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An analysis of the nitrate‐like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle
Author(s) -
Okada Yuji,
Yanagisawa Teruyuki,
Taira Norio
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12514.x
Subject(s) - glibenclamide , contraction (grammar) , chemistry , vasodilation , potassium channel , nicorandil , methylene blue , potassium channel opener , potassium , muscle contraction , artery , coronary vasodilator , biophysics , pharmacology , stereochemistry , medicine , biochemistry , endocrinology , biology , organic chemistry , photocatalysis , diabetes mellitus , catalysis
1 To clarify the mechanism of action of KRN2391, a new vasodilator containing a nitroxy group, its effects on intracellular Ca 2+ concentration ([Ca 2+ ] i ) and force of contraction in canine coronary artery were compared with those of two derivatives lacking the nitro group. 2 KRN2391, its hydroxy and acetoxy derivative (Compound 2 and Compound 3, respectively) partially reduced [Ca 2+ ] i in 5 or 30 m m KCl physiological salt solution (PSS), effects which were antagonized by glibenclamide. No KRN2391‐induced change in [Ca 2+ ] i was observed in 90 m m KCl‐PSS. 3 The order of potency in reducing [Ca 2+ ] i and inhibiting the contracture in 30 m m KCl‐PSS was: KRN2391 > Compound 3 > Compound 2. 4 In 30 m m KCl‐PSS, KRN2391 shifted the [Ca 2+ ] i ‐force relationship so that a greater increase in [Ca 2+ ] i was needed to produce force. Compounds 2 and 3 were ineffective. The [Ca 2+ ] i ‐force curve obtained in 90 m m KCl‐PSS was shifted to the right by KRN2391 (10 −4 m ). 5 The ability of KRN2391 to reduce the force of contraction in both 30 m m and 90 m m KCl‐PSS was inhibited by 10 −5 m methylene blue. 6 KRN2391 inhibited U46619‐induced contractions; this effect was associated with a reduction of [Ca 2+ ] i , which decreased below the basal level. 7 Thus, KRN2391 is a potent vasodilator in canine coronary artery. It possesses nitrate‐like and potassium channel opening actions and can be designated as a nitrate‐potassium channel opener (N‐K) hybrid. The denitrate derivatives of KRN2391 are specific K channel openers. The nitroxy moiety in KRN2391 is important for not only its action as a nitrate but also its potency as a K channel opener.