Inhibition of calcium channels by harmaline and other harmala alkaloids in vascular and intestinal smooth muscles

Abstract

Effects of harmaline and other harmala alkaloids on the contractions induced in the vascular smooth muscle of rabbit aorta and intestinal smooth muscle of taenia isolated from guinea‐pig caecum were examined. In rabbit isolated aorta, harmaline inhibited the sustained contraction induced by 65.4 mM K+ with an IC50 (concentration needed for 50% inhibition) of 4.6 × 10−5 M. This inhibitory effect on high K+‐induced contraction was antagonized by raising the concentration of external Ca2+ but not by Bay K 8644, a Ca2+ channel facilitator. Harmaline also inhibited the sustained contraction induced by noradrenaline (10−6 M) with an IC50 of 7.6 × 10−5 M. The inhibitory effects on noradrenaline‐induced contractions were not antagonized by raising the external Ca2+ concentrations or by Bay K 8644. In guinea‐pig taenia, harmaline inhibited the 45.4 mM K+‐induced contraction with an IC50 of 6.8 × 10−5 M and the carbachol (10−6 M)‐induced contraction with an IC50 of 7.0 × 10−5 M. The inhibitory effects on both high K+‐ and carbachol‐induced contractions were antagonized by raising the external Ca2+ concentrations but not by Bay K 8644. Harmaline, at the concentrations needed to inhibit the muscle contraction, inhibited the increase in 45Ca2+ uptake induced by high K+, noradrenaline and carbachol in aorta and taenia. Harmaline did not change the cellular Na+ and ATP contents in resting and high K+ stimulated taenia. Other harmala alkaloids also inhibited the contractions in these smooth muscles. The order of the inhibitory potency was 6‐methoxyharman = harmine > harmaline = 2‐methylharmine = harmane > 6‐methoxyharmalan > harmalol = harmol for the contractions induced by high K+ in aorta and taenia and by carbachol in taenia, and 2‐methylharmine > 6‐methoxyharman > 6‐methoxyharmalan = harmol = harmalol = harmane > harmine > harmaline for the contraction induced by noradrenaline in aorta. These results suggest that harmaline inhibits the contractile response of rabbit aorta and guinea‐pig taenia by inhibiting different types of Ca2+ channel. The structure‐activity relationship indicates that the potency and selectivity of the inhibitory effects on these channels are varied by modification of the structure of this alkaloid. 1986 British Pharmacological Society