An analysis of the nitrate-like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle.
1. To clarify the mechanism of action of KRN2391, a new vasodilator containing a nitroxy group, its effects on intracellular Ca2+ concentration ([Ca2+]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 [Ca2+]i in 5 or 30 mM KCl physiological salt solution (PSS), effects which were antagonized by glibenclamide. No KRN2391-induced change in [Ca2+]i was observed in 90 mM KCl-PSS. 3. The order of potency in reducing [Ca2+]i and inhibiting the contracture in 30 mM KCl-PSS was: KRN2391 greater than Compound 3 greater than Compound 2. 4. In 30 mM KCl-PSS, KRN2391 shifted the [Ca2+]i-force relationship so that a greater increase in [Ca2+]i was needed to produce force. Compounds 2 and 3 were ineffective. The [Ca2+]i-force curve obtained in 90 mM 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 mM and 90 mM KCl-PSS was inhibited by 10(-5) M methylene blue. 6. KRN2391 inhibited U46619-induced contractions; this effect was associated with a reduction of [Ca2+]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.
Okada
Y
Y
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yanagisawa
T
T
Taira
N
N
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009566:Nitrates / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D009566:Nitrates; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; C074245:KI 3315; C074246:KI 4032; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005905:Glyburide; D002118:Calcium; D008751:Methylene Blue