A study on the hypotensive mechanism of pinacidil: relationship between its vasodilating effect and intracellular Ca2+ levels.
The direct effect of pinacidil on contractile protein systems and the relationship between its vasodilating effects and intracellular Ca2+ concentration were studied in isolated smooth muscle of guinea pigs. Pinacidil, nifedipine and hydralazine did not inhibit Ca2+-induced contracture in saponin-treated taenia caecum of guinea pig, while trifluoperazine and W-7 markedly suppressed it. Simultaneous determination of the intracellular Ca2+ concentration (fura 2 method) and tension development of the isolated femoral artery of guinea pigs showed that the intracellular Ca2+ level always decreased before vasorelaxation after pinacidil or nifedipine administration. Pinacidil showed no effect on cyclic AMP or cyclic GMP contents in rabbit aortic strips. These results indicate that pinacidil, like nifedipine and hydralazine, do not seem to directly act on the process from the formation of Ca2+-calmodulin to the actinmyosin interaction in the contracting mechanism of vascular smooth muscle, and that pinacidil relaxes the vascular smooth muscle by decreasing intracellular Ca2+-levels without elevating cyclic nucleotides.
Nakajima
S
S
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Kurokawa
K
K
Imamura
N
N
Ueda
M
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis / Q000502:physiology*; D000242:Cyclic AMP / Q000032:analysis; D006152:Cyclic GMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006830:Hydralazine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D020110:Pinacidil; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D000959:Antihypertensive Agents; D006146:Guanidines; D013449:Sulfonamides; D014268:Trifluoperazine; D006830:Hydralazine; C017967:W 7; D020110:Pinacidil; D000242:Cyclic AMP; D006152:Cyclic GMP; D009543:Nifedipine; D002118:Calcium