Chronic calcium antagonist therapy: some unexpected results.

The calcium antagonists protect the myocardium against the deleterious effects of ischemia and postischemic reperfusion provided that they are used prophylactically. This requires chronic therapy. Experiments were undertaken to establish whether chronic verapamil therapy alters the cardiac noradrenaline reserves or provokes a change in beta 1 adrenoceptor density. Sprague-Dawley (SD) rats were fed a diet containing placebo, or placebo plus dl verapamil (V) to provide plasma V levels of around 100 ng/ml. After 6 weeks of therapy the hearts were excised and assayed for noradrenaline (NA), adrenaline (A), and dopamine (DA) using high performance liquid chromatography. In addition, cardiac membranes were isolated in the presence of Tris, 10 mM MgCl2 and 9 microM phenylmethylsulfoxylfluoride and assayed for beta 1 adrenoceptor density (Bmax) and affinity (KD), using [3H]dihydroalprenolol as the ligand. Three days of therapy reduced left ventricular NA by 45%. Asymptote was reached within 11 days, when the NA content has decreased (p less than 0.001) to only 0.9 +/- 0.1 mu/g dry wt, mean +/- SEM, n = 6. The tissue level of DA was also reduced from 0.14 +/- 0.02 to 0.08 +/- 0.01 microgram/g dry weight (p less than 0.02). Further treatment for up to 6 weeks caused no further change in NA, A, or DA. Even after 6 weeks of therapy the density (35.5 +/- 1.9 before and 31.2 +/- 2.3 fmol/mg protein after therapy) and affinity (0.24 +/- 0.02 and 0.21 +/- 0.02 nM) of the beta 1 adrenoceptors were unchanged. These results show that although chronic verapamil therapy depletes the cardiac reserves of NA, beta-adrenoceptor density remains constant.