Mechanism of Action of KRN2391 in Canine Coronary Vascular Bed

Abstract

ABSTRACT-The present studies were performed to clarify the mechanism of action of KRN2391 in various sizes of canine coronary artery. We used the responses of isolated large and small coronary arteries and the changes in coronary blood flow (CBF) as indicators reflecting the responses of conductive arteries and resistive arterioles, respectively. In isolated small coronary artery, the effect of KRN2391 (10-8-10-5 M) was antagonized by either methylene blue or glibenclamide. In isolated large coronary artery, the vasorelaxant effect of KRN2391 (10-'-10-'M) and nicorandil (10-'-10-4 M) were antagonized by methylene blue (10-'M) but not by glibenclamide (10-'M). The relaxant effect of cromakalim was an tagonized by glibenclamide but not by methylene blue in isolated large coronary artery. Intracoronary arterial injection of KRN2391, nicorandil or cromakalim produced an increase in CBF dose-dependently. Glibenclamide (5 mg/kg, i.v.) attenuated the increase in CBF caused by KRN2391, nicorandil and cromakalim. ED20, the dose that produced an increase in CBF by 20 ml/min, increased about 5-fold for KRN2391 and nicorandil and about 12-fold for cromakalim after administration of glibenclamide. These results suggest that the mechanism of action of KRN2391 and nicorandil depends on the segment of coro nary arteries; i.e., they show a nitrate action alone in large coronary artery, and a K-channel opening action in addition to a nitrate action as the size of the coronary artery decreases.

Effects of KRN2391 on ionic currents in rabbit femoral arterial myocytes

“…In porcine coronary artery, the relaxing effect of KRN2391 against agonist‐induced contractions was 10–20 times greater than that of nicorandil ( Fukata et al ., 1993 ; Kasai et al ., 1993 ; Jinno et al ., 1992 ; Miwa et al ., 1993 ). In the present study, KRN2391 and nicorandil elicited a glib‐sensitive current in a concentration‐dependent manner.…”

Vasodilator Action of the Nitroxylated Cyanoamidine Derivative, KRN2391, in Rabbit Basilar Artery

“…Furthermore, KRN2391 acted mainly as a nitrate in canine large coronary arteries, since methylene blue inhibited the KRN2391-induced relaxation, while glibenclamide was inactive. However, in canine small coronary arteries, glibenclamide also inhibited the vasodilator response, indicating activation of KATp (Fukata et al 1993). This shows that the mechanism of action of KRN2391 may differ between different types of blood vessel.…”

Krn2391: Dual Action On Rat Pulmonary Artery And No Loss Of Potency In Pulmonary Hypertension

“…9,10,12-15,28 Its potency on rat pulmonary arteries is comparable to that seen in rat aorta. 11 Methylene blue was the guanylate cyclase inhibitor used in the present study so that the data could be directly compared with data from the various previous studies on KRN2391 in other blood vessel types. This is in contrast with porcine large coronary artery, where KRN2391 was five-fold more potent if preparations were contracted with NA compared with U46619.…”

“…Two other classes of vasodilator that may be of value in the future are nitric oxide (NO) donor drugs 4 and potassium (KATP) channel openers. coronary, [9][10][11] femoral, 12 mesenteric 13 and renal 14 arteries and aorta 15,16 ). Alternatively, it may be beneficial to use a single drug that causes vasodilatation by more than one mechanism.…”

“…8 However, the mechanism(s) of KRN2391-induced vasorelaxation can vary depending on the type and size of the artery 8 and, so far, characterization of the mechanism of action of this drug has been confined to systemic blood vessels (e.g. coronary, [9][10][11] femoral, 12 mesenteric 13 and renal 14 arteries and aorta 15,16 ). Thus, the first aim of the present study was to determine whether KRN2391 has a dual mechanism of action on rat pulmonary arteries.…”