dihydropyridines and Shock--Cardiogenic

This study was designed to test the hypothesis that the properties of novel 1,4-dihydropyridine PCA50941 could favor the recovery of cardiogenic shock. Coronary blood flow (CBF), measured with an electromagnetic flow probe placed on the left circumflex coronary artery, systemic arterial pressure and heart rate were recorded in 24 anesthetized goats; left ventricular pressure and dP/dt were also recorded in 19 of these goats. Under control conditions, intracoronary injections in 5 goats of PCA50941 (10-120 microg) caused smaller reductions of CBF than those of Bay K 8644 (0.3-10 microg) (the reduction of CBF by 120 microg PCA50941 was 25% and that by 10 microg Bay K 8644 was 43%), and i.v. infusions in 4 goats of PCA50941 (10-300 microg/min) did not modify CBF nor the other hemodynamic variables recorded, whereas i.v infusion of Bay K 8644 (10-30 microg/min) reduced CBF by 20% and increased arterial pressure, left ventricular pressure and dP/dt. During control conditions and endothelin-induced cardiogenic shock, respectively, the values for 15 goats were: for CBF, 33+/-4 vs. 16+/-4 ml/min; for mean arterial pressure, 88+/-4 vs. 60+/-5 mm Hg; for left ventricular systolic pressure, 102+/-5 vs. 75+/-4 mm Hg; for dP/dt, 1453+/-147 vs. 925+/-101 mm Hg/s (all P<0.05), and for heart rate, 77+/-6 vs. 81+/-6 beats/min (P>0.05). Intravenous infusion of PCA50941 (100 microg/min) reversed the hemodynamic variables from the shock state to control values within 20 min in 5 of 6 animals, whereas i.v. administration of Bay K 8644 (10-30 microg/min) was not effective in 4 of 5 animals, and the vehicle (DMSO) was not effective in none of 4 animals in reversing the hemodynamic shock state. Therefore, it is suggested that PCA50941, a novel 1,4-dihydropyridine, has a cardiovascular profile that might be suitable for treating cardiogenic shock states.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Blood Flow Velocity; Blood Pressure; Calcium Channel Agonists; Coronary Circulation; Dihydropyridines; Endothelin-1; Female; Goats; Heart; Heart Rate; Infusions, Intravenous; Shock, Cardiogenic; Thiazoles; Ventricular Function, Left

Mibefradil is a T-type and L-type calcium channel blocker (CCB) released in the United States in 1997 for management of hypertension and chronic stable angina. Postmarketing surveillance revealed a potential serious interaction between mibefradil and beta-blockers, digoxin, verapamil, and diltiazem, especially in elderly patients. The manufacturer voluntarily withdrew mibefradil on June 8, 1998. We describe 4 cases of cardiogenic shock in patients taking mibefradil and beta-blockers who began taking dihydropyridine CCBs. One case resulted in death; the other 3 survived episodes of cardiogenic shock with intensive support of heart rate and blood pressure. Physicians who are preparing to switch patients' medications from mibefradil to other antihypertensive agents should be aware of these potentially life-threatening drug-drug interactions.

Topics: Adrenergic beta-Antagonists; Aged; Benzimidazoles; Calcium Channel Blockers; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dihydropyridines; Drug Interactions; Female; Half-Life; Humans; Mibefradil; Mixed Function Oxygenases; Shock, Cardiogenic; Sinoatrial Node; Tetrahydronaphthalenes