Vasodilator actions of HA1077 in vitro and in vivo putatively mediated by the inhibition of protein kinase.
The in vitro and in vivo vasorelaxant effects of HA1077, 1-(5-isoquinolinesulphonyl)-homopiperazine HCl, a novel vasodilator were examined. The inhibitory effects of HA1077 on contractile responses to various agonists were examined on strips of rabbit aorta. The concentration-response curves to 5-hydroxytryptamine, prostaglandin F2alpha, histamine, angiotensin II, noradrenaline and dopamine were concentration-dependently shifted to the right in the presence of HA1077 (0.3-3.0 microM). The in vivo vasodilator effects of HA1077 were examined in the constant-pressure autoperfused coronary vascular bed of dogs. Intra-coronary administration of HA1077 (3-30 micrograms per dog) dose-dependently increased coronary blood flow (CBF), with no effect on mean blood pressure (MBP) or heart rate (HR). Intra-coronary infusion of atropine, propranolol or diphenhydramine did not modify the in vivo coronary vasodilator response to HA1077. To determine the flow profile for HA1077 in dogs, blood flow in four vascular beds was measured, by use of noncannulating electromagnetic flow probes. HA1077 (0.01-0.3 mg kg-1, i.v.) dose-dependently decreased MBP and increased vertebral blood flow (VBF), CBF, renal blood flow (RBF) and femoral blood flow (FBF). A haemodynamic analysis showed that continuous i.v. infusion of HA1077 (0.01 and 0.033 mg kg-1min-1) dose-dependently decreased peripheral vascular resistance and increased cardiac output. There were no significant changes in right atrial pressure, dP/dt or ventricular minute work. The effects of HA1077 on various enzymes considered to be related to the regulation of smooth muscle contraction were examined. HA1077 had little effect on cyclic nucleotide phosphodiesterases, yet it potently inhibited protein kinases such as cyclic nucleotide dependent protein kinases and Ca2+/calmodulin dependent myosin light chain kinase. The present study demonstrates that HA1077 is a novel type of arterial vasodilator.
Asano
T
T
Department of Pharmacology, Asahi Chemical Industry, Nobeoka, Japan.
Suzuki
T
T
Tsuchiya
M
M
Satoh
S
S
Ikegaki
I
I
Shibuya
M
M
Suzuki
Y
Y
Hidaka
H
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007537:Isometric Contraction; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009529:Nicardipine; C049347:fasudil; D002118:Calcium