Effect of KT-362, a Putative Intracellular Calcium Antagonist, on Norepinephrine-Induced Contractions and Inositol Monophosphate Accumulation in Canine Femoral Artery

Abstract

Summary: The purpose of the present study was to determine if the intracellular calcium antagonist, KT-362, inhibits norepinephrine- IN Hi induced contractions and inositol monophosphate (IP) accumulation in canine femoral arteries preincubated with [3H]inositol. Norepinephrine dose-dependently increased contractile tension and produced a parallel stimulation of inositol phospholipid hydrolysis as measured by IP accumulation. This stimulation was inhibited by the selective α1 adrenoceptor antagonist. prazosin (0.1 μM), indicating that the NE-induced stimulation of inositol phospholipid hydrolysis is coupled to α1 adrenoceptor activation in canine femoral artery. Pretreatment with nitroglycerin (100 μM). 8-Brcyclic guanosine monophosphate (cGMP) (1 μM), or diltiazem (40 μM) inhibited contractile responses produced by NE; however, these agents had no significant effect on NE-indueed IP accumulation. In contrast, pretreatment with KT-362 (10− 100 μM) greatly inhibited both the NE-induced contractions and IP accumulation. KT-362 also produced a marked inhibition of NE-induced contractions in normal as well as zero calcium buffer, whereas diltiazem (40 μM) had no effect in zero calcium buffer. These results indicate that the mechanism of action of KT-362 differs from diltiazem, nitroglycerin, and 8-Br cGMP. and these data suggest that one of the mechanisms by which KT-362 antagonizes NE-induced vasoconstrictor responses is by decreasing inositol phospholipid hydrolysis in canine femoral artery.