Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans.
Rho-kinase plays an important role in modulating Ca(2+) sensitivity of vascular smooth muscle and has been suggested to be involved in the increased systemic vascular resistance in hypertensive animals. However, it remains to be examined whether this is also the case in patients with essential hypertension. Recently, it has been shown that fasudil is a specific Rho-kinase inhibitor. The aim of this study was to examine whether Rho-kinase is involved in the pathogenesis of hypertension in humans by using this Rho-kinase inhibitor. Studies were performed in hypertensive patients (HT group, n=14) and age-matched normotensive subjects (NT group, n=12). Forearm blood flow was measured by a strain-gauge plethysmograph during intra-arterial infusion of graded doses of fasudil (3.2, 6.4, 12.8, and 25.6 microg/min) or sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 microg/min). Resting forearm vascular resistance was significantly higher in the HT group than in the NT group (22+/-4 versus 17+/-5 U, respectively; P<0.05). The extent of the increase in forearm blood flow evoked by fasudil was significantly greater in the HT group than in the NT group (12.3+/-1.4 versus 6.0+/-0.6 mL. min(-1). 100 mL(-1), respectively; P<0.01). The percent decrease in forearm vascular resistance was significantly greater in the HT group than in the NT group (63.6+/-4.7% versus 29.6+/-3.9%, respectively; P<0.01). By contrast, forearm vasodilator response evoked by sodium nitroprusside was comparable between the 2 groups. These results provide the first evidence that Rho-kinase may be involved in the pathogenesis of the increased peripheral vascular resistance in hypertension in humans.
Masumoto
A
A
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Hirooka
Y
Y
Shimokawa
H
H
Hironaga
K
K
Setoguchi
S
S
Takeshita
A
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular; D009599:Nitroprusside / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009599:Nitroprusside; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil