Effect of accumulation of NKY-722, a water-soluble vasoselective Ca++ antagonist, on KCl-induced contraction in isolated canine mesenteric arteries

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 258; no. 2; pp. 676 - 680
• Main Authors: Shimaji, H, Shirahase, H, Kanda, M, Osumi, S, Kurahashi, K
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.1991
• Subjects: Animals; Antihypertensive Agents - metabolism; Calcium Channel Blockers - metabolism; Dihydropyridines - metabolism; Dihydropyridines - pharmacology; Dogs; Female; In Vitro Techniques; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Potassium Chloride - pharmacology; Vasoconstriction - drug effects
• ISSN: 0022-3565; 1521-0103

The relationship between the accumulation of NKY-722 and its vasoinhibitory effect on KCl-induced contraction was examined in canine mesenteric arteries. NKY-722 showed a high level of accumulation in canine mesenteric arteries and reached near maximal levels at 60 min. The tissue/medium ratio measured at 60 min was independent of the bath concentration of NKY-722 (10(-9), 10(-8) and 10(-7) M). NKY-722 (10(-9) and 10(-7) M) attenuated the KCl (30 mM)-induced contraction of canine mesenteric arteries, and this effect was dependent on the pretreatment time (5-60 min). The vasoinhibitory effect of NKY-722 (during incubation) on KCl-induced contraction correlated with its accumulation in the vascular preparations. Preparations were incubated with NKY-722 (5 x 10(-9) M) for 60 min and repetitively washed out, showing that the accumulation of NKY-722 decreased slowly over 300 min. When the preparations were incubated with NKY-722 (5 x 10(-9) M) for 60 min, the vasoinhibitory effect on KCl-induced contraction remained for over 300 min after repetitive washouts. The vasoinhibitory effect of NKY-722 (during washout) on KCl-induced contraction also correlated with its accumulation in the vascular preparations. The present experiments indicate that NKY-722 accumulates in canine mesenteric arteries at high levels and should be washed out slowly, and suggest that NKY-722 accumulation in vessel walls may contribute to the long duration of its antihypertensive effect.