Effects of Nicorandil on Receptor-Mediated Ca2+ Release and Ca2+ Entry in Vascular Smooth Muscle

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In a solution containing La3+, or one without Ca2+ (Ca2+-free) and containing 1.0 mM cthylene glycol bis(β-aminoethyl ether)-N,N,N‘.N’-tetraacctic acid (EGTA), norepinephrine (NE)-induced transient contractions in rabbit aorta attributed to Ca2+ release are depressed 31 and 38%, respectively, by an approximate ED60, relaxing concentration of nicorandil (SG-75). In addition, after 15 min in a Ca2+-free, low-EGTA (0.01 mM) solution, plus D600 to eliminate any potential-dependent Ca2+ entry, NE elicits a similar phasic response that is attenuated 34% by SG-75. Apparently, this is primarily due to inhibition of Ca2+ release rather than to stimulation of rebinding, uptake, and/or extrusion of Ca2+ following release. For, when tissues initially exposed to a Ca2+ -free, low-EGTA plus D600 solution with or without SG-75 and NE are then rinsed with the same solution for 20 min to remove SG-75 and/or NE and again exposed to NE there is only a small residual maintained response in tissues not exposed to SG-75. However, in tissues that have been exposed to SG-75 prior to NE, a measurable phasic response is elicited that is approximately 50% of control NE responses. When Ca2+ is added to a Ca2+free, low-EGTA plus D600 solution after NE-induced Ca2+ release, a rapid and significant increase in tension ensues that is well maintained and is proposed to represent specific α-adrenoceptor-mediated Ca2+ entry. This NE-mediated, D600-insensitive Ca2+ entry is readily inhibited or relaxed by SG-75. Therefore, SG-75 appears to directly depress NE-mediated Ca2+ release and specific receptor (NE)-mediated (D600-insensitive) Ca2+ entry, independent of any additional effects on any other intracellular Ca2+ buffering mechanisms and/or Ca2+ extrusion.