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.

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.

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.

Cardioprotective effects of hydrolyzed bopindolol against contractile dysfunction produced by coronary stenosis and reperfusion in dogs.

The effects of the active metabolite (18-502) of bopindolol, which is a new nonselective beta-adrenoceptor antagonist, were studied on the ischemic changes in myocardial segment shortening, cardiac lactate metabolism and S-T segment of subendocardial electrocardiogram during coronary stenosis and on their recoveries after reperfusion in anesthetized dogs, and were compared with those of propranolol at a dose exhibiting a comparable degree of beta 1-blocking activity. In the presence of coronary stenosis, intravenous administration of 18-502 (5 micrograms/kg) and propranolol (0.2 mg/kg), but not saline, produced significant improvements of regional myocardial dysfunction, lactate production and S-T segment elevations in the ischemic myocardium, which were associated with significant decreases in heart rate and cardiac contractility. After release of the stenosis, administration of 18-502, but not propranolol, resulted in a significantly accelerated recovery of the ischemic segment function as compared with the control group. In rat heart homogenates, 18-502 inhibited the lipid peroxidation approximately 4 times more potently than propranolol. These data show that 18-502 exerts favorable effects during myocardial ischemia produced by coronary stenosis and that it has a cardioprotective action against the contractile dysfunction following reperfusion.

Effects of pilsicainide on systemic hemodynamics and cardiac function of anesthetized dogs.

The effects of pilsicainide, propafenone and flecainide on systemic hemodynamics and cardiac function were compared in anesthetized open-chest dogs. Pilsicainide, propafenone and flecainide given intravenously at 1 and 3 mg/kg produced dose-dependent decreases in the mean aortic pressure. The heart rate was decreased by pilsicainide and flecainide, but not by propafenone. The three drugs increased the left ventricular end-diastolic pressure and reduced the first derivative of left ventricular pressure and myocardial oxygen consumption. Pilsicainide decreased aortic, vertebral, coronary and renal blood flows in a dose-dependent manner at 1 and 3 mg/kg. Propafenone increased aortic and vertebral blood flows at 1 mg/kg and decreased coronary and renal blood flows at 3 mg/kg. Flecainide did not significantly change blood flow, except for an increase in the aortic blood flow with 3 mg/kg. The total peripheral, vertebral, coronary and renal vascular resistances were increased by pilsicainide, but not by flecainide. Propafenone decreased total peripheral and vertebral vascular resistances, but hardly affected the coronary and renal vascular resistances. The stroke volume was decreased by 1 and 3 mg/kg pilsicainide in a dose-dependent manner, and increased by 1 and 3 mg/kg propafenone, but not significantly changed by 1 or 3 mg/kg flecainide. The stroke work index was decreased by 3 mg/kg pilsicainide and 3 mg/kg flecainide. The effects of pilsicainide correlated with the changes in its plasma concentration with time. The results indicate that pilsicainide has a negative inotropic activity similar to that of propafenone and flecainide. Pilsicainide and flecainide show almost the same effects with a slightly different efficacy, while propafenone exerts different effects upon some cardiovascular functions.

Effects of adrenergic stimulants on the splenic diameter, haemoglobin content and haematocrit in anaesthetized dogs: determination of the adrenoceptor subtype responsible for changes in the splenic diameter.

Changes in splenic diameter measured by sonomicrometry in response to various adrenergic stimulants were estimated together with simultaneously measured arterial haemoglobin content (HGB) and haematocrit (HCT) in anaesthetized dogs. Splenic diameter decreased following intravenous injections (i.v.) of adrenaline, noradrenaline and phenylephrine and splenic nerve stimulation associated with increases in arterial HGB and HCT, which were significantly attenuated by prazosin i.v. After prazosin i.v., adrenaline i.v. increased splenic diameter significantly, but noradrenaline i.v. did not. Isoprenaline i.v. increased splenic diameter transiently, followed by a decrease that was abolished by prazosin i.v. During occlusion of splenic arteries and veins, adrenaline i.v. and phenylephrine i.v. did not cause any change in arterial HGB and HCT. Injection to splenic artery (i.a.) of phenylephrine induced a significant decrease in splenic diameter that was attenuated by prazosin i.a. but not by yohimbine i.a. Clonidine i.a. did not change splenic diameter. The present results indicate that splenic contraction, which is mediated through alpha 1-adrenoceptor activation, causes a significant increase in arterial HGB and HCT.

Effects of intraduodenal administration of "kyushin," a senso (toad venom)-containing drug, on systemic hemodynamics, cardiacfunction and myocardial oxygen consumption in anesthetized dogs.

The effects of "Kyushin" (KY), a Senso (toad venom)-containing drug, on the cardiovascular system were examined by intraduodenal administration of KY in anesthetized open-chest dogs. KY (3 or 10 mg/kg) dose-dependently increased the peak positive first derivative of left ventricular pressure ((+)LVdP/dt) and mean aortic pressure, and decreased the left ventricular end-diastolic pressure (LVEDP). Myocardial oxygen consumption (MVO2) and heart rate (HR) were not significantly influenced by KY. KY produced a cardiotonic effect without any increase in MVO2, because the increase in MVO2 due to the cardiotonic effect of KY may have been cancelled by a decrease in MVO2 due to reduction of preload and the lack of increase in HR. In order to clarify the relationship between the cardiovascular effects of KY and the drug concentration in plasma, the concentration of anti-bufalin IgG reactive substance (BRS) in plasma was measured by enzyme immunoassay. The maximum BRS concentrations 20 min after administration of 3 and 10 mg/kg KY were dose-dependent. From the relationship between changes in (+)LVdP/dt and changes in BRS concentration after administration of KY, it is inferred that the effective concentration of BRS in plasma at which KY produces a cardiotonic effect in dogs is approximately 2-3 ng/ml.

Regional vascular responses to thromboxane A2 analogue and their blockade with vapiprost, a selective thromboxane receptor blocking drug, in anesthetized dogs.

Regional vascular responses to the thromboxane A2 analogue U46619 and effects of the selective thromboxane receptor blocking drug vapiprost on these responses were examined in anesthetized dogs. Hemodynamic responses to U46619 (0.5 micrograms/kg into the left atrium), norepinephrine (NE, 0.3 microgram/kg, i.v.) and angiotensin II (AII, 30 or 60 ng/kg, i.v.) were periodically tested before and after administration of vapiprost (10, 30 or 100 micrograms/kg, i.v.) or its vehicle. In the absence of vapiprost, U46619 increased total peripheral (TPR), vertebral (VR), coronary (CR) and renal (RR) vascular resistance by 60.1 +/- 4.7%, 33.6 +/- 4.9%, 15.3 +/- 1.3% and 120.8 +/- 17.4%, respectively, indicating that vasoconstrictor responses to U46619 were most prominent in the renal vascular bed as compared to those in the vertebral or coronary vasculatures. Vapiprost as well as the vehicle did not affect the base-line hemodynamics. However, vapiprost apparently inhibited the U46619-induced vasoconstriction in all measured vascular beds in a dose-related manner without attenuating vasoconstrictor responses to NE compared to the inhibitions of VR and CR. These results demonstrate that there was a regional difference both in the vasoconstrictor responses to U46619 and in the blocking effects of vapiprost, and indicate that vapiprost is a potent and selective antagonist for thromboxane receptors in vivo.

Simultaneous measurement of renal blood flow of the outer and inner cortex by laser-Doppler flowmetry in anesthetized dogs: effect of enalapril diacid.

Renal hemodynamic effects of the angiotensin-converting enzyme inhibitor enalapril diacid (30 micrograms/kg, i.v.; n = 8) were examined using laser-Doppler flowmetry in anesthetized dogs. Two laser-Doppler flowmetry probes were applied simultaneously to measure the renal blood flow of the outer and inner cortex. Changes in cortical renal blood flow, obtained by the laser-Doppler flowmetry method, were intimately related to those in total renal blood flow measured with the electromagnetic flow probe during occlusion of the abdominal aorta or after administration of angiotensin II, norepinephrine, acetylcholine or dopamine. Enalapril diacid produced a significant increase in total renal blood flow, despite moderate hypotension. The blood flow of the inner cortex significantly increased by 21% following enalapril diacid, while that of the outer cortex did not. These data indicate that there may be a regional difference in the intrarenal vasodilating effect of enalapril diacid. These results also demonstrate that the laser-Doppler flowmetry method is suitable for the continuous measurement of directional changes in both outer and inner cortical blood flows.

Effects of denopamine with or without diltiazem on the ischemic heart of anesthetized dogs.

Effects of denopamine with or without diltiazem on the ischemic heart were investigated in anesthetized open-chest dogs. Partial occlusion of the left circumflex coronary artery (LCX) produced significant decreases in LCX flow and regional myocardial segment shortening rate (%SS) in the LCX-perfused area, and a significant increase in left ventricular enddiastolic pressure (LVEDP). Heart rate (HR) and mean aortic pressure (mAoP) were not altered, but aortic flow (AoF), positive first derivative of left ventricular pressure ((+)LVdP/dt), stroke volume (SV), stroke work index (SWI) and double product showed a tendency to decrease. Total peripheral vascular resistance (TPR) tended to increase. During coronary stenosis, saline infusion (vehicle group) did not change any parameter, but diltiazem infusion (diltiazem group) decreased HR, mAoP, TPR and double product and increased SV and SWI. Under these conditions, denopamine infusion produced increases in HR, mAoP, AoF, (+)LVdP/dt and double product and decreases in LVEDP and TPR in both groups. %SS in the left anterior descending coronary artery-perfused area was increased, but %SS in the LCX-perfused area was slightly decreased in both groups. SV and SWI were decreased by denopamine infusion in the vehicle group, while they were increased in the diltiazem group. Differences in changes in SV and SWI between the groups were statistically significant. Results suggest that combined treatment of denopamine and diltiazem may exert an advantage in alleviation of heart failure due to coronary stenosis.

Comparative studies of the systemic hemodynamics and myocardial oxygen consumption of FRC 8653, a new Ca++ channel blocker, and nifedipine in anesthetized dogs.

Effects of FRC 8653, a new dihydropyridine derivative, on regional blood flow, cardiac function and myocardial oxygen consumption were examined and compared with those of nifedipine in anesthetized open-chest dogs. Intravenous administration of FRC 8653 at doses of 1, 3 and 10 micrograms/kg dose-dependently decreased aortic pressure and increased aortic, vertebral and coronary blood flow similar to nifedipine. No significant change was observed in left ventricular end-diastolic pressure, left ventricular positive dP/dt and heart rate following i.v. administration of FRC 8653. Myocardial oxygen consumption was dose-dependently decreased by FRC 8653. When changes in mean aortic pressure and aortic and coronary blood flow were compared at the same dose of 10 micrograms/kg i.v., both FRC 8653 and nifedipine showed almost the same degree of reduction of mean aortic pressure, but the time from drug administration to peak responses and the duration for which half the maximal effects were maintained, were significantly longer with FRC 8653 than nifedipine. Results suggest that FRC 8653 may be useful for the treatment of patients with hypertension and ischaemic heart disease.

Cardiovascular effect of a senso (toad venom) - containing drug in anesthetized dogs (2): Influence of propranolol.

Effects of a Senso (toad venom)-containing drug KY on systemic hemodynamics were examined, and participation of beta-adrenoceptor in its action was evaluated by using propranolol in anesthetized dogs. KY produced a positive inotropic action, and decreased total peripheral (TPR) and coronary vascular resistances (CR), while renal vascular resistance (RR) was increased. After propranolol, KY significantly increased TPR, CR, vertebral vascular resistance and RR. KY-induced positive inotropic action was partly diminished but not abolished by beta-blockade. These results indicate that the beta-adrenergic action may be involved in the vasodilating effect of KY and partly in the positive inotropic action.

Cardiac effects of beta-2 adrenoceptor stimulation with intracoronary procaterol in the absence and presence of regional myocardial ischemia in dogs.

To evaluate consequences of cardiac beta-2 adrenoceptor stimulation on coronary hemodynamics and regional myocardial function assessed by sonomicrometry in the normal and regionally ischemic heart, the effects of administration of procaterol, a selective beta-2 adrenoceptor agonist, into the left circumflex coronary artery (LCX) were examined in the absence and presence of a stenosis of the LCX in anesthetized open-chest dogs. The stenosis of the LCX was made sufficient to decrease percent segment shortening in the LCX-perfused region to around 2 to 3%. When coronary stenosis was absent, intracoronary infusion of procaterol (6.7 ng/min for 15 min) produced significant increases in LCX flow and myocardial segment shortening in the infused region without changes in global hemodynamics. During coronary stenosis, on the contrary, intracoronary procaterol at the same dose significantly deteriorated regional myocardial dysfunction without changing LCX flow, global hemodynamics and cardiac lactate metabolism. These changes induced by procaterol were not observed in the dogs treated with a selective beta-2 antagonist, erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol. These results suggest the presence of functional beta-2 adrenoceptors in the canine heart both with and without myocardial ischemia.

Effects of a senso (toad venom) containing drug on systemic hemodynamics, cardiac function and myocardial oxygen consumption in anesthetized dogs.

Effects of a Senso (toad venom)-containing drug, KY, on cardiovascular system were examined in anesthetized open-chest dogs. KY increased aortic pressure, peak positive first derivative of left ventricular pressure, stroke work index, percent segment shortening in left ventricular myocardium and myocardial oxygen consumption, and decreased heart rate and total peripheral vascular resistance (TPR). Propranolol augmented the increase in aortic pressure with KY, inhibited the increase in aortic flow with KY and reversed KY-induced decrease in TPR to an increase. These results indicate that KY has positive inotropic and vasodilating actions possibly originating from both digitalis- and adrenaline-like action of a Senso.

Regional vasodilating effects of spirapril diacid and enalapril diacid in anesthetized dogs.

The acute regional hemodynamic effects of spirapril diacid, a novel nonsulfhydryl angiotensin-converting enzyme inhibitor, and enalapril diacid at an equidepressor dose were examined in anesthetized dogs by simultaneously measuring renal, coronary, vertebral arterial and aortic blood flow. Spirapril diacid (30 micrograms/kg, i.v.) lowered aortic pressure and increased aortic and renal blood flow associated with no marked change in heart rate, myocardial contractility, vertebral and coronary blood flow in a similar manner to enalapril diacid (30 micrograms/kg, i.v.). Both inhibitors thus produced an increase in stroke volume and a decrease of the rate-pressure product. The decrease of renal vascular resistance after administration of both agents was greater than that in vertebral and coronary vascular beds. A relatively more prolonged renal vasodilatation and a shortened coronary vasodilatation were seen with spirapril diacid as compared with enalapril diacid, despite practically identical reductions in total peripheral resistance. Each of the drugs markedly inhibited the pressor and renal vasoconstrictor responses to angiotensin I. These results indicate that the two inhibitors exhibit a similar profile of regional differences in vasodilatory effects, although they might display different durations of regional vasodilatation.

Effect of polyoxyethylene-modified superoxide dismutase on recovery of myocardial dysfunction after coronary stenosis in dogs.

The effects of superoxide dismutase modified with polyoxyethylene (SOD-POE) on impairment of myocardial segment shortening (SS) during coronary stenosis plus pacing-induced tachycardia (CSPT) and the recovery after reperfusion was examined in anesthetized dogs. SOD-POE or saline was administered i.v. 30 min before reperfusion. Changes in hemodynamic variables and SS by CSPT were similar in both groups. However, the SOD-POE group showed improved recovery of SS compared with the control group. Results indicate that oxygen-derived free radicals may partially be involved in the genesis of myocardial dysfunction after CSPT-induced regional ischemia.

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.

Glutathione S-transferases and chloroform toxicity in streptozotocin-induced diabetic rats.

The glutathione S-transferase activity in liver and kidney cytosol was significantly decreased in short term diabetes induced with streptozotocin, whereas no decrease in the transferase was observed in phenobarbital-treated diabetic rats. Toxicity of chloroform was potentiated in streptozotocin- or phenobarbital-treated rats. The decrease in liver cytosolic and microsomal glutathione S-transferase activity was observed in long term diabetic rats, and only microsomal transferase activity was restored by insulin treatment. There was no release of glutathione S-transferases into the serum in the diabetic rats, and the transferases were not inhibited by streptozotocin in vitro. These results showed that glutathione S-transferase activity decreased during diabetes, and this decrease may contribute to altering drug metabolism and toxicity in diabetes.