Effect of KT-362, a putative intracellular calcium antagonist, on norepinephrine-induced contractions and inositol monophosphate accumulation in canine femoral artery.
The purpose of the present study was to determine if the intracellular calcium antagonist, KT-362, inhibits norepinephrine- (NE) 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 alpha 1 adrenoceptor antagonist, prazosin (0.1 microM), indicating that the NE-induced stimulation of inositol phospholipid hydrolysis is coupled to alpha 1 adrenoceptor activation in canine femoral artery. Pretreatment with nitroglycerin (100 microM), 8-Br cyclic guanosine monophosphate (cGMP) (1 microM), or diltiazem (40 microM) inhibited contractile responses produced by NE; however, these agents had no significant effect on NE-induced IP accumulation. In contrast, pretreatment with KT-362 (10-100 microM) 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 microM) 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.
Eskinder
H
H
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Hillard
C J
CJ
Wilke
R A
RA
Gross
G J
GJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013403:Sugar Phosphates / Q000378:metabolism*; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D013403:Sugar Phosphates; D013841:Thiazepines; D014665:Vasodilator Agents; C051271:KT 362; D004110:Diltiazem; D005996:Nitroglycerin; D009638:Norepinephrine