Acceleration of stiffness in underperfused diabetic rat hearts by glyburide, a KATP channel blocker, and its prevention by levcromakalim and insulin.

OBJECT: To clarify the role of the KATP channels in myocardial dysfunction during underperfusion with norepinephrine (NE) in the diabetic heart, particularly the heart treated with sulphonylurea derivatives. METHODS: Isolated 6-week streptozotocin-diabetic rat hearts with a balloon in the left ventricle (LV) were paced and perfused with normoxic Krebs-Henseleit solution. Agents were infused for 15-25 min before as well as during 60-min underperfusion (2 ml/min/g heart weight) with 10(-6) M NE. Regional myocardial flow distribution was measured using dye microspheres. The effects of ex vivo glyburide (10(-6) M, a sulphonylurea anti-diabetic drug and a specific KATP channel inhibitor) on contractile dysfunction and abnormal regional myocardial energy metabolism were examined during underperfusion with NE in the absence of presence of levcromakalim (10(-4) M, a selective K+ channel opener) and insulin (2 mU/min/g heart weight). RESULTS: The flow rate was greater in the LV subendocardium than the subepicardium during normal perfusion, and smaller at 60-min underperfusion with NE. The LV diastolic tension and pressure during underperfusion with NE increased more rapidly in the presence of glyburide. At 60-min underperfusion with NE, the diastolic pressure elevation was still higher in the glyburide-treated heart, and decreases in tissue ATP, creatine phosphate (CP), energy charge, phosphorylation potential and CP/inorganic phosphate (P(i)) ratio, and increases in AMP, P(i) and lactate were more marked in the glyburide-treated heart, particularly in the LV subendocardium. Thus, ex vivo glyburide enhanced the increase in LV stiffness and abnormal myocardial energy metabolism during underperfusion with NE in diabetic hearts. These changes were reduced by levcromakalim to the level during underperfusion with NE without glyburide. Insulin did not prevent the glyburide-induced earlier exacerbation of the increase in LV stiffness during underperfusion with NE, but reduced the detrimental effects 20 min after the onset of underperfusion. CONCLUSIONS: KATP channels in the diabetic myocardium probably open during underperfusion with NE, and it helps delay the initiation of the increase in cardiac stiffness. Glyburide may have harmful effects in the ischemic diabetic heart; the myocardial KATP channel blockade during underperfusion with NE enhanced the increase in LV stiffness and abnormal myocardial energy metabolism. The glyburide-induced detrimental effects in the ischemic diabetic heart are prevented by levcromakalim and partly by insulin.

Effects of nipradilol on myocardial ischaemia produced by coronary stenosis in dogs.

Effects of nipradilol which is a new beta-adrenoceptor blocking agent endowed with nitroglycerin-like vasodilator actions, its denitrated derivative (denitro nipradilol) and propranolol on abnormalities of regional myocardial shortening produced by partial occlusion of the left circumflex coronary artery (LCX) were studied in anaesthetized open-chest dogs. In the presence of LCX stenosis, nipradilol (0.1 mg kg-1, i.v.) produced marked decreases in heart rate and LVdP/dt without a significant increase in left ventricular end-diastolic pressure (LVEDP). It improved impaired myocardial segment shortening and restored normal cardiac lactate metabolism. Denitro nipradilol (0.2 mg kg-1 i.v.) and propranolol (0.2 mg kg-1 i.v.) both caused similar haemodynamic changes to nipradilol but also produced a significant increase in LVEDP. However, improvement by these two agents of regional dysfunction in the ischaemic myocardium was comparable to those seen with nipradilol. All three agents markedly inhibited isoprenaline-induced tachycardia, but vehicle did not. Atrial pacing abolished the beneficial effect of nipradilol on myocardial shortening in the ischaemic region without affecting other haemodynamic parameters. These results indicate that nipradilol alleviates acute myocardial ischaemia produced by coronary stenosis with similar efficacy to denitro nipradilol and propranolol suggesting, that a major part of the beneficial effect of nipradilol may be attributable to its beta-adrenoceptor blocking action.

Nitroglycerin relaxes coronary artery of the pig with no change in glutathione content or glutathione S-transferase activity.

1. The role of glutathione content and glutathione S-transferase activity in vascular relaxant responses to nitroglycerin was evaluated in potassium (30 mM)-contracted coronary artery strips of the pig by measuring changes in tension, glutathione content and glutathione S-transferase activity. 2. Prior exposure of coronary artery strips to nitroglycerin (10(-5)M or 10(-4)M for 20 min) resulted in tachyphylaxis to subsequent relaxation to nitroglycerin (10(-8)-10(-5)M). 3. The glutathione content and glutathione S-transferase activity of the arterial strips rendered tachyphylactic by prior exposure to nitroglycerin (10(-5)M for 20 min or 10(-3)M for 120 min) were not significantly different from those of control strips. 4. Treatment with diethyl maleate (10(-4)M or 10(-3)M for 60 min) markedly depleted arterial glutathione content in a concentration-dependent manner with no change in glutathione S-transferase activity. 5. The relaxant response of coronary artery strips to nitroglycerin (10(-8)-10(-5)M) was completely unaffected following treatment with diethyl maleate (10(-4)M or 10(-3)M for 60 min). 6. The results suggest that vascular glutathione content does not play an important role in vascular relaxation or tolerance development to nitroglycerin, at least in pig isolated coronary artery.

Effect of 1-week treatment with erythropoietin on the vascular endothelial function in anaesthetized rabbits.

Chronic administration of erythropoietin (EPO) is often associated with hypertension in animals and humans. The aim of this study was to estimate whether 1-week treatment with EPO can affect the vascular endothelial function. Rabbits were given with EPO (400 iu kg(-1) s.c.) or saline each other day for 1 week. Hypotensive responses to intravenously given acetylcholine (ACh), endothelium-independent nitric oxide donors (NOC7, nitroprusside and nitroglycerin) and prostaglandin I2 were tested before and after administration of N(G)-nitro-L-arginine methyl ester (L-NAME), a specific nitric oxide synthase inhibitor, under pentobarbitone anaesthesia. Blood haemoglobin concentration in EPO group was significantly higher than that in control group, whereas baseline values of aortic pressure, heart rate and femoral vascular resistance were similar. The dose of ACh (172 ng kg(-1)) requiring for a 15 mmHg hypotension from the baseline in EPO group was apparently higher than that (55 ng kg(-1)) in control group. On the contrary, hypotensive responses to NOC7, nitroprusside, nitroglycerin and prostaglandin I2 were comparable between two groups. The extent of ACh-induced hypotension did not correlate with haemoglobin concentration. L-NAME significantly inhibited the ACh-induced vasodilating response in control group but did not in EPO group. In another set of rabbits, the same treatment with EPO also decreased vasodilating responses to carbachol, bradykinin and substance P besides ACh as compared with control group. These results indicate that 1-week treatment with EPO selectively attenuates depressor responses to endothelium-dependent vasodilators in anaesthetized rabbits, most likely due to inhibition of endothelial nitric oxide synthase.

Involvement of nitric oxide and eicosanoids in platelet-activating factor-induced haemodynamic and haematological effects in dogs.

1. Platelet-activating factor (PAF) is a phospholipid mediator with potent cardiovascular and haematological actions. But its mechanisms of action in vivo have not been fully elucidated, probably due to difficulties arising from previous findings that the effects of PAF are largely mediated by the release of a variety of other autacoids. In the present study, the roles of nitric oxide and eicosanoids in the effects of PAF (0.01-0.25 microgram kg-1 i.v.) on systemic and pulmonary vasculatures and circulating blood cell count were pharmacologically evaluated in anaesthetized dogs. 2. Higher doses of PAF (> 0.1 microgram kg-1) produced a biphasic systemic hypotension. The first hypotension seen 30 s after the injection was accompanied by a decrease in systemic vascular resistance, thrombocytopenia and leukopenia, while the second hypotension seen 1-2 min after PAF was accompanied by a marked rise in pulmonary vascular resistance and decreases in aortic blood flow and cardiac contractility. Lower doses of PAF (0.01 - 0.05 microgram kg-1) caused only the first responses in a dose dependent manner. 3. Pretreatment with indomethacin inhibited the second responses to PAF without affecting the first responses. The thromboxane A2/prostaglandin H2 (TP)-receptor antagonist vapiprost blocked the PAF-induced rise in pulmonary vascular resistance. AA-861, a 5-lipoxygenase inhibitor, attenuated the PAF-induced cardiac depression. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester inhibited the PAF-induced early decrease in systemic vascular resistance. 4. All observed changes in haemodynamics and blood cell count after PAF were almost abolished by TCV-309, a PAF-receptor antagonist. 5. Reproducible hypotension and thrombocytopenia produced by a lower dose of PAF (0.05 microgram kg-1) were respectively attenuated and potentiated by pretreatment with NG-nitro-L-arginine, another nitric oxide synthase inhibitor. Administration of L-arginine reversed the effects of the nitric oxide synthase inhibitor. 6. These results indicate that PAF-receptor-mediated production of not only eicosanoids but also nitric oxide may contribute to the cardiovascular and haematological responses to PAF in the dog.

Microsomal calcium-accumulating ability of bovine coronary artery and aorta.

Calcium uptake and binding activities of microsomal fractions from bovine coronary artery and aorta were examined. The isolated microsomal fraction of the coronary artery and aorta showed 7- to 8-fold higher glucose-6-phosphatase activity and 4- to 6-fold higher NADPH-cytochrome c reductase activity as compared with the corresponding values for the homogenate fraction. Coronary artery and aorta microsomal calcium uptake activities were 118 and 159 nmoles Ca2+/mg protein/10 min in the presence of 100 microM CaCl2, respectively. These activities for bovine vascular smooth muscle microsomes are higher than those of other species investigated. The calcium uptake activities were dependent on calcium concentrations ranging from 5 to 50 microM in the assay medium. The onset of the reaction for aorta microsomal calcium uptake was faster than that for the coronary artery. The calcium uptake activity was also dependent on ATP, but it was practically independent of oxalate ions in the assay medium. Microsomal calcium binding activities of the coronary artery and aorta were maximal at 20 min of incubation under the present experimental conditions. A lower Km value of the aortic calcium binding for ATP was obtained as compared with that for the coronary artery. The present experiment explored several characteristics of the microsomal calcium-accumulating ability of vascular smooth muscle, which provides meaningful information for further study on cellular calcium movements in vascular smooth muscle.

A possible action of nicardipine on the cardiac sarcolemmal Na+-Ca2+ exchange.

The effects of nicardipine on sodium-calcium exchange activity of cardiac sarcolemma-enriched vesicles isolated from the rat heart were examined. Sodium-loaded, sarcolemma-enriched vesicles, when exposed to a medium containing 40 microM CaCl2, exhibited about 5 nmoles Ca2+/mg protein of the maximal calcium uptake; the initial rate was 21 nmoles Ca2+/mg protein/min. The calcium uptake was dependent on the extravesicular concentration of calcium ion. Nicardipine at concentrations of 0.1 to 10 microM depressed the rate of calcium uptake activity by 60-90%. The isolated membrane vesicles preloaded with Ca2+ showed a calcium efflux activity, when exposed to a medium containing sodium ion. The rate of calcium efflux was 2.5 nmoles Ca2+/mg protein/min, when measured in a medium containing 6.5 mM NaCl. The efflux rate was facilitated with increased concentrations of sodium ion in the medium. About 75% of the preloaded calcium in the vesicles was released within 3 min of incubation. The rate of calcium efflux was stimulated in the presence of 0.1 to 10 microM nicardipine (2.5- to 4-fold increase). The present results suggest a possible action of nicardipine on the sodium-calcium exchange mechanism at cardiac sarcolemmal sites.

Effects of prostaglandin E1 on isolated dog renal artery.

Actions of prostaglandin (PG) E1 were investigated using isolated dog renal arterial strips. Norepinephrine increased the tension of the renal arterial strips contracted with potassium, and this response was depressed by phentolamine. Isoproterenol produced relaxant effects on these arteries, and this response was converted to contractile one by propranolol. Diltiazem dose dependently relaxed the potassium-contracted strips. PGE1 (10(-9)-3 X 10(-8) Gm./ml.) constricted the renal arterial strips, while in higher concentrations (10(-7)-3 x 10(-7) Gm./ml.) it caused relaxations of them. Contractile responses by PGE1 were not affected by phentolamine or phenoxybenzamine, but were suppressed by diltiazem. On the other hand, relaxant effects of PGE1 were not changed by propranolol. Papaverine or theophylline significantly inhibited the contractions induced by PGE1. From these results it is suggested that (1) in the dog renal artery adrenergic alpha-receptors must be more dominant than beta-receptors; (2) PGE1 will produce a depolarization of renal arterial smooth muscle and/or increase an active transport of calcium ions into smooth muscle cells; and (3) the relaxant responses by PGE1 may be related to an increase in cellular cyclic adenosine monophosphate (AMP) contents.

Relaxation of isolated dog coronary artery induced by propranolol.

The effects of propranolol and atenolol on isolated dog coronary arteries contracted with potassium were investigated in vitro. Propranolol at high concentrations (3 x 10(-5)-10(-4) M) produced relaxations of the coronary arterial strips, which were restored or prevented by exogenous calcium ions. Atenolol (10(-5)-10(-4) M) never changed the tension of the strips. The results suggest that propranolol may inhibit the coronary arteries through its calcium antagonistic action.

Ex vivo effect of insulin on normal and diabetic rat hearts hypoperfused with norepinephrine.

The effect of ex vivo insulin on contractile and energy metabolism dysfunctions was examined during hypoperfusion (0.6 ml/min per g heart weight) with 10(-6) M norepinephrine in isolated non-diabetic and streptozotocin-diabetic rats hearts. Insulin (2 mU/min per g heart weight) was infused for 15 min before as well as during 60-min hypoperfusion. Insulin significantly reduced the elevated diastolic tension in diabetic hearts (from 3.8 to 0.7 delta g), but not in non-diabetic hearts (from 1.4 to 1.2 delta g). Insulin partly improved the ATP decrease in the subendocardium of the left ventricle of the diabetic hearts (from 3.5 to 10.2 mumol/g dry weight) but did not affect non-diabetic hearts (from 6.9 to 6.8 mumol/g dry weight). Insulin also partly improved the creatine phosphate decrease and the inorganic phosphate increase in diabetic hearts only. Lactate accumulation was greater in non-diabetic than in diabetic hearts, even in the presence of insulin (77 vs. 45 mumol/g dry weight). The results indicate that acute intracoronary application of insulin in diabetic hearts improves hypoperfusion with norepinephrine injury to a level above that of non-diabetic hearts, but does not improve a less severe injury in non-diabetic hearts.

On the mode of action of ergometrine in the isolated dog coronary artery.

Coronary vasoconstrictor responses to ergometrine were examined in spiral coronary arterial preparations of dogs. Either ergometrine or serotonin (5-HT) produced dose-dependent contractions of the strips. Methysergide significantly depressed the contractions induced by ergometrine or 5-Ht. Dihydroergotamine and phentolamine depressed constrictor responses to ergometrine, while phenoxybenzamine did not. The 5-HT antagonistic action of phentolamine was stronger than that of phenoxybenzamine. The results indicate that ergometrine may act on coronary arteries mainly through activation of 5-HT receptors.

Alleviation of myocardial dysfunction and abnormal lactate metabolism during coronary stenosis in dogs by ICI 118,551.

Hemodynamic parameters, segment shortening in the ischemic myocardium and cardiac lactate extraction were estimated in the presence of a critical coronary stenosis, before and after administration of the selective beta 2-adrenoceptor antagonist, ICI 118,551, or the beta 1-adrenoceptor antagonist, atenolol, to anesthetized dogs. ICI 118,551 (0.2 and 0.5 mg/kg i.v.) and atenolol (0.2 mg/kg i.v.) produced significant decreases in both heart rate (by 6, 14 and 20% of the predrug value, respectively) and maxLVdP/dt (by 15, 26 and 24% of the predrug value, respectively). ICI 118,551 (0.5 mg/kg) and atenolol significantly improved the impaired shortening of the myocardial segment when compared with the change seen after saline administration. ICI 118,551 at both doses and atenolol significantly increased depressed cardiac lactate extraction while saline did not. Increasing heart rate by pacing abolished the beneficial effects of ICI 118,551 and atenolol on ischemic myocardial segment shortening and lactate metabolism. The data suggest that not only beta 1- but also beta 2-adrenoceptor blockade may contribute to the amelioration of myocardial ischemia in a model of coronary stenosis.

Effects of intracoronary propranolol on coronary blood flow and regional myocardial function in dogs.

The study was conducted to evaluate the effects of intracoronary administration of dl-propranolol on coronary blood flow and regional myocardial function in anesthetized open-chest dogs. The results were compared with those obtained with d-propranolol, atenolol and lidocaine. Bolus intracoronary injections of dl-propranolol (0.02-2 mg) dose dependently produced transient increases in coronary blood flow and subsequent depression in regional segment shortening which qualitatively resembled those produced by the dextro isomer (0.02-2 mg) and lidocaine (0.2-10 mg). Atenolol (up to 2 mg) was almost devoid of these effects. Isoproterenol-induced responses were abolished by dl-propranolol and atenolol but only incompletely blocked by d-propranolol. These results demonstrate that propranolol at high doses has direct coronary vasodilating and cardiodepressant effects in situ, and indicate that the major part of these effects can be attributed to the membrane-stabilizing action rather than beta-adrenoceptor blockade.

Effect of intracoronary captopril on coronary blood flow and regional myocardial function in dogs.

To evaluate the cardiac effect of an inhibitor of angiotensin-converting enzyme, the effect of intracoronary (i.c.) captopril on coronary blood flow and regional myocardial function was examined in the anesthetized open-chest dog. Blood flow of the left circumflex coronary artery (LCX), left ventricular pressure (LVP), aortic pressure (AoP) and regional myocardial segment length were measured continuously. Captopril i.v. (0.3 mg/kg) produced an immediate reduction in AoP and an increase in percent shortening of myocardial segments followed by a decrease in coronary vascular resistance and increases in heart rate and LVdP/dt. Reductions in LCX flow induced by i.c. angiotensin were attenuated and i.c. bradykinin-induced increases in LCX flow were augmented after captopril. On the contrary, i.c. infusion of captopril (0.01 mg/min) into the LCX caused no change in hemodynamic variables and myocardial shortening although responses to angiotensin I and bradykinin were markedly modified. These results suggest that captopril may have no direct cardiac effect.

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs.

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.

Effects of dihydroergotamine methanesulfonate on the microcirculation of the rat cremaster muscle.

Effects of dihydroergotamine on the microcirculation of the rat cremaster muscle were investigated microscopically using colour photographic technique. 1. Dihydroergotamine 10(-4) g/ml constricted arterioles of the rat cremaster. 2. Dihydroergotamine 10(-4) g/ml produced a significant contraction of venules. 3. Dihydroergotamine 10(-4) g/ml markedly inhibited the contractile response of noradrenaline 10(-6) g/ml on arterioles of the rat cremaster. The results suggest that dihydroergotamine has an appreciable vasoconstrictive action, especially upon venules, and that dihydroergotamine also has an adrenergic alpha-receptor blocking action. By means of highly sensitive negative colour film we obtained a satisfactory photograph of the rat cremaster's circulation.

Haemodynamic and haematologic effects of Acanthaster planci venom in dogs.

This study was designed to examine haemodynamic and haematologic effects of the crown-of-thorns starfish venom (Acanthaster planci venom: APV) in dogs. Severe systemic hypotension, thrombocytopenia and leukopenia were induced by APV (1.0 mg protein/kg i.v.), followed by gradual return to the baseline level within 60 min. Hypotension was presumably caused by two factors: an early decrease in systemic vascular resistance and the large reduction in cardiac output due to reduced ventricular filling. Indomethacin, a cyclooxygenase inhibitor, remarkably suppressed systemic hypotension induced by APV. The peak reduction in systemic pressure was associated with concomitant rise of plasma 6-keto-PGF1 alpha, a major stable metabolite of prostacyclin. Thus, the hypotensive effect of APV may be caused primarily by prostacyclin and/or some vasodilating prostaglandins. In contrast, thrombocytopenia and leukopenia were not affected by cyclooxygenase inhibitor, 5-lipoxygenase inhibitor or platelet activating factor (PAF) receptor antagonist. When APV was administered repeatedly, tachyphylaxis was developed in haemodynamic effects, but not in haematologic effects. These findings suggest that APV-induced hypotensive effects may occur mainly through endogenous production of vasodilating prostaglandins including prostacyclin, although APV-induced thrombocytopenia and leukopenia may be caused by other mechanism(s) unrelated to arachidonate metabolites and/or PAF.

Effects of habu (Trimeresurus flavoviridis) venom on isolated and perfused hearts of rats.

Crude habu venom decreased coronary perfusion pressure and produced a small increase in myocardial tension of isolated and perfused rat hearts. Indomethacin infusion depressed the fall in perfusion pressure caused by the venom, without affecting the increase in tension. Heated venom decreased perfusion pressure, but did not increase myocardial tension. These results suggest that crude habu venom has coronary vasodilating and positive inotropic effects, possibly through actions of a phospholipase A2 and a heat-labile component, respectively.

Cardiovascular effects of Acanthaster planci venom in the rat: possible involvement of PAF in its hypotensive effect.

Cardiovascular effects of the crowns-of-thorns starfish (Acanthaster planci) venom were examined in rats. The crude venom extracted from the spines of A. planci caused systemic hypotension associated with an increase in heart rate and a decrease in renal cortical blood flow when given i.v. The hypotensive effect of the venom was not inhibited by pretreatment with atropine, indomethacin or aprotinin, but was significantly inhibited by SRI 63-441, a platelet activating factor (PAF) antagonist. The venom caused dose-dependent vasorelaxation of the isolated rat aortic ring preparation precontracted by noradrenaline, an effect which was significantly attenuated by pretreatment with SRI 63-441, methylene blue or parabromophenacyl bromide. Denudation of the endothelium also diminished the vasorelaxing effect of the venom. Both the vasorelaxing and the hypotensive effects showed tachyphylaxis. These results suggest the release of PAF or a PAF-like substance from the endothelium by the venom.

Beneficial hemodynamic effects of nicorandil in a canine model of acute congestive heart failure: comparison with nitroglycerin and cromakalim.

Comparative hemodynamic effects of nicorandil (NCR), nitroglycerin (NTG) and cromakalim (CRM) were examined in a canine model of acute congestive heart failure (CHF). CHF was produced by injections of saponin into coronary arteries of anesthetized dogs followed by volume loading and continuous i.v. infusion of methoxamine. After the treatment, aortic blood flow (AoF), left ventricular dP/dt and myocardial segment shortening (SS) markedly decreased, while the left ventricular end-diastolic pressure (LVEDP), the right atrial pressure (RAP) and the systemic vascular resistance (SVR) increased. NCR (n = 6), NTG (n = 6) and CRM (n = 8), which were administered i.v. after production of CHF, caused a comparable reduction in LVEDP. NCR and CRM profoundly increased AoF and SS but NTG did only slightly. On the other hand, NTG and NCR but not CRM significantly reduced RAP. Intracoronary NCR (n = 8) exerted no or similar effects on SS as well as systemic hemodynamic indices to those observed with i.v. NCR despite distinct coronary vasodilation. These results indicate that NCR may exert beneficial hemodynamic effects in an experimental CHF mainly due to lessening both afterload and preload rather than the coronary vasodilating effect.