Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs.

Abstract

To assess the direct and indirect effects of the commonly used calcium entry blockers (CEB) upon the major determinants of isovolumic left ventricular relaxation, we administered equidepressant intracoronary (IC, n = 7) and equihypotensive intravenous (n = 12) dosages of diltiazem (16±3 SE ,Ag/kg IC and 63±9 gg/kg i.v.), verapamil (10±2 and 57±5 Ag/kg), and nifedipine (1±0.1 and 8±0.3 ,g/kg) to preinstrumented awake dogs with normal ventricular function. The time constant of left ventricle (LV) relaxation, analyzed by two methods (T1, from the linear relation of the natural logarithm of LV pressure and time; T2, from the linear relation of LV pressure and negative high fidelity LV pressure), was significantly and equivalently prolonged by IC diltiazem (T, + 48%, P < 0.02), verapamil (T1 + 43%, P < 0.001), and nifedipine (T1 + 30%, P < 0.03). Lesser amounts of each CEB that did not affect rate of LV pressure development or extent of shortening produced no change in T1 or T2. By contrast, intravenous calcium entry blockade either produced no significant change (diltiazem and verapamil) or shortened (nifedipine T1 -18%, P < 0.01) LV isovolumic relaxation. However, after beta adrenergic blockade with propranolol (2 mg/kg i.v., n = 6) no change in ventricular relaxation was observed during nifedipine and the time constant was significantly prolonged by verapamil (T1 + 15%, P < 0.05).We conclude that calcium entry blockade directly impairs normal left ventricular relaxation: This effect is closely linked to the negative inotropic properties of these drugs. The prolongation of isovolumic relaxation produced by calcium blockade is attenuated or even reversed by reflex sympathetic stimulation and favorably altered loading conditions during systemic administration.

Improvement of the age-related impairment in left ventricular diastolic filling with verapamil in the normal human heart.

“…Numerous echocardiographic and radionuclide angiographic studies have demonstrated age-related decreases in the rate and extent of early rapid diastolic filling'-4 and increases in atrial contribution to filling. 35,6 These changes are similar to those observed in patients with coronary artery disease,2' systemic hypertension,22 and hypertrophic cardiomyopathy.23 However, LV diastolic function declines as a function of age even in subjects without these conditions.13 '24 The data in the present study confirm these earlier results. The mechanism for this decline in humans is not known, but experimental studies suggest two possibilities.…”

Radionuclide Angiographically Determined Left Ventricular Diastolic Filling in Hypertensive Patients: Apparent ‘Improvement’ with Intravenous Verapamil

“…Walsh and O'Rourke [32] demonstrated that when calcium channel blocking drugs were administered di rectly into the coronary arteries of the conscious dog model, LV relaxation was impaired whereas when simi lar drugs were administered intravenously, LV relax ation was either unchanged or improved. This suggests that the direct effect of calcium blocking drugs may be attenuated or even reversed by reflex sympathetic stimu lation and altered loading conditions occurring during systemic administration.…”

Treatment of diastolic dysfunction in hypertensive patients without left ventricular hypertrophy

“…6,7 Calcium antagonists and diuretics are also useful in controlling high BP (HBP); non-dihydropyridinic calcium antagonists, especially verapamil, exhibit a good profile on these patients: bradycardiac action, increasing the filling rate, and lusotropic, improving the ventricular relaxation through a complex mechanism of decreased intracellular calcium overload, reduction in functional ischaemia and steady relaxing conditions. 8,9 Diuretics, besides decreasing congestive symptoms, if present, improve load conditions in both ventricles, indirectly reduce pericardic constriction and ventricular cross-talk conditions, thus improving ventricular filling. 10 Moreover, possible drug effects on diastolic dysfunction might be independent of those on left ventricular mass, a hypothesis to be tested in patients with diastolic dysfunction without LVH.…”