title: 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 X 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 X 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 X 10(-5) M and the carbachol (10(-6) M)-induced contraction with an IC50 of 7.0 X 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. 7 These results suggest that harmaline inhibits the contractile response ofrabbit 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.
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers; D002217:Carbachol / Q000494:pharmacology; D006246:Harmaline / Q000031:analogs & derivatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D012503:Saponins; D012964:Sodium / Q000378:metabolism
chemical_list: D000470:Alkaloids; D002121:Calcium Channel Blockers; D012503:Saponins; D000255:Adenosine Triphosphate; D002217:Carbachol; D012964:Sodium; D006246:Harmaline; D011188:Potassium; D002118:Calcium