Assessment of the bradycardic and inotropic properties of ST 567 using a new scheme of administration.

In 10 patients undergoing diagnostic cardiac catheterisation a bolus of 15 mg ST 567 was administered intravenously in 1.5 min followed by a 30 min infusion of 7.5 mg. The maximal plasma level was 343 +/- 131 ng ml-1 (mean +/- s.d.) 1 min after bolus injection and stabilised around 179 ng ml-1 thereafter. Heart rate decreased from 71 +/- 10 beats min-1 at baseline to 66 +/- 10 beats min-1 at the end of the bolus injection (-7%). This decrease in heart rate persisted during the whole observation period. Also there was an 8% reduction in peak positive first derivative of LV pressure. Cardiac output measured by thermodilution during atrial pacing decreased from 5.9 +/- 1.1 l min-1 to 5.3 +/- 0.7 l min-1 (P less than 0.02). In 3 patients with the largest decrease in cardiac output, the end diastolic LV pressure at the end of the observation period decreased, which may reflect a decrease in pre-load. Only in 1 patient the decrease in end diastolic LV pressure exceeded twice the standard deviation of the random error component of duplicate measurements. Thus, although normal therapeutic plasma levels were achieved, ST 567 demonstrated negative inotropic properties independent of changes in heart rate with this scheme of administration.

Coronary and systemic hemodynamic effects of intravenous nisoldipine.

Systemic and coronary hemodynamic effects of the new dihydropyridine calcium antagonist nisoldipine were studied over a 30-minute period in 12 patients with angina pectoris. Previously instituted beta-blocker therapy was continued. Nisoldipine was administered in an intravenous bolus of 6 micrograms/kg over 3 minutes. Heart rate increased as mean aortic pressure and systemic vascular resistance decreased in all patients. Cardiac output increased significantly, from 5.8 +/- 0.3 to 7.9 +/- 0.5 liters/min, 10 minutes after nisoldipine infusion. These trends were maintained over the 30-minute observation period. Coronary sinus blood flow increased from 103 +/- 11 to 139 +/- 13 ml/min immediately after nisoldipine, but had returned to the control level by 30 minutes, as had the reduction in coronary vascular resistance. Myocardial oxygen consumption and heart rate-systolic blood pressure product did not change significantly. Nisoldipine is a potent peripheral and coronary vasodilator free of major myocardial depressant effects after acute intravenous administration. The systemic vasodilatory effects appear to outlast the coronary effects over 30 minutes.

Maintenance of increased coronary blood flow in excess of demand by nisoldipine administered as an intravenous infusion.

Systemic and hemodynamic effects of nisoldipine, administered as a 4.5-micrograms/kg intravenous bolus over 3 minutes followed immediately by an infusion of 0.2 microgram/kg/min over 30 minutes, were studied in 13 patients undergoing diagnostic catheterization for suspected coronary artery disease or follow-up catheterization after coronary angioplasty. Responses to the drug tended to be exaggerated in the first 8 minutes of the infusion, but thereafter produced a steady state, with heart rate increased by 14 +/- 3% at 16 minutes and by 15 +/- 3% at 24 minutes (p less than 0.05), mean aortic pressure decreased 12 +/- 2% and 13 +/- 3% at the same times (p less than 0.05) and coronary venous blood flow increased by 31 +/- 5% and 34 +/- 6% (p less than 0.05). Myocardial oxygen consumption and the heart rate-systolic aortic pressure product were unchanged and cardiac output and stroke volume were significantly increased. Study during matched coronary sinus pacing produced similar trends. Nisoldipine is a potent coronary and peripheral vasodilator that maintains an increase in myocardial oxygen supply in excess of demand when given as an intravenous infusion.

The haemodynamic effects of nifedipine, verapamil and diltiazem in patients with coronary artery disease. A review.

Of the 3 most widely used calcium antagonists--nifedipine, verapamil and diltiazem--nifedipine is the most potent arterial vasodilator. Increases in cardiac output and coronary blood flow following nifedipine administration result in part from the afterload reduction. Reflex adrenergic stimulation produces an increase in heart rate and masks a direct inhibitory effect on myocardial contractility. The negative inotropic action of nifedipine is observed during intracoronary administration or may be made apparent by concurrent beta-blocker therapy. While verapamil is also a potent vasodilator, negative inotropic and dromotropic properties are more apparent in therapeutically used dosages. Reflex sympathetic activation is also triggered by verapamil, with an offsetting of the negative inotropic effects such that little change in cardiac output results. A decrease in myocardial oxygen consumption, with or without a decrease in coronary sinus blood flow, has regularly been observed following verapamil administration. Reduced oxygen demand appears to be a major mechanism of its antianginal effect. The heart rate X systolic pressure product is decreased both by the fall in arterial pressure and, particularly after oral administration, by a decrease in heart rate. Diltiazem produces similar haemodynamic and electrophysiological effects to those of verapamil but has less potency in inducing arterial dilatation and more of a tendency to slow the heart rate. Diltiazem does not appear to cause significant increases in coronary blood flow or bring about improvement in ejectional and isovolumic indices of myocardial contraction - evidence of its intrinsic negative inotropic effect.

Acute coronary hemodynamic effects of equihypotensive doses of nisoldipine and diltiazem.

The hemodynamic effects of nisoldipine and diltiazem were investigated in two groups of patients undergoing investigation for suspected coronary artery disease. Emphasis was placed on the coronary hemodynamic changes. Approximately equihypotensive doses of these two calcium channel blockers, nisoldipine (6 micrograms/kg) and diltiazem (500 micrograms/kg) were given intravenously. Although both drugs decreased peak systolic pressure by 28% and 24%, respectively, heart rate increased with nisoldipine (68 +/- 9 to 82 +/- 12 bpm) and remained unchanged with diltiazem (70 +/- 9 to 67 +/- 10 bpm). Nisoldipine increased mean coronary sinus blood flow from 146 +/- 40 to 176 +/- 35 ml/min and great cardiac vein flow from 87 +/- 20 to 109 +/- 24 ml/min, producing a significant reduction in the calculated global (from 0.79 +/- 0.2 to 0.43 +/- 0.12 mmHg min/ml) and regional (from 1.43 +/- 0.2 to 0.70 +/- 0.13 mmHg min/ml) coronary vascular resistances. There were no significant flow changes when corrected for heart rate. Global and regional myocardial oxygen consumptions were not significantly altered. Diltiazem had no significant effects on heart rate or global and regional blood flows, although the vascular resistances decreased by 32% and 35%, respectively. Diltiazem reduced global and regional arterio-coronary sinus oxygen differences, resulting in significant decreases in global (from 14.9 +/- 4.7 to 12.1 +/- 2.3 ml/min) and regional (from 5.6 +/- 0.9 to 5.2 +/- 1.2 ml/min) myocardial oxygen consumptions. The major difference between the drugs was in heart rate, despite the similar reductions in aortic pressure. The lack of a positive chronotropic response after diltiazem may explain the reduction in myocardial oxygen consumption.

Emergency coronary angioplasty in refractory unstable angina.

We performed percutaneous transluminal coronary angioplasty as an emergency procedure in 60 patients with unstable angina pectoris that was refractory to treatment with maximally tolerated doses of beta-blockers, calcium antagonists, and intravenous nitroglycerin. The initial success rate for angioplasty was 93 per cent (56 patients). There were no deaths related to the procedure, although total occlusion occurred in four patients. Despite emergency bypass grafting, all four sustained a myocardial infarction. All the patients were followed for at least six months. Late cardiac death occurred in one patient, whereas eight had recurrent angina pectoris. There was no progression to myocardial infarction. The restenosis rate was 28 per cent (13 of 46) in the patients with initially successful coronary angioplasty who had repeat angiography. Improved cardiac functional status after sustained successful coronary angioplasty was demonstrated by an almost normal capacity on bicycle exercise testing and the absence of ischemia during thallium isotope studies in 80 per cent. We conclude that emergency percutaneous transluminal coronary angioplasty may be useful for the treatment of selected patients with unstable angina pectoris who are unresponsive to intensive pharmacologic treatment.