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.