Akihiro Narimatsu

Contractile proteins: possible targets for the cardiotonic action of MCI-154 a novel cardiotonic agent?

The effect on the contractile protein system of MCI-154, a novel and potent cardiotonic agent, was examined by using thin bundles of chemically skinned fibers from the guinea-pig papillary muscles. MCI-154 increased the Ca2+ sensitivity of the contractile protein system of the cardiac skinned fibers. Moreover, MCI-154 enhanced the maximum tension developed at pCa 4.4. These results suggest that an increase in responses of the contractile protein system to Ca2+ ion is, at least in part, responsible for the positive inotropic action of MCI-154.

[Antihypertensive effect of betaxolol, a cardioselective beta-adrenoceptor antagonist, in experimental hypertensive rats].

Betaxolol is a highly selective beta 1-adrenoceptor antagonist without intrinsic sympathomimetic activity. In this study, the antihypertensive effect of betaxolol was investigated in experimental hypertensive rats; and the antihypertensive mechanism was also studied. Betaxolol (1 and 10 mg/kg, p.o.) produced acute hypotensive effects in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats, deoxycorticosterone/saline hypertensive rats and normotensive rats. The effect was particularly marked in SHR. Furthermore, daily oral administration of betaxolol to SHR for 3 weeks showed sustained antihypertensive effects without producing tolerance. In pithed rats, the pressor response induced by an electrical stimulation of the spinal cord was inhibited by both betaxolol and atenolol. However, only betaxolol reduced the pressor response to norepinephrine. These findings suggest that a certain relaxing effect on peripheral vascular beds in addition to inhibition of presynaptic beta-adrenoceptors may contribute to the antihypertensive mechanism of betaxolol.

The affinity of betaxolol, a β1‐adrenoceptor‐selective blocking agent, for β‐adrenoceptors in the bovine trachea and heart

1 The specificity of betaxolol, a β‐adrenoceptor antagonist, for β1 and β2‐adrenoceptors was compared with that of other β‐antagonists, atenolol, ICI‐118551, butoxamine and (±)‐propranolol, in the bovine trachea and heart by competitive interaction with [3H]‐CGP12177 as a radioligand. 2 The radioligand Kd values were 0.75 ±0.12 and 1.60 ± 0.11 nm in the trachea and heart, respectively, and the Bmax values were 34.00 ± 4.41 and 21.54 ± 2.94 fmol mg−1 protein, respectively. 3 Using ICI‐118551, we determined the ratio of β1:β2‐adrenoceptors in the trachea and heart to be approximately 29:71 and 56:44, respectively. 4 In the trachea, a β2‐predominant tissue, betaxolol and atenolol were more selective for β1‐adrenoceptor binding sites than β2‐adrenoceptor binding sites, whereas ICI‐118551 and butoxamine were more selective for β2‐adrenoceptor binding sites. 5 The β1‐selectivity of betaxolol was 2.2 and 2.7 fold higher than that of atenolol in the bovine trachea and heart. These findings suggest that betaxolol may be useful in the treatment of hypertension, cardiac arrhythmia and angina pectoris.

Effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure in anesthetized dogs

The effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure (an index of total body venous tone), total peripheral resistance and the heart were examined in anesthetized dogs. The bolus injection of MCI-154 (10-100 micrograms/kg i.v.) caused a dose-dependent decrease in mean circulatory filling pressure and resistance to venous return. MCI-154 also decreased the mean blood pressure and total peripheral resistance, and increased cardiac output and heart rate. Right atrial pressure was reduced only by the lowest dose (10 micrograms/kg i.v.) of MCI-154. These hemodynamic effects of MCI-154, except those on mean circulatory pressure and resistance to venous return, reached a maximum with 30 micrograms/kg of the drug. Nitroglycerin (50 micrograms/kg i.v.), a venodilator, decreased mean circulatory filling pressure, resistance to venous return, mean blood pressure and total peripheral resistance, and increased heart rate. However, unlike MCI-154, nitroglycerin did not alter cardiac output and right atrial pressure. These results suggest that the venodilator effect of MCI-154, as well as the positive inotropic and vasodilator effects, could potentially benefit patients with congestive heart failure.

Improvement of postischemic contractile dysfunction of dog heart by MC1-154, a novel cardiotonic agent

The effects of MCI-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 microgram/kg per min) was more pronounced than that caused by milrinone (1 microgram/kg per min) or dobutamine (1 microgram/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.