Enhancement of phenoxybenzamine-induced irreversible blockade by organic Ca antagonists of the histamine response in guinea pig taenia caecum

Abstract

Listen

Translate article

Structurally different organic Ca antagonists such as D600, diltiazem and nicardipine enhanced the irreversible blockade by phenoxybenzamine (POB) of the histamine response in guinea pig taenia caecum. The isotonic contraction of the muscle to histamine was tested after incubation with POB (5xlO-6M, 10 min) with or without an organic Ca antagonist. The blockade by POB was greater in muscles treated with an organic Ca antagonist at concentrations that singly depressecene contraction to histamine to less than 50% of the control (D600, 5×10-7 M; di 1 tiazem, 1×10−5M;and nicardipine,3xlO-8M), and the effect lasted for more than 8 hrs;but the blockade was unchanged at lower concentrations of Ca antagonists. Mn ion had no such enhancing effect. The response to 40 mM K ion was not affected. The organic Ca antagonists alone at these concentrations did not affect the contraction to histamine after washing for 3 hrs. D557(desmethoxyverapamil) and 1-cis-isomer of diltiazem were less effective in enhancing than D600 & diltiazem, respectively. Antihistamines failed to protect the histamine receptor from the enhanced effect of POB. Only high doses of diphenhydramine which have high membrane stabilizing action could protect only the response to the maximal dose of histamine. Tritiated-POB binding to the intact muscle strips was significantly increased by nicardipine (3×10−°M). As the enhancing effect is parallel with the Ca antagonistic actions of the drugs used, it is concluded that the effect originated from the blockade of the Ca channel. We speculate as follows:The organic Ca antagonists stabilize the Ca channel in resting conformation, which makes some components of the receptor system more susceptible to POB. Eur.J.Pharmacol. 87 319 (1983)