Vasorelaxation of Rat Thoracic Aorta Caused by Two Ca2+-Channel Blockers, HA-22 and HA-23

The pharmacological effects of HA-22 (2-(4'methoxyphenylmethyl)-3,4-dimethylpyrano[2,3-c]pyrazol- 6(2H)-one) and HA-23 (2-(2'-thienylmethyl)-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H) -one) on rat isolated thoracic aorta have been examined. In high potassium medium (60 mM), Ca2+ (0.03-3 mM)-induced vasoconstriction was inhibited by HA-22 and HA-23 (10-100 micrograms mL-1). Cromakalim-relaxed aortic rings precontracted with 15 mM but not 60 mM K+. However, HA-22, HA-23 and verapamil produced a greater relaxation in 60 mM than in 15 mM K(+)-induced contraction. The tonic contractions elicited by KCl (60 mM) and Bay K 8644 (10(-7)M) were also relaxed by the addition of HA-22 and HA-23. The phenylephrine concentration-response curves displayed antagonism by HA-22 and HA-23 (10-100 micrograms mL-1) in a non-competitive manner. The caffeine (10 mM)-induced contraction and cAMP or cGMP levels were not affected by HA-22 or HA-23. It is concluded that HA-22 and HA-23 relaxed the rat aorta by suppressing the Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ channels.