1. The haemodynamic effects of cilnidipine, a new calcium channel blocker, were examined in a canine model of acute congestive heart failure and were compared with those of nicardipine at equihypotensive doses. 2. The model was prepared by injections of saponin into coronary arteries of anaesthetized open-chest dogs followed by volume loading and continuous i.v. infusion of methoxamine. After the treatment, aortic blood flow (AoF) and left ventricular dP/dt markedly decreased, while left ventricular end-diastolic pressure (LVEDP), right atrial pressure and systemic vascular resistance (SVR) increased. Cilnidipine (0.3, 1.0 and 3.0 micrograms/kg per min), nicardipine (0.3, 1.0 and 3.0 micrograms/kg per min) or the respective vehicle was given i.v. after accomplishment of heart failure. 3. These drugs both produced a comparable reduction in aortic pressure and an increase in AoF associated with profound decreases in LVEDP, SVR and coronary vascular resistance. In contrast, administration of nicardipine was associated with significant increases in heart rate and cardiac contractility but that of cilnidipine was not. 4. These results indicate that cilnidipine as well as nicardipine can exert beneficial haemodynamic effects in a model of acute heart failure probably through lessening afterload and cilnidipine may moderate reflex-induced sympathetic stimulation.
The influence of extracellular Ca2+ concentration on contractile responses of aortae isolated from diabetic rats to KCl and alpha-adrenoceptor agonists was compared with that of non-diabetic rat aortae. Diabetic rats 6 weeks after administration of streptozotocin showed significantly lower body weight and higher plasma glucose concentration, but the protein content per each aortic ring preparation was not significantly different from that of non-diabetic preparation. Both diabetic and non-diabetic aortae showed concentration-dependent contractile responses to norepinephrine, which were concentration-dependently inhibited by prazosin. On the other hand, clonidine induced small contractions in both aortae, which tended to be more inhibited by prazosin than yohimbine. In non-diabetic aortae, the contractile responses to KCl, norepinephrine, methoxamine and clonidine were significantly greater with 2.5 mmol/l of extracellular Ca2+ than 1.25 mmol/l. In diabetic aortae, however, the contractile responses were not significantly influenced by changes in extracellular Ca2+ concentration. Additionally, the contractile responses to each agonist were markedly greater in non-diabetic aortae than diabetic ones. The present results indicate that the contractions of diabetic vasculature do not respond to changes in extracellular Ca2+ concentration, suggesting that there may be some impairment of Ca2+ related mechanisms.
1. beta-Adrenoceptor blocking activities of nipradilol, its four optical isomers (RR, RS, SR, SS) and denitro nipradilol were evaluated using pig isolated coronary arteries. 2. (-)-Isoprenaline produced concentration-dependent relaxations of the arteries, which were antagonized by nipradilol, its four optical isomers or denitro nipradilol under KCl-induced contracture. 3. The order of pA2 values for beta-adrenoceptor blocking activities was SR > nipradilol > SS > or = denitro nipradilol > RR > RS. 4. The nitroxy group in nipradilol appears to enhance its beta-adrenoceptor blocking activity, because the beta-adrenoceptor blocking activity of nipradilol was more potent than that of denitro nipradilol. 5. Isomers that have the S configuration (SR, SS) at the 2' position (having a hydroxyl group) in the aryloxypropanolamine showed more potent beta-adrenoceptor blocking activity than isomers that have the R configuration (RR, RS). 6. Isomers that have the R configuration (SR, RR) at the 3 position (having a nitroxy group) in the benzopyran ring showed more potent beta-adrenoceptor blocking activity than those with the S configuration (SS, RS). 7. It is suggested that the difference in configuration of the chemical structure of nipradilol may result in variations of binding affinity for the beta-adrenoceptor.
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.
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