Effects of long-term verapamil therapy on serum lipids and other metabolic parameters.

Calcium antagonists have been used successfully in the management of hypertension for more than a decade, but less is known about their long-term metabolic effects. To define the impact of one calcium antagonist, verapamil, on serum lipids and other metabolic parameters, we placed 45 hypertensive patients on verapamil monotherapy and followed them for 4 to 8 years. After a mean treatment period of 5.3 years, total cholesterol and triglyceride levels were not significantly different from baseline, whereas the mean high-density lipoprotein cholesterol value increased significantly from 1.17 +/- 0.41 mmol/L at the initiation of treatment to 1.39 +/- 0.36 mmol/L at 5.3 years (p less than 0.05). Other important biochemical parameters, including serum glucose, potassium and uric acid levels were unaffected by verapamil therapy. No serious side effects or adverse cardiovascular events occurred during verapamil therapy, and there were no study dropouts. It therefore seems likely that this agent will become increasingly useful in the long-term management of essential hypertension.

Comparative hemodynamic dose-response effects of five slow calcium channel-blocking agents in coronary artery disease.

A prospective, randomized study compared the hemodynamic effects of equivalent doses of five slow calcium channel blockers (verapamil, diltiazem, nicardipine, nisoldipine, and amlodipine) in 50 patients with ischemia. After a stable control period, dose-response curves were constructed for each drug with hemodynamics measured 10 minutes after intravenous boluses. Each drug reduced mean systemic arterial pressure (P less than 0.01) and systemic vascular resistance index (P less than 0.01). The heart rate increased after nicardipine, nisoldipine, and amlodipine (P less than 0.01) but was unchanged after verapamil and reduced after diltiazem (P less than 0.01). The left ventricular filling pressure increased after amlodipine (P less than 0.05) and verapamil (P less than 0.01) but was unchanged with the other compounds. Cardiac index increased substantially after the dihydropyridines (P less than 0.01), with little change after verapamil or diltiazem. Cardiac double product fell only after verapamil and diltiazem. These studies provide quantitation of the comparative actions of acute intravenous calcium channel blockade in coronary disease.

Depressor effects of ionized calcium infusion in essential hypertension.

The circulatory effects of an acute increase in serum ionized calcium were assessed in 27 patients with mild to moderate hypertension. Following a control period of fifteen minutes with confirmed circulatory variables, 1,375 mg calcium gluconate was infused over three minutes. Systemic mean arterial blood pressure and heart rate were recorded before, at one-minute intervals during, and for five minutes following the infusion. There was a brief increase of serum ionized calcium concentration (from 1.28 +/- 0.06 mmol/liter to 1.42 +/- 0.07 mmol/liter; p less than 0.001) maximum by one minute after infusion with return toward control by a further four minutes. This was accompanied by a significantly decreased mean arterial blood pressure (from 117 +/- 8 mmHg to 110 +/- 9 mmHg at three minutes; p less than 0.05) and heart rate (from 70 +/- 11 min-1 to 63 +/- 10 min-1 at three minutes; p less than 0.01). There was a significant correlation between the change in ionized calcium and that of the systemic arterial blood pressure (r = 0.68; p less than 0.01). No major side effects were recorded. The blood pressure reduction may theoretically be related to increased membrane stabilization of vascular smooth muscle cells, the acute increase in extracellular ionized calcium impairing calcium ions influx.

A haemodynamic and radionuclide assessment of diltiazem in coronary heart disease.

To obtain multiple dose-response haemodynamic and radionuclide data on i.v. diltiazem, 12 ischaemic patients were studied during routine catheterization. At rest, following a 20 min stable control period, the effects of four doses (0.0625, 0.0625, 0.125 and 0.25 mg kg-1 diltiazem at 5 min intervals) were measured in the 3-5 min following i.v. injection. The exercise effects of the cumulative 0.5 mg kg-1 dosage were assessed by comparing a control and post drug period of supine bicycle exercise. The increase in plasma diltiazem levels correlated linearly with the administered dose and achieved therapeutic levels. There were significant dose-related reductions in systemic arterial blood pressure and vascular resistance index; the heart rate fell and cardiac stroke index increased. The calculated double-product (heart rate X systolic blood pressure) was significantly reduced. The left ventricular filling pressures, ejection fraction and cardiac volumes were unaltered. During supine bicycle exercise, the systemic diastolic blood pressure, heart rate and calculated double-product were reduced without change in other parameters. Over the dose range 0.0625-0.5 mg kg-1, diltiazem acutely increased cardiac stroke index and reduced resting heart rate. These haemodynamic data, taken together with its described coronary vasodilator activity suggest that its role in acute vasospastic angina and during angiographic procedures ought to be explored further.

Comparative haemodynamic dose-response effects of dobutamine and amrinone in left ventricular failure complicating acute myocardial infarction.

The comparative haemodynamic dose-response effects of intravenous (i.v.) amrinone and dobutamine were evaluated in 20 male patients with haemodynamic (pulmonary artery occluded pressure (PAOP) greater than 20 mm Hg) and radiographic left heart failure following a recent myocardial infarction. Following a 1-h control period, 10 patients were each randomised to amrinone (800, 1,600, or 3,200 micrograms/kg/h) or dobutamine (200, 400, or 800 micrograms/kg/h) sequentially infused for 30 min at each dose level; haemodynamic parameters were recorded at the end of each infusion period. Amrinone reduced systemic arterial blood pressure and vascular resistance index with a moderately increased heart rate; PAOP (-10 mm Hg; p less than 0.01) fell substantially without change in cardiac or stroke work indices. Dobutamine increased systemic arterial blood pressure, heart rate, and stroke work index at an unchanged PAOP; cardiac index (+0.7 L/min/m2; 25%; p less than 0.01) increased. Systemic vascular resistance index was significantly reduced by both drugs. Thus, dobutamine increased cardiac index at an unchanged PAOP; myocardial stroke work increased. Amrinone had lesser effect on cardiac pumping but reduced PAOP (preload) at an unchanged stroke work. The implications of these differential actions for the clinical therapy of myocardial infarction deserves further evaluation.

A haemodynamic study of the effects of combined slow-calcium channel blockade (nisoldipine) and beta-blockade (metoprolol) in coronary heart disease.

The interaction of a new slow-calcium blocker (nisoldipine) and the beta-blocker metoprolol was evaluated in 16 patients with stable angina. Haemodynamic parameters were determined in a control rest and exercise period. Patients were then randomised equally to nisoldipine (4-8 micrograms/kg) or metoprolol (10 mg) and the haemodynamics of monotherapy assessed; finally the second drug was administered and the effects of combination determined. At rest nisoldipine reduced systemic blood pressure and vascular resistance (P less than 0.01); heart rate, cardiac and stroke volume indices increased (P less than 0.01) at an unchanged pulmonary artery occluded pressure. Metoprolol alone reduced heart rate (P less than 0.05) and increased the pulmonary artery occluded pressure (P less than 0.05). Combination therapy reduced systemic blood pressure and vascular resistance (P less than 0.01); cardiac index and pulmonary artery occluded pressure increased (P less than 0.01) at an unchanged heart rate. The effect of combination was influenced by the order of administration; an improvement in cardiac performance was particularly evident when nisoldipine was added to metoprolol. The interaction during dynamic exercise was similar to that at rest. Thus these data indicated the haemodynamic safety of concurrent nisoldipine/metoprolol therapy; the addition of nisoldipine to metoprolol appeared to offset in part the cardiodepressant properties of beta-blockade.

A new sustained-release formulation of verapamil in the treatment of hypertension.

The study was carried out in 24 patients with mild to moderate essential hypertension to assess the antihypertensive efficiency and tolerability of a new sustained-release formulation of verapamil (tablets containing 240 mg). The trial was conducted as a single-blind crossover study for periods of 4 weeks, preceded by a 2-week placebo period, comparing sustained-release verapamil twice daily with instant-release verapamil (conventional tablets of 80 mg) mg) 160 mg twice daily. Both regimens induced a significant reduction in blood pressure and heart rate, and this effect was (particularly for sustained-release verapamil) significant from the very first day of treatment. Both formulations were well tolerated. The pharmacokinetic data obtained and the even blood pressure reduction achieved demonstrate that this new verapamil formulation has sustained-release characteristics and is sufficient as a twice-daily medication in mild/moderate essential hypertension.