Katsuhiko Harada

Effects of KRN2391, nicorandil and diltiazem on the changes in the electrocardiogram caused by endothelin‐1 in anaesthetized rats

1 The effect of KRN2391, a novel vasodilator, on the changes of electrocardiogram caused by endothelin‐1 (ET‐1) was studied in anaesthetized rats and compared with the effects of nicorandil and diltiazem. In addition, the effect of KRN2391 on the action potential of guinea‐pig papillary muscle was studied. 2 The intracoronary administration (i.c.) of ET‐1 (5 μg) induced not only ST segment elevation of the electrocardiogram due to contraction of the coronary artery, but also arrhythmias involving atrioventricular block (A‐V block), ventricular premature contraction (VPC) and ventricular fibrillation (VF), and resulted in death in most animals. However, the administration of methacholine (3 μg, i.c.) produced ST segment elevation alone without developing arrhythmias. 3 Pretreatment with intravenous administration of KRN2391 (30 μg kg−1) inhibited the ST segment elevation and the development of arrhythmias induced by ET‐1, and decreased the incidence of death. 4 Nicorandil (1000 μg kg−1) prevented the ST segment elevation without suppression of the occurrence of VF. Diltiazem (100 μg kg−1) suppressed both the ST segment elevation and the occurrence of VF but not other arrhythmias. Nicorandil at 3000 μg kg−1 and diltiazem at 300 μg kg−1 produced not only a suppression of ST segment elevation and VF incidence but also a decrease in the occurrence of arrhythmias. These doses of nicorandil and diltiazem produced a decrease in death in a dose‐dependent manner. 5 KRN2391 (10 and 30 μg kg−1), nicorandil (1000 and 3000 μg kg−1) and diltiazem (100 and 300 μg kg−1) significantly decreased mean blood pressure in a dose‐dependent manner. Heart rate was decreased by nicorandil (3000 μg kg−1) and diltiazem (100 and 300 μg kg−1) but was not affected by KRN2391 (10 and 30 μg kg−1). 6 KRN2391 (30 μm) significantly shortened the action potential duration of guinea‐pig ventricle at 50% and 90% repolarization (APD50 and APD90). The effect of KRN2391 was inhibited by a K+ channel blocker, glibenclamide (30 μm). 7 These results suggest that the occurrence of ST segment elevation and arrhythmias induced by ET‐1 are due to a dual direct action on both coronary vascular smooth muscle and myocardium. Therefore, the protective effects of KRN2391, nicorandil and diltiazem on ET‐1‐induced heart disorders appear to be due to their direct actions on coronary vascular smooth muscle and the myocardium.

Dissimilarity in the mechanisms of action of KRN2391, nicorandil and cromakalim in canine renal artery

Abstract— In the present study, we examined the mode of action of KRN2391 (N‐cyano‐N′‐(2‐nitroxyethyl)‐3‐pyridinecarboximida‐mide monomethanesulphonate) in isolated canine renal artery compared with those of nicorandil and cromakalim. KRN2391 (10−8‐3 × 10−5 m), nicorandil (10−7‐3 × 10−4 m) and cromakalim (10−8‐3 × 10−5 m) relaxed renal arteries contracted by 25 Mm KCl in a concentration‐dependent manner. KRN2391‐induced relaxation was inhibited by methylene blue (10−5 m) and glibenclamide (10−6 m). Nicorandil‐induced relaxation was inhibited by methylene blue, but not by glibenclamide. The concentration‐relaxation curve for cromakalim displayed a rightward parallel shift in the presence of glibenclamide. In the control observation, KRN2391 and nicorandil also produced full relaxation, but cromakalim did not. The present results suggest that KRN2391 acts as both a nitrate and a potassium channel opener, and nicorandil acts only as a nitrate and only in canine renal artery.

Effects of K+ channel openers on ischemic dysfunction and metabolic disturbance in isolated perfused rat heart

The effects of two structurally different K+ channel openers, KRN2391 and cromakalim, on cardiac mechanisms during ischemia and reperfusion were studied in isolated perfused rat hearts. Isolated buffer-perfused rat hearts pretreated with KRN2391, cromakalim and vehicle were subjected to 25 min of ischemia followed by 30 min of reperfusion. Before ischemia, KRN2391 (1-10 microM) and cromakalim (1-10 microM) increased coronary flow, but did not modify cardiac function or biochemical parameters (adenine nucleotides, energy charge potential: ECP, lactate). During ischemia, KRN2391 (3, 10 microM) and cromakalim (10 microM) significantly accelerated the reduction in cardiac function and attenuated the decreased levels of ATP and ECP, but did not change the lactate content. After 30 min of reperfusion, pretreatment with KRN2391 and cromakalim resulted in a significant improvement in cardiac function, ischemic contracture and biochemical parameters. Thus, both KRN2391 and cromakalim have beneficial effects on biochemical parameters during ischemia and reperfusion, effects which may be related to cardiodepression during ischemia.

Effect of KRN2391 on canine ventricular arrhythmia models

1. KRN2391 (3-30 micrograms/kg, i.v.) produced a decrease in mean blood pressure (MBP) with concomitant increase in heart rate (HR) and change in electrocardiogram (ECG) such as the shortening of PP and PQ intervals and the prolongation of QTc and these changes in HR and ECG were attenuated by pretreatment with propranolol (1 mg/kg) in normal dogs. 2. KRN2391 at 30 micrograms/kg induces neither suppression nor aggravation of ventricular arrhythmias caused by adrenaline and digitalis. 3. In two-stage coronary ligation-induced arrhythmia, KRN2391 inhibited arrhythmia at 48 hr. 4. These results suggest that KRN2391 may be effective on arrhythmia related to ischemia. In addition, it is considered that arrhythmia is not induced even by a high dose of KRN2391 in the normal condition.

Effects of Pegylated Recombinant Human Megakaryocyte Growth and Development Factor on 5‐Fluorouracil‐induced Thrombocytopenia in Balloon‐injured Rats

We examined whether pegylated recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF) affected 5‐fluorouracil‐induced thrombocytopenia without inducing more severe intimal thickening after injury to rat carotid arteries. Rat carotid arteries were injured using a balloon catheter on day 0. 5‐Fluorouracil (100 mg kg−1) or vehicle was intravenously administered on day 1 in balloon‐injured rats. PEG‐rHuMGDF (100 μg kg−1) or vehicle was intravenously administered once a day on days 1–5 to balloon‐injured rats given 5‐fluorouracil or vehicle.

A mild transient decrease of peripheral red blood cell counts induced by a suprapharmacological dose of pegylated human megakaryocyte growth and development factor in rats

Previous studies have shown that pegylated recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF) at suprapharmacological dose induces a mild transient decrease of red blood cell counts according to thrombopoiesis in normal mice. To unravel the mechanism underlying this mild transient decrease of red blood cells, we have studied the effect of PEG‐rHuMGDF on the circulating plasma and blood volume, and the serum biochemical parameters of anaemia and splenectomy. Also, we have performed histological studies of the bone marrow and the spleen of PEG‐rHuMGDF‐treated rats.