Calcium-entry blockade, beta-adrenergic blockade and the reflex control of circulation.

THE INCREASING USE of calcium-entry blocking agents requires that their pharmacologic interaction with other cardiovascular drugs be carefully investigated. Although marketed in this country for its antiarrhythmic properties, verapamil is a potent dilator of vascular smooth muscle and has proved effective in the management of stable angina pectoris, both alone'13 and in combination with f3-adrenergic blocking agents.4' In vitro studies have shown that verapamil has significant negative inotropic, chronotropic and dromotropic effects.6 Clinical studies in patients with wellpreserved ventricular function have documented reflex sympathetic stimulation in response to vasodilation that usually compensates for any expected depression of left ventricular performance.7 8 However, verapamil has produced marked depression of left ventricular function in patients with poor left ventricular function.9 Beta-adrenergic blocking drugs also have negative chronotropic and dromotropic properties, as well as potentially negative inotropic properties. Although these effects are similar to those of the calcium blockers, their pharmacologic site of action is different. At the cellular level, calcium-entry blockers uncouple excitation-contraction, whereas 3-adrenergic blockers competitively antagonize the f-adrenergic membrane receptor. There is legitimate concern about the potential deleterious effects of combination of these independently useful antianginal therapies. Addition of a 3-adrenergic blocking drug may blunt the reflex f-adrenergic stimulation that occurs with calcium-entry blockers, thereby unmasking the latter drug's myocardial depressant effect. Two articles published in the current issue1'O 11 assess the effect of combined 3-adrenergic and calcium-entry blockade on left ventricular performance. Kieval and associates'0 studied patients with well-preserved left ventricular function (mean ejection fraction 59.9 ± 11.2%) who were receiving maintenance doses of oral propranolol (plasma range 65.7-81.7 ng/ml). After left ventriculography, the patients were given short infusions of i.v. verapamil, and standard hemodynamic variables and several determinants of left ventricular function were assessed. Kieval et al. found no change in left ventricular performance as assessed by cardiac index, stroke volume index, left ventricular ejection fraction and mean velocity of circumferential fiber shortening, despite several dosing