An analysis of the nitrate‐like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle

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 (10⁻⁴ m). 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. 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. 1991 British Pharmacological Society