The mode of vasorelaxant action of 2-aminoisoquinoline, 1.3 (2H.4H)-dione, a novel 'intracellular calcium inhibitor'

Abstract

In rabbit aorta, pretreatment with 2-aminoisoquinoline, 1.3 (2H.4H)-dione (AQ, 10(-5) M and 10(-4) M) shifted the concentration-response relationship to noradrenaline (NA, 10(-9) M to 10(-4) M) in a parallel manner whereas the agent (10(-4) M) failed to affect the response to potassium and only slightly depressed Ca2+-induced contractions in a Ca2+-free medium in the presence of K+ (40 mM). Ca2+-entry blockers such as nifedipine and diltiazem (10(-6) M and 10(-5) M) had very weak or no apparent effects on the response to NA but markedly attenuated or abolished the K+- and Ca2+-induced contractions. Following incubation of tissues for 15 min in a Ca2+-free medium with low EGTA (0.01 mM) and methoxyverapamil (D600, 10(-5) M), NA (3 X 10(-7) M) caused a phasic (transient) contraction and the subsequent application of Ca2+ (2mM) resulted in a tonic contraction. This NA-induced, Ca2+-dependent, D600-insensitive contraction was inhibited by AQ (10(-5) M and 10(-4) M) in a concentration-dependent manner. This suggests that the inhibitory action of AQ may be related to Ca2+ entry through specific receptor activated pathways. Following incubation of tissues for 30 min in a Ca2+-free medium with high EGTA (2.0 mM), NA (10(-5) M) caused a contraction of rabbit aorta which is dependent upon release of intracellular Ca2+, but the response was 50% to 60% less than that in a normal medium. This contraction was inhibited by AQ (10(-5) M and 10(-4) M) and nitroglycerin (10(-5) M) but not by nifedipine or diltiazem. The inhibitory action of combined treatment with AQ and nitroglycerin (10-5 M) on the response to NA was not different from that of either agent alone. 5 These results suggest that AQ may have inhibitory actions on the release of intracellular Ca2+ and also on Ca2+-entry through D600-insensitive, receptor-activated Ca2+ pathways in rabbit aorta.