Article date: December 1991
By: Yuji Okada, Teruyuki Yanagisawa, Norio Taira, in Volume 104, Issue 4, pages 829-838
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.
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.
The order of potency in reducing [Ca2+]i and inhibiting the contracture in 30 mm KCl‐PSS was: KRN2391 > Compound 3 > Compound 2.
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 (10−4m).
The ability of KRN2391 to reduce the force of contraction in both 30 mm and 90 mm KCl‐PSS was inhibited by 10−5m methylene blue.
KRN2391 inhibited U46619‐induced contractions; this effect was associated with a reduction of [Ca2+]i, which decreased below the basal level.
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.
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.
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.
The order of potency in reducing [Ca2+]i and inhibiting the contracture in 30 mm KCl‐PSS was: KRN2391 > Compound 3 > Compound 2.
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 (10−4m).
The ability of KRN2391 to reduce the force of contraction in both 30 mm and 90 mm KCl‐PSS was inhibited by 10−5m methylene blue.
KRN2391 inhibited U46619‐induced contractions; this effect was associated with a reduction of [Ca2+]i, which decreased below the basal level.
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.
DOI: 10.1111/j.1476-5381.1991.tb12514.x
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