Effect of chronic verapamil therapy on cardiac norepinephrine and beta-adrenoceptor density.
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.
Nayler
W G
WG
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
Dillon
J S
JS
Sturrock
W J
WJ
Buckley
D J
DJ
D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004082:Dihydroalprenolol; D006321:Heart / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013997:Time Factors; D014700:Verapamil / Q000097:blood / Q000494:pharmacology*
D000777:Anesthetics; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; D014700:Verapamil; D009638:Norepinephrine