Shoichi Imai

Cardiac actions of methoxamine with special reference to its antagonistic action to epinephrine.

The cardiac action of large doses of methoxamine and its antagonistic action to epinephrine were studied, using a dog heart-lung preparation. In doses of 4 mg. and above, methoxamine showed a marked negative inotropic action, while it produced only a slight decrease in the heart rate. Pretreatment of animals with 0.1 mg./Kg. of reserpine did not modify the inotropic action, but the decrease in the heart rate disappeared. Simultaneous with these changes, a decrease in the coronary flow and a rise of the pulmonary arterial pressure were observed. Methoxamine in doses of 1 mg. and more abolished both the positive inotropic and the positive chronotropic actions of epinephrine. The negative inotropic action of methoxamine was ascribed to a nonspecific, as yet undetermined mechanism, and the antagonistic action was ascribed to the competitive antagonism at the receptor site (thus methoxamine may be looked upon as a blocking agent of adrenergic β receptor). The weak negative chronotropic action was taken to be an expression of the blockade of the humoral effects of the intrinsic sympathomimetic amines.

Effective Plasma Concentrations of Antiarrhythmic Drugs Against Sustained Halothane-Adrenaline Arrhythmia in Dogs

Summary We determined the minimum effective plasma concentrations of several antiarrhythmic agents against canine halothane-adrenaline arrhythmia. Sustained ventricular tachycardia was produced by continuous adrenaline infusion at rates of 1.5 to 4 μg/kg/min under 1.5% halothane anesthesia. Procainamide, 20 mg/kg, produced ventricular fibrillation in three of nine dogs. Disopyramide, 3 mg/kg, suppressed the arrhythmia in nine of 11 dogs at a minimum effective plasma concentration of 4.2 μg/ml, but produced ventricular fibrillation in the remaining two dogs. Phenytoin, 5 mg/kg, was effective at a minimum concentration of 12 μg/ml. Lidocaine, 10 mg/kg, suppressed the arrhythmia at a minimum concentration of 15 μg/ml, which is much higher than the human toxic plasma level. These drugs may have suppressed the adrenaline arrhythmia by inhibiting the sodium channel, because their effective concentrations were very close to membrane-stabilizing concentrations in vitro. Small doses of 30 μg/kg propranolol and 0.1 mg/kg N-696, two β-blockers, and 0.1 mg/kg verapamil, a calcium channel blocker, yielding a concentration of 0.03 μg/ml, suppressed the arrhythmia, probably by indirectly or directly blocking the calcium channel.

Effects of l- and d-propranolol on the ischemic myocardial metabolism of the isolated guniea pig heart, as studied by 31P-NMR.

Summary Using 31P nuclear magnetic resonance (NMR) spectroscopy (acquisition time of 3 min). we studied the effects of l- and d-propranolol on the ischemic derangement of myocardial energy metabolism in the isolated perfused guinea pig heart. The myocardial pH and concentration of high-energy phosphate were used as measures of the energy metabolism. Cardiac pH progressively declined during ischemia from 7.41 ± 0.04 to 7.13 ± 0.05, 6.91 ± 0.04, 6.74 ± 0.04, and 6.61 ± 0.04 (before ischemia and 3, 6, 9, and 12 min after ischemia, respectively). After 3 min of reperfusion, pH rapidly returned to 7.42 ± 0.04. Creatine phosphate (CP) and adenosine triphosphate (ATP) contents were reduced, while inorganic phosphate (Pi) contents were increased during ischemia. Whereas CP and Pi contents were restored to the normal values after reperfusion, the recovery of ATP contents was poor. Both l- and d-propranolol (10-6M) significantly suppressed the fall of the myocardial pH. Changes in the high-energy phosphate contents were also attenuated by l- and d-propranolol. These results suggest that not only l-propranolol, but also d-propranolol can produce beneficial effects on the ischemic derangements of myocardial energy metabolism.

Modification by LY 83583 and methylene blue of relaxation induced by nitric oxide, glyceryl trinitrate, sodium nitroprusside and atriopeptin in aortae of the rat, guinea-pig and rabbit

1. The relaxation by nitroglycerin (GTN) and nitric oxide (NO) of aortic smooth muscles from rabbit and rat contracted by phenylephrine was inhibited by LY 83583 (LY) and methylene blue (MB) (the same applied to guinea-pig aorta), while the relaxation by SNP was not inhibited in rabbit. The relaxation by ANP was not inhibited. 2. All these agents produced concentration-dependent increases in cyclic GMP. While the increases by GTN and NO were inhibited by LY and MB, the increases by SNP were inhibited only in rat and those by ANP were not inhibited. 3. Thus, LY behaved essentially similar to MB, indicating that the substance is an inhibitor of activation of soluble guanylate cyclase by NO and NO-related vasodilators. It was assumed that, like MB, LY facilitated intracellular release of NO from SNP in rabbit.

Effects of parathyroid hormone and related polypeptides on the heart and coronary circulation of dogs.

Summary The effects of parathyroid hormone and related polypeptides on the heart were examined using the canine heart-lung preparation supported by a donor. Synthetic bovine parathyroid hormone (PTH) containing 34 amino acids [PTH-(1–34)] and natural bovine PTH containing 84 amino acids [PTH-(1–84)] showed slight positive chronotropic and inotropic action and prominent coronary vasodilator action. The effects of the two compounds were very similar. The cardiac stimulatory action was not blocked by pindolol. The coronary vasodilation occurred without increase in the myocardial oxygen consumption, suggesting that it is due to a direct action on the coronary vasculature. All effects occurred soon after intra-arterial injection, lasted only about 20 min, and were not accompanied by changes in plasma Ca and Pi levels. Fragments of PTH, PTH-(24–34) containing 11 amino acids, PTH-(24–28) containing 5 amino acids, and PTH-(25–27) containing 3 amino acids showed very weak transient coronary dilatory action without cardiac stimulatory effects.

Adrenoceptor-blocking activity and cardiohemodynamic effects of carvedilol in animals.

Summary: The β-blocking activities of a new β-adrenoceptor blocking drug, carvedilol, evaluated in isolated atria and trachea of the guinea pig were 2.0 (β1) and 3.2 times (β2), respectively, as potent as those of propranolol. Carvedilol exhibited the α-blocking activities in the aorta of guinea pigs and rats. Carvedilol was 2 and 50 times less potent in guinea pigs and rats, respectively, than prazosin as an α-blocker. Thus, the α-blocking activities were twice as potent as the β-blocking activity in the rat and one-fifth that of the β-blocking activity in the guinea pig. In anesthetized open-chest dogs, the β-blocking activity of carvedilol was 1.5 times more potent than that of propranolol and had 3.8 times the α-blocking activity. Thus, carvedilol is a nonselective β-blocking drug with a potent α-blocking activity. Carvedilol and propranolol showed dose-dependent and significant decreases in the blood pressure, total cardiac output, left ventricular pressure, dp/dt, heart rate, coronary flow, and oxygen consumption in anesthetized open-chest dogs. Carvedilol decreased the total peripheral resistance significantly (the decrease was not proportional to the decreases in the blood pressure at high doses), while propranolol increased it significantly and dose-dependently. These results indicate the importance of α-adrenoceptor blocking activity in the decrease in blood pressure produced by carvedilol.

Contribution of activation of K+ channels to glyceryl trinitrate-induced relaxation of rabbit aorta.

1. Possible contribution of K+ channel opening to the relaxation by glyceryl trinitrate (GTN) was examined using isolated rabbit aorta. 2. While glibenclamide and apamin failed to affect relaxation by GTN, both charybdotoxin (ChTx) and iberiotoxin (IbTx) effectively attenuated GTN-induced relaxation. 3. The increase in cGMP produced by GTN was not attenuated by ChTx and IbTx. 4. The inhibitory effect of ChTx on GTN-induced relaxation was not reduced in the presence of zaprinast, indicating that cGMP but not GMP was responsible for activation of the K+ channel. 5. Okadaic acid, a selective inhibitor of protein phosphatase 2A, had no effect on the relaxation by GTN. These results indicate that, though small in degree, activation of a ChTx-sensitive K+ channel (large conductance Ca(2+)-activated K+ channel) is involved in the GTN-induced relaxation in rabbit aorta.

Effects of beta-blockers on the fall of pH in the early phase of ischemia in the isolated perfused rat heart: a nuclear magnetic resonance study.

To elucidate the role played by catecholamines in the early phase of ischemic derangement of the myocardial energy metabolism, effects of beta-blockers (propranolol, pindolol, and celiprolol) and isoproterenol, and of pretreatment with reserpine and 6-hydroxydopamine (6-OHDA), were studied using the isolated perfused rat heart. beta-Blockers and isoproterenol were infused for 12 min prior to induction of global ischemia. The myocardial energy consumption rate was assessed by calculating the product of left ventricular pressure and heart rate (LVP x HR). The myocardial cell creatine phosphate (CP), ATP and pH were determined with 31P nuclear magnetic resonance (31P-NMR). Global ischemia induced by cross-clamping of the aortic inflow line for 15 min resulted in falls in CP, ATP, and pH. Propranolol (6 x 10(-8) and 1.8 x 10(-7) mol/min) and pindolol (6 x 10(-7) mol/min) produced a decrease in LVP x HR and suppressed the pH fall during ischemia. Celiprolol was without significant effects on these two parameters. Isoproterenol (6 x 10(-12) mol/min) produced an increase in LVP x HR and tended to accelerate the pH fall. Catecholamine depletion with reserpine or 6-OHDA produced no beneficial effects on the pH fall. It was concluded that the beneficial effects of beta-blockers on the pH fall during early ischemia were not due to the specific beta-blocking action but to the nonspecific cardiodepressant effects of these compounds.

Antiarrhythmic effects of bupuranolol against canine ventricular arrhythmias induced by halothane-adrenaline or two-stage coronary ligation.

Summary We compared the β-adrenoceptor blocking actions of bupuranolol and propranolol using the response to isoprenaline of the strength of contraction of the canine blood-perfused ventricular muscle, of the rate and strength of contraction of the isolated guinea pig heart and of a guinea pig tracheal ring preparation. The potency ratios of bupuranolol to propranolol were 3.6, 3.0, 3.4, and 2.4, respectively. Bupuranolol decreased the maximum dV/dt of the canine ventricular action potential and had no sympathomimetic action. Bupuranolol effectively suppressed halothane-adrenaline ventricular arrhythmias in the dog, reflecting its potency as a β-adrenoceptor antagonist. In contrast, bupuranolol did not suppress ventricular arrhythmias induced by two-stage coronary ligation in the dog. Compared to propranolol and certain other antiarrhythmic drugs, bupuranolol had weaker effects on prolonging the effective refractory period than on the maximum dV/dt of canine ventricular muscle. This suggests that lengthening of the refractory period may be important for suppressing the two-stage coronary ligation arrhythmia and that the mechanism of this arrhythmia might be reentry.

Effects of spiraprilat, an angiotensin-converting enzyme inhibitor, on anesthetized dogs in a new model of acute left ventricular failure.

Summary Spiraprilat, a new angiotensin-converting enzyme (ACE) inhibitor, was compared with enalaprilat for its ability to improve left ventricular (LV) function and metabolism in anesthetized open-chest dogs with a new model of acute LV failure (ALVF) induced by embolization of the left coronary artery with 50 μm plastic micro-spheres followed by intravenous (i.v.) infusion of methoxamine. With this procedure, LV end-diastolic pressure (LVEDP) increased from 4.2 ± 0.7 to 12.8 ± 1.3 mm Hg and remained at ±12 mm Hg throughout the experiment. Cardiac output (CO) decreased from 1.25 ± 0.12 to 0.79 ± 0.06 and 0.55 ± 0.02 L/min at 30 and 90 min after meth-oxamine infusion, respectively. L±dP/dtmax and dP/dt/P decreased, while total peripheral resistance (TPR) increased. These hemodynamic changes indicated establishment of stable ALVF of a moderate degree. More over, decreases in myocardial lactate consumption and contents of creatine phosphate in the myocardium indicated the existence of moderate ischemia. The new ACE inhibitor, spiraprilat, as well as enalaprilat (30 μg/kg i.v.) effectively decreased mean aortic pressure (30%), LVEDP (20%), and TPR (30%) and increased stroke volume (SV) CO, and dP/dt/P. Both agents decreased myocardial oxygen consumption (20%) and caused a significant increase in myocardial creatine phosphate contents. These data indicate that the beneficial effects of both inhibitors extended not only to LV function but also to myocardial energy metabolism in ALVF.