felodipine caused a slight reduction in mean arterial blood pressure and a decrease in coronary vascular resistance in both normal myocardium and partly ischemic myocardium of the border zone. In another series of experiments, felodipine was infused at a higher rate (0.38 nmol X kg-1 X min-1). The resultant decrease in mean arterial blood pressure, which was about 30%, was counterbalanced by inflation of an aortic balloon to keep the afterload and the coronary perfusion pressure constant. In this situation, felodipine caused a pronounced increase in blood flow to all parts of the heart except the central ischemic zone, where blood flow was extremely low. We conclude that felodipine has a coronary vasodilator action which is at least of the same magnitude as its peripheral vasodilator action, and that it markedly increases coronary blood flow in the border zone of an ischemic area.

The effects of intracoronary leukotriene C4 (LTC4) and D4 (LTD4) (both 0.1 microgram/kg) were studied in 23 anesthetized open-chest dogs at normal (= mean aortic pressure) and reduced (51 +/- 2 and 32 +/- 2 mm Hg) coronary perfusion pressures. The left anterior descending coronary artery was cannulated and blood flow measured. Subendocardial fiber segment length was obtained with ultrasonic crystals. At normal coronary perfusion pressure, LTC4 and LTD4 reduced coronary blood flow from 81 +/- 6 and 78 +/- 7 ml/min per 100 g by 41 +/- 4% and 41 +/- 4% (both p less than 0.0005), respectively. However, segment length shortening was not depressed by LTC4 or LTD4. At reduced coronary perfusion pressure, LTC4 and LTD4 diminished coronary blood flow from 35 +/- 5 and 32 +/- 3 ml/min per 100 g, by 28 +/- 5% (p less than 0.0025) and 30 +/- 5% (p less than 0.005). Thus, reduction of coronary blood flow was less by both LTC4 (p less than 0.01) and LTD4 (p less than 0.05) at reduced rather than at normal coronary perfusion pressure. Segment length shortening was depressed by LTC4 from 6.5 +/- 1.2% to 2.4 +/- 1.6% (p less than 0.05) and by LTD4 from 5.6 +/- 1.4% to 3.1 +/- 0.9% (p less than 0.05), respectively. Indomethacin (5 mg/kg, i.v.) and nifedipine (10 micrograms/kg, i.v.) did not abolish the LT-induced coronary artery constriction. However, in animals pretreated with indomethacin or nifedipine, reduction of coronary blood flow by LTs was not attenuated at reduced coronary perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Furosemide is an effective diuretic that initiates a rapid diuresis and peripheral vasodilatation through renal adenylate cyclase inhibition and prostaglandin synthesis. Recently, it has been shown to be associated with activation of the neurohumoral vasoconstrictor mechanism and a further compromise of left ventricular function in patients with heart failure. The present study was performed to investigate the direct effects of furosemide on myocardial performance in the isolated perfused rabbit heart. Furosemide (10(-3) M) caused a significant decrease in developed pressure as well as a similar fall in coronary perfusion pressure. Furosemide also decreased myocardial contractility when the coronary perfusion pressure was kept constant. The change in developed pressure but not the decrease in coronary perfusion pressure could be blocked by treatment with indomethacin. Furosemide did not antagonize rabbit cardiac membrane adenylate cyclase. Therefore, furosemide has a direct inhibitory effect on cardiac contractility that is related to prostaglandin synthesis.

The effects of Bay K 8644, aortic constriction, and a placebo on regional myocardial blood flows (RMBFs) and contractile function (RCF) were compared in three groups of open-chest anesthetized dogs during coronary stenosis. Bay K 8644 was investigated in two doses: 0.1 micrograms/kg, which exhibited no systemic hemodynamic effect, and 1 microgram/kg, which significantly increased arterial pressure. Aortic constriction was performed to raise afterload to the same extent as Bay K 8644 1 microgram/kg. As compared with placebo, Bay K 8644 0.1 microgram/kg, significantly increased coronary resistance, decreased RMBFs without changing RCF in nonischemic myocardial zones, and affected neither RMBFs nor RCF in ischemic zones. In nonischemic myocardium, Bay K 8644 1 microgram/kg increased RMBFs without affecting RCF, whereas aortic constriction did not modify RMBFs but decreased RCF. In ischemic myocardium, both Bay K 8644 1 microgram/kg and aortic constriction increased RMBFs but did not affect RCF. Thus, the low dose of Bay K 8644 exerts a direct and selective coronary vasoconstrictor effect that has no deleterious consequences on nonischemic RCF. Despite this intrinsic coronary vasoconstrictor effect, the high dose of Bay K 8644 increases RMBFs and maintains RCF in both ischemic and nonischemic zones in relation with the drug-induced increases in coronary perfusion pressure (both zones) and in contractility (nonischemic zones).

The release of NO from SIN-1, the active metabolite of molsidomine, was measured in vitro in Langendorff-perfused rabbit hearts. NO in the coronary effluent was determined on-line using the oxyhemoglobin technique. Left ventricular and coronary perfusion pressure were also recorded continuously. Glyceryl trinitrate and iloprost were used as reference compounds. Infusion of SIN-1 or glyceryl trinitrate into the coronary inflow resulted in a significant and dose-dependent NO release. An apparently identical response was seen when SIN-1 was infused into the coronary effluent while the response to glyceryl trinitrate was greatly reduced or abolished. The glyceryl trinitrate-induced coronary vasodilation was only slightly diminished in presence of oxyhemoglobin whereas the response to SIN-1 was abolished. This is explained by complete scavenging of NO by oxyhemoglobin within the vessel lumen. In isolated porcine aortic endothelial cells, SIN-1 induced a significant and dose-dependent increase in cyclic GMP, whereas glyceryl trinitrate was ineffective. This would argue against biotransformation of glyceryl trinitrate to NO by endothelial cells. Finally, glyceryl trinitrate-tolerant heart preparations exhibited a considerably reduced or even undetectable release of NO, whereas the response to SIN-1 was unchanged.