Effect of Chronic Verapamil Therapy on Cardiac Norepinephrine and β-Adrenoceptor Density

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Experiments were undertaken to establish whether the chronic administration of verapamil, to provide a therapeutically relevant plasma level, results in a loss of cardiac norepinephrine (NE) and, if so, whether this is accompanied by a change in cardiac beta 1-adrenoceptor density, affinity, or selectivity. Adult male Sprague-Dawley rats were used. Verapamil was mixed with the food to provide a daily verapamil intake of 50 mg/kg body weight. This yielded a plasma level of 80-110 ng/ml and caused a significant but reversible decrease in left ventricular NE (77%, p less than 0.001), dopamine (43%, p less than 0.02), and 3,4-dihydroxyphenylethyleneglycol (30%, p less than 0.02). Cardiac membranes prepared from rats maintained on standard (control) diet contained a single population of high affinity beta 1-adrenoceptor binding sites, with an affinity (Kd) of 0.24 +/- 0.02 nM and a density (Bmax) of 35.5 +/- 19.5 fmol/mg protein. Including verapamil (dissolved in either ethanol or water) in the diet for less than or equal to 6 weeks had no effect on the Kd, Bmax, or selectivity of these sites. However, the ethanol containing, but not the ethanol-free, placebo diet caused a small (p less than 0.05) reduction in Bmax after 6 but not after 2 weeks treatment. These results show that the chronic oral administration of verapamil to provide a clinically relevant plasma level depletes the cardiac stores of NE by 77% without causing an increase in beta 1-adrenoceptor density during 6 weeks therapy.