- Email: [email protected]
Effects of calcium channel blockers on tissue distribution of digoxin in guinea pigs
j Mol Cell Cardiol 18 (Supplement 1) (1986) 117 EFFECTSOF CALCIUMCHANNELBLOCKERSON TISSUE DISTRIBUTIONOF DIGOXIN IN GUINEAPIGS. K. Taubert, S. Hardman, D. Huante. Departmentof Physiology and Pharmacology, University of the Pacific, School of Pharmacy, Stockton, California 95211, USA 19 male guinea pigs were studied in order to assess a possible drug interaction between digoxin (DIG) and diltiazem (DIL) or verapamil (V). All animals received DIG, 240 ~g/kg/da. The control group (A) was saCrificed 12 da later. Group B received V (4 mg/kg/da) and group C received DIL (2 mg/kg/da) on days 10-14 and were then sacrificed. Sera were drawn on da 10 in B & C. At sacrifice, serum and several tissue sites were assayed for DIG by RIA. Sacrifice serum DIG level (SDL) in A was 0.6 ng/cc, and da 10 sera in B & C were not significantly different from A. In B, SDL declined 41~ after V dosing (p
118POTENTIATION OF THE CHRONOTROPICACTIONSOF VERAPAMILAND NIFEDIPINE BY ETHANOL. Philip Posner, Stephen P. Baker, and Robert L. Isaacson, University of Florida, College of Medicine, Gainesville, FL 32610. Ethanol, verapamil, and nifedipine are known to affect the transmembranemovement of Ca++ in several biological systems including the nervous system and cardiac tissue. Ethanol, verapamil, and nifedipine administered acutely have negative chronotropic actions on the isolated superfused rat sinus node. We have shown that chronic ethanol ingestion leads to a reduced baseline f i r i n g rate in S-A nodes isolated from rats. The following study was designed to determine i f these negative chronotropic actions were synergistic. Studies on S-A node atrial preparations from white rats pair fed either sucrose or ethanol liquid diets showedthat the preparations from the ethanol ingesting rats were more sensitive to verapamil and nifedipine. The threshold effect was 27% greater and the maximumeffect (asystole) occurred at a significantly lower dose (0.5 mg/L vs 2.0 mg/L). Studies on S-A node atrial preparations from control rats showedthat acutely administered ethanol (20mg%, 40mg%) reduced spontaneous beating. In addition, both verapamil and nifedipine had a significantly greater negative chronotropic effect in the presence of ethanol (2Omg%, 40mg%) than either did alone. It is hypothesized that the interaction between ethanol and verapamil or nifedipine is mediated through a reduction in transmembrane Ca++ movement.
119CARDIOPROTECTIVE AND ANTIHYPERTENSIVE EFFECTS OF THE NEW CALCIUM ANTAGONIST ANIPAMIL IN RATS AND HAMSTERS. M. Raschack, J. Gries. Department of Pharmacology, Knoll AG, Ludwigshafen, F.R. Germany. Anipamil (A) is a new derivative of verapamil with good oral efficacy and longer duration of action. In rats A inhibits breakdown of myocardial CP and ATP due to hypoxic ventilation (2% 02, 7 min). It dose-dependently protects hearts of rats 6 h after oral pretreatment, not so nifedipine, verapamil, tiapamil and falipamil which act shorter. The protection by a high dose of A lasts up to 24 h. With repeated administration, once daily, the protective effect increases as compared to single dosage. In spontaneously hypertensive rats (SHR} oral A lowers blood pressure longer than verapamil, diltiazem and nifedipine. A, in contrast to nifedipine, does not increase heart rate. With repeated administration no tachyphylaxis occurs. - In 10-week-old stroke prone SHR with already elevated blood pressure chronic oral A, administered either by gavage or with the food, inhibits further progression of hypertension without pronounced influence on heart rate and body weight. Life-span is markedly prolonged with life-long administration of A and also after treatment for only 26 weeks. In hereditary cardiomyopathic hamsters chronic oral administration of A (15, 30, 60 mg/kg with the food) from 30.-72. day dose-dependently prevents myocardial Ca-overload and necroses. - The beneficial action of anipamil against experimental and hereditary cardiac damage and the pronounced antihypertensive and life-prolonging effects in SHR encourage clinical testing.
Vj
118POTENTIATION OF THE CHRONOTROPICACTIONSOF VERAPAMILAND NIFEDIPINE BY ETHANOL. Philip Posner, Stephen P. Baker, and Robert L. Isaacson, University of Florida, College of Medicine, Gainesville, FL 32610. Ethanol, verapamil, and nifedipine are known to affect the transmembranemovement of Ca++ in several biological systems including the nervous system and cardiac tissue. Ethanol, verapamil, and nifedipine administered acutely have negative chronotropic actions on the isolated superfused rat sinus node. We have shown that chronic ethanol ingestion leads to a reduced baseline f i r i n g rate in S-A nodes isolated from rats. The following study was designed to determine i f these negative chronotropic actions were synergistic. Studies on S-A node atrial preparations from white rats pair fed either sucrose or ethanol liquid diets showedthat the preparations from the ethanol ingesting rats were more sensitive to verapamil and nifedipine. The threshold effect was 27% greater and the maximumeffect (asystole) occurred at a significantly lower dose (0.5 mg/L vs 2.0 mg/L). Studies on S-A node atrial preparations from control rats showedthat acutely administered ethanol (20mg%, 40mg%) reduced spontaneous beating. In addition, both verapamil and nifedipine had a significantly greater negative chronotropic effect in the presence of ethanol (2Omg%, 40mg%) than either did alone. It is hypothesized that the interaction between ethanol and verapamil or nifedipine is mediated through a reduction in transmembrane Ca++ movement.
119CARDIOPROTECTIVE AND ANTIHYPERTENSIVE EFFECTS OF THE NEW CALCIUM ANTAGONIST ANIPAMIL IN RATS AND HAMSTERS. M. Raschack, J. Gries. Department of Pharmacology, Knoll AG, Ludwigshafen, F.R. Germany. Anipamil (A) is a new derivative of verapamil with good oral efficacy and longer duration of action. In rats A inhibits breakdown of myocardial CP and ATP due to hypoxic ventilation (2% 02, 7 min). It dose-dependently protects hearts of rats 6 h after oral pretreatment, not so nifedipine, verapamil, tiapamil and falipamil which act shorter. The protection by a high dose of A lasts up to 24 h. With repeated administration, once daily, the protective effect increases as compared to single dosage. In spontaneously hypertensive rats (SHR} oral A lowers blood pressure longer than verapamil, diltiazem and nifedipine. A, in contrast to nifedipine, does not increase heart rate. With repeated administration no tachyphylaxis occurs. - In 10-week-old stroke prone SHR with already elevated blood pressure chronic oral A, administered either by gavage or with the food, inhibits further progression of hypertension without pronounced influence on heart rate and body weight. Life-span is markedly prolonged with life-long administration of A and also after treatment for only 26 weeks. In hereditary cardiomyopathic hamsters chronic oral administration of A (15, 30, 60 mg/kg with the food) from 30.-72. day dose-dependently prevents myocardial Ca-overload and necroses. - The beneficial action of anipamil against experimental and hereditary cardiac damage and the pronounced antihypertensive and life-prolonging effects in SHR encourage clinical testing.
Vj