doi: 10.1161/hy1201.096541
(Hypertension. 2001;38:1307.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Possible Involvement of Rho-Kinase in the Pathogenesis of Hypertension in Humans
From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Correspondence to Yoshitaka Hirooka, MD, PhD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail hyoshi{at}cardiol.med.kyushu-u.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Rho-kinase plays an important role in modulating Ca2+ 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 µg/min) or sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 µg/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.
Key Words: hypertension, essential • muscle, smooth, vascular • blood flow • vascular resistance
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Increased systemic vascular resistance plays an important role in the pathogenesis of hypertension; however, the molecular mechanism remains to be elucidated. Phosphorylation of myosin light chain (MLC) is a crucial step for vascular smooth muscle (VSMC) contraction, the extent of which is regulated in a dual manner by MLC kinase and MLC phosphatase (MLCPh).1 Inhibition of MLCPh results in an increase in MLC phosphorylation and subsequent VSMC hypercontraction (Ca2+ sensitization).1 Indeed, this Ca2+ sensitization mechanism of VSMCs has been reported to be enhanced in hypertensive animals.2
Rho-kinase/ROK
/ROCKII,3–5 which is activated by the small GTPase Rho, inhibits MLCPh activity and thus plays a key role in Ca2+ sensitization and hypercontraction of VSMCs.1,6 It has been previously reported that Y-27632, a Rho-kinase inhibitor, preferentially lowers arterial pressure in rat models of hypertension in vivo, which indirectly suggests an involvement of Rho-kinase in hypertension.7 We have recently demonstrated that Rho-kinase is upregulated and plays a key role in VSMC contraction in a porcine model of coronary artery spasm8 and in spontaneously hypertensive rats (SHR).9 However, it remains to be examined whether this is also the case in humans.
Fasudil,10 a protein kinase inhibitor, is currently used in Japan for the treatment of cerebral vasospasm after subarachnoid hemorrhage. It has been recently demonstrated that fasudil is a specific Rho-kinase inhibitor, as is Y-27632,7,11,12 although the latter has not been approved for human use. Thus, fasudil is regarded as a specific Rho-kinase inhibitor that can be used in humans.13
The present study was thus designed to determine whether Rho-kinase is involved in the increased peripheral vascular resistance in patients with essential hypertension by examining the vasodilator effect of fasudil.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Fourteen patients with essential hypertension (8 men and 6 women) and 12 normal subjects (7 men and 5 women) were enrolled in the present study. The mean age of the hypertensive patients was 56±9 years; that of the normotensive subjects, 55±10 years. The hypertensive patients had no other coronary risk factors. Normal subjects did not have systemic hypertension, diabetes mellitus, or hyperlipidemia. Nine of the hypertensive patients had not received any antihypertensive therapy previously. Although the remaining 5 patients had previously received antihypertensive therapy, all vasodilator agents were discontinued >24 hours before the study. Written informed consent was obtained from all subjects. The present study was approved by the ethics committee for human research in our institute.
General Procedures
The present study was performed with subjects in a supine position and in a postabsorptive state with room temperature at 25°C to 26°C. With the subjects under local anesthesia, the left brachial artery was cannulated with a 20-gauge intravascular cannula for drug infusion, and the cannula was connected to a pressure transducer for direct measurement of arterial pressure.
Measurement of FBF
Forearm blood flow (FBF) was measured by using a strain-gauge plethysmograph with a venous-occlusion technique, as previously reported.14 FBF (mL · min-1 · 100 mL of forearm volume-1) was calculated from the rate of increase in forearm volume while venous return from the forearm was prevented by inflating the cuff on the upper arm. The pressure in the venous-occlusion or congesting cuff was 40 mm Hg. Circulation to the hand was arrested by a cuff inflated around the wrist. An average of 4 measurements made at 15-second intervals was used for later analysis. Forearm vascular resistance (FVR) was calculated by dividing mean arterial pressure (diastolic pressure plus one third of pulse pressure in mm Hg) by FBF. These values are expressed as units throughout the study.
Protocol
FBF, arterial pressure, and heart rate were measured at rest and during the administration of graded doses of fasudil (3.2, 6.4, 12.8, and 25.6 µg/min) or sodium nitroprusside (SNP; 0.4, 0.8, 1.6, and 3.2 µg/min). Each dose of fasudil was infused for 15 minutes, and the FBF was measured in the last minute of each infusion. Each dose of SNP was infused for 5 minutes, and FBF was measured after each infusion. Venous blood samples were drawn from the antecubital vein before and immediately after infusion of the peak dose of fasudil (25.6 µg/min) and at the end of the study for determination of the concentration of fasudil.
Drugs
The following drugs were used: fasudil (Asahi Chemical Industries) and SNP. All drugs were dissolved in physiological saline immediately before use.
Statistical Analysis
All results are expressed as mean±SEM. Values at rest were compared by unpaired t test. Responses to graded doses of drugs in each group were examined by ANOVA for repeated measures. Two-way ANOVA was used to compare responses of FBF and FVR in the 2 groups. Values of P<0.05 were considered to be statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Characteristics
Mean blood pressure at rest was significantly higher in hypertensive patients than in normotensive subjects (103±7 versus 73±6 mm Hg, respectively; P<0.01). Heart rate at rest did not significantly differ between the hypertensive patients and normotensive subjects (70±5 versus 69±6/min, respectively). Basal FBF did not differ between the hypertensive patients and normotensive subjects (3.2±1 versus 3.8±2 mL · 100 mL-1 · min-1). Basal FVR was significantly higher in the hypertensive patients than in the normotensive subjects. (22±4 versus 17±5 U, respectively; P<0.05). The 2 groups were comparable in age, gender difference, body mass index, plasma total cholesterol, triglycerides, LDL and HDL cholesterol, hemoglobin AIc, and current smoking habits (data not shown).
Plasma Concentrations of Fasudil
Just after the peak dose of fasudil, its plasma concentrations significantly increased in both groups; however, the levels were comparable between the hypertensive patients and normotensive subjects (71±22 versus 72±23 µmol/L, respectively).
Forearm Vascular Responses to Fasudil and SNP
Fasudil significantly evoked dose-dependent increases in FBF in the hypertensive patients but not in the normotensive subjects (Figure 1). By contrast, SNP caused comparable increases in FBF in the 2 groups (Figure 1). Fasudil evoked significantly greater decreases in FVR in the hypertensive patients compared with the normotensive subjects, thus normalizing FVR in those patients (Figure 2). In contrast, SNP caused comparable decreases in FVR in the 2 groups (Figure 2). Systemic arterial blood pressure and heart rate did not change significantly during the intra-arterial infusion of fasudil or SNP in either group (data not shown).
|
). The results are expressed as mean±SEM.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study was conducted on the assumption that fasudil is a specific Rho-kinase inhibitor.7,11,12 Davies et al11 recently examined the specificity of 16 commonly used protein kinase inhibitors against 24 protein kinases. They found that the inhibitory effect of fasudil on Rho-kinase is as specific as that of Y-27632.11 Because Y-27632 has not been approved for human use, we chose fasudil as a specific Rho-kinase inhibitor for the present study.
The major finding of the present study was that the forearm vasodilator response to fasudil was significantly greater in hypertensive patients than in normal subjects, whereas SNP caused a similar forearm vasodilator response in the 2 groups. The extent of the increase in plasma concentration of fasudil was comparable between the 2 groups, and the administration of fasudil into the forearm circulation did not significantly change systemic blood pressure or heart rate in either group. The preferential vasodilator effect of fasudil in hypertensive patients was not due to the structural change of the arterial wall, because the response to SNP 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 hypertensive patients.
The involvement of Rho-kinase in hypertension was first indirectly suggested by Uehata et al,7 inasmuch as they observed that Y-27632 preferentially lowered blood pressure in various rat models of hypertension in vivo. Recently, we were able to directly demonstrate that in hypertensive blood vessels of SHR, both the expression and the activity of Rho-kinase are enhanced, causing VSMC hyperreactivity through suppression of MLCPh.9 The same molecular mechanism appears to be involved in the pathogenesis of coronary artery spasm in our porcine model.8,13 Thus, it is conceivable that Rho-kinase is involved in a wide variety of disorders with VSMC hyperreactivity.13
Rho-kinase plays an important role in various cellular functions, not only in VSMC contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expression.6 Indeed, we and others have recently demonstrated that Rho-kinase is involved in the pathogenesis of arteriosclerosis in general.15,16 We also have recently demonstrated that long-term oral treatment with fasudil inhibits the development of coronary vascular lesions (medial thickening and perivascular fibrosis) in SHR in vivo.9 The present study suggests that Rho-kinase is also substantially involved in the pathogenesis of hypertension in humans. Taken together, it is suggested that Rho-kinase could be regarded as a novel therapeutic target for the treatment of hypertension.
|
Acknowledgments |
|---|
This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports, and Culture, Tokyo, Japan (Nos. 09470169, 10357006, 12032215, and 12470158).
Received May 24, 2001; first decision June 5, 2001; accepted July 9, 2001.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Somlyo AP, Somlyo AV. Signal transduction by G-proteins, rho-kinase and phosphatase to smooth muscle and non-muscle myosin II. J Physiol. 2000; 522: 177–185.
2. Satoh S, Kreutz R, Wilms C. Augmented agonist-induced Ca2+-sensitization of coronary artery contraction in genetically hypertensive rats: evidence for altered signal transduction in the coronary smooth muscle cells. J Clin Invest. 1997; 94: 1397–1403.
3. Kimura K, Ito M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996; 273: 245–248.[Abstract]
4. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 1996; 15: 1885–1893.[Medline] [Order article via Infotrieve]
5.
Leung T, Manser E, Tan L, Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem. 1995; 270: 29051–29054.
6. Kaibuchi K, Kuroda S, Amano M. Regulation of cytoskeletons and cell adhesions by the Rho family GTPases in mammalian cells. Annu Rev Biochem. 1999; 68: 459–486.[Medline] [Order article via Infotrieve]
7. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997; 389: 990–994.[Medline] [Order article via Infotrieve]
8.
Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, Higo T, Egashira K, Takahashi S, Kaibuchi K, Takeshita A. Inhibition of myosin phosphatase by up-regulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1ß. Circulation. 2000; 101: 1319–1323.
9.
Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Kaibuchi K, Takeshita A. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 2001; 15: 1062–1064.
10. Asano T, Suzuki M, Tsuchiya S, Satoh S, Ikegami I, Shibuya Y, Hidaka H. Vasodilator actions of HA1077 in vitro and in vivo putatively mediated by the inhibition of protein kinase. Br J Pharmacol. 1989; 98: 1091–1100.[Medline] [Order article via Infotrieve]
11. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000; 351: 95–105.[Medline] [Order article via Infotrieve]
12. Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y. Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. Am J Physiol. 2000; 278: C57–C65.
13. Shimokawa H. Cellular and molecular mechanism for coronary artery spasm: lessons from animal models. Jpn Circ J. 2000; 64: 1–12.[Medline] [Order article via Infotrieve]
14.
Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S, Momohara M, Takeshita A. Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients. Hypertension. 1992; 20: 175–180.
15. Eto Y, Shimokawa H, Hiroki J, Morishige K, Kandabashi T, Matsumoto Y, Amano M, Hoshijima M, Kaibuchi K, Takeshita A. Gene transfer of dominant negative Rho-kinase suppresses neointimal formation after balloon injury in pigs. Am J Physiol. 2000; 278: H1744–H1750.
16.
Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y, Kaibuchi K, Takeshita A. Adenovirus-mediated transfer of dominant-negative Rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo. Arterioscler Thromb Vasc Biol. 2001; 21: 548–554.
This article has been cited by other articles:
 |
|
 |
|
  M. Lohn, O. Plettenburg, Y. Ivashchenko, A. Kannt, A. Hofmeister, D. Kadereit, M. Schaefer, W. Linz, M. Kohlmann, J.-M. Herbert, et al. Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor Hypertension, September 1, 2009; 54(3): 676 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Y. Chan, J. C. Mak, R. Y. K. Man, and P. M. Vanhoutte Rho Kinase Inhibitors Prevent Endothelium-Dependent Contractions in the Rat Aorta J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 820 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Badejo Jr., J. S. Dhaliwal, D. B. Casey, T. B. Gallen, A. J. Greco, and P. J. Kadowitz Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L828 - L836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Sun, P. Yue, Z. Ying, A. J. Cardounel, R. D. Brook, R. Devlin, J.-S. Hwang, J. L. Zweier, L. C. Chen, and S. Rajagopalan Air Pollution Exposure Potentiates Hypertension Through Reactive Oxygen Species-Mediated Activation of Rho/ROCK Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1760 - 1766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Machida, Y. Hamaya, S. Izumi, Y. Hamaya, K. Iizuka, Y. Igarashi, M. Minami, R. Levi, and M. Hirafuji Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Induced by Interleukin-1{beta} in Rat Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 200 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Dhaliwal, D. B. Casey, A. J. Greco, A. M. Badejo Jr., T. B. Gallen, S. N. Murthy, B. D. Nossaman, A. L. Hyman, and P. J. Kadowitz Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1306 - L1313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Allahdadi, B. R. Walker, and N. L. Kanagy ROK contribution to endothelin-mediated contraction in aorta and mesenteric arteries following intermittent hypoxia/hypercapnia in rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2911 - H2918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yada, H. Shimokawa, O. Hiramatsu, Y. Shinozaki, H. Mori, M. Goto, Y. Ogasawara, and F. Kajiya Important Role of Endogenous Hydrogen Peroxide in Pacing-Induced Metabolic Coronary Vasodilation in Dogs In Vivo J. Am. Coll. Cardiol., September 25, 2007; 50(13): 1272 - 1278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Holowatz and W. L. Kenney Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1090 - H1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Thompson-Torgerson, L. A. Holowatz, N. A. Flavahan, and W. Larry Kenney Rho kinase-mediated local cold-induced cutaneous vasoconstriction is augmented in aged human skin Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H30 - H36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Bussemaker, F. Pistrosch, S. Forster, K. Herbrig, P. Gross, J. Passauer, and R. P. Brandes Rho kinase contributes to basal vascular tone in humans: role of endothelium-derived nitric oxide Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H541 - H547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Lin, G. P. Craig, L. Zhang, V. G. Yuen, M. Allard, J. H. McNeill, and K. M. MacLeod Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats Cardiovasc Res, July 1, 2007; 75(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Holowatz and W. L. Kenney Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans J. Physiol., June 1, 2007; 581(2): 863 - 872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Thompson-Torgerson, L. A. Holowatz, N. A. Flavahan, and W. L. Kenney Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1700 - H1705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Noma, C. Goto, K. Nishioka, D. Jitsuiki, T. Umemura, K. Ueda, M. Kimura, K. Nakagawa, T. Oshima, K. Chayama, et al. Roles of Rho-Associated Kinase and Oxidative Stress in the Pathogenesis of Aortic Stiffness J. Am. Coll. Cardiol., February 13, 2007; 49(6): 698 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Doe, R. Bentley, D. J. Behm, R. Lafferty, R. Stavenger, D. Jung, M. Bamford, T. Panchal, E. Grygielko, L. L. Wright, et al. Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 89 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nohria, M. E. Grunert, Y. Rikitake, K. Noma, A. Prsic, P. Ganz, J. K. Liao, and M. A. Creager Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease Circ. Res., December 8, 2006; 99(12): 1426 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Song, C. K. Kost Jr., and D. S. Martin Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway Cardiovasc Res, December 1, 2006; 72(3): 456 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. H. Zucker Novel Mechanisms of Sympathetic Regulation in Chronic Heart Failure Hypertension, December 1, 2006; 48(6): 1005 - 1011. [Full Text] [PDF]
|
|
|
|
|
|
H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, Y. Hirooka, Y. Kimura, Y. Sagara, and K. Sunagawa Ovariectomy Augments Hypertension Through Rho-Kinase Activation in the Brain Stem in Female Spontaneously Hypertensive Rats Hypertension, October 1, 2006; 48(4): 651 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yada, H. Shimokawa, O. Hiramatsu, Y. Haruna, Y. Morita, N. Kashihara, Y. Shinozaki, H. Mori, M. Goto, Y. Ogasawara, et al. Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1138 - H1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Liao Rho-Kinase: A Potential Link Between Hypercholesterolemia and Abnormal Vascular Smooth Muscle Contraction Circ. Res., August 4, 2006; 99(3): 238 - 239. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Alemany, O. Vogler, S. Teres, C. Egea, C. Baamonde, F. Barcelo, C. Delgado, K. H. Jakobs, and P. V. Escriba Antihypertensive action of 2-hydroxyoleic acid in SHRs via modulation of the protein kinase A pathway and Rho kinase J. Lipid Res., August 1, 2006; 47(8): 1762 - 1770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jin, Z. Ying, R. H. P. Hilgers, J. Yin, X. Zhao, J. D. Imig, and R. C. Webb Increased RhoA/Rho-Kinase Signaling Mediates Spontaneous Tone in Aorta from Angiotensin II-Induced Hypertensive Rats J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 288 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Calo, E. Pagnin, M. Mussap, P. A. Davis, and A. Semplicini Rho/Rho-kinase and C-reactive protein relationship in hypertension and atherosclerosis Nephrol. Dial. Transplant., April 1, 2006; 21(4): 1131 - 1132. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Noma, N. Oyama, and J. K. Liao Physiological role of ROCKs in the cardiovascular system Am J Physiol Cell Physiol, March 1, 2006; 290(3): C661 - C668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ying, L. Jin, T. Palmer, and R. C. Webb Angiotensin II Up-Regulates the Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (RhoGEF), a Regulator of G Protein Signaling Domain-Containing RhoGEF, in Vascular Smooth Muscle Cells Mol. Pharmacol., March 1, 2006; 69(3): 932 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Naik, L. Xiang, and R. L. Hester Enhanced role for RhoA-associated kinase in adrenergic-mediated vasoconstriction in gracilis arteries from obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R154 - R161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Noma, C. Goto, K. Nishioka, K. Hara, M. Kimura, T. Umemura, D. Jitsuiki, K. Nakagawa, T. Oshima, K. Chayama, et al. Smoking, Endothelial Function, and Rho-Kinase in Humans Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2630 - 2635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Rikitake, H.-H. Kim, Z. Huang, M. Seto, K. Yano, T. Asano, M. A. Moskowitz, and J. K. Liao Inhibition of Rho Kinase (ROCK) Leads to Increased Cerebral Blood Flow and Stroke Protection Stroke, October 1, 2005; 36(10): 2251 - 2257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Shimokawa and A. Takeshita Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1767 - 1775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Thakali, S. L. Demel, G. D. Fink, and S. W. Watts Endothelin-1-induced contraction in veins is independent of hydrogen peroxide Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1115 - H1122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, Y. Hirooka, N. Hori, Y. Kimura, Y. Sagara, H. Shimokawa, A. Takeshita, and K. Sunagawa Inhibition of Rho-Kinase in the Nucleus Tractus Solitarius Enhances Glutamate Sensitivity in Rats Hypertension, August 1, 2005; 46(2): 360 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Rikitake and J. K. Liao Rho-Kinase Mediates Hyperglycemia-Induced Plasminogen Activator Inhibitor-1 Expression in Vascular Endothelial Cells Circulation, June 21, 2005; 111(24): 3261 - 3268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kishi, Y. Hirooka, A. Masumoto, K. Ito, Y. Kimura, K. Inokuchi, T. Tagawa, H. Shimokawa, A. Takeshita, and K. Sunagawa Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure Circulation, May 31, 2005; 111(21): 2741 - 2747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes Statin-Mediated Inhibition of Rho: Only to Get More NO? Circ. Res., May 13, 2005; 96(9): 927 - 929. [Full Text] [PDF]
|
|
|
|
|
|
L. A. Calo, E. Pagnin, P. A. Davis, M. Sartori, A. Semplicini, A. C. Pessina, S. Wolfrum, Y. Rikitake, J. K. Liao, A. Dendorfer, et al. Rho Kinase Inhibition and Vascular Protection: Support From Studies in Bartter and Gitelman Syndrome Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): e34 - e35. [Full Text] [PDF]
|
|
|
|
 |
|
 Y Fukumoto, T Matoba, A Ito, H Tanaka, T Kishi, S Hayashidani, K Abe, A Takeshita, and H Shimokawa Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension Heart, March 1, 2005; 91(3): 391 - 392. [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhu, S. Zhu, D. Liu, T. Cao, L. Wang, and M. Tepel Thiazide-Like Diuretics Attenuate Agonist-Induced Vasoconstriction by Calcium Desensitization Linked to Rho Kinase Hypertension, February 1, 2005; 45(2): 233 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Friel, M. Curley, N. Ravikumar, T. J. Smith, and J. J. Morrison Rho A/Rho Kinase mRNA and Protein Levels in Human Myometrium During Pregnancy and Labor Reproductive Sciences, January 1, 2005; 12(1): 20 - 27. [Abstract] [PDF]
|
|
|
|
|
|
D. L. Lee, R. C. Webb, and L. Jin Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature: Highlights From the Recent Literature Hypertension, December 1, 2004; 44(6): 796 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jin, Z. Ying, and R. C. Webb Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1495 - H1500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagaoka, Y. Morio, N. Casanova, N. Bauer, S. Gebb, I. McMurtry, and M. Oka Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L665 - L672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, Y. Hirooka, Y. Sagara, Y. Kimura, K. Kaibuchi, H. Shimokawa, A. Takeshita, and K. Sunagawa Inhibition of Rho-Kinase in the Brainstem Augments Baroreflex Control of Heart Rate in Rats Hypertension, October 1, 2004; 44(4): 478 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chrissobolis, K. Budzyn, P. D. Marley, and C. G. Sobey Evidence That Estrogen Suppresses Rho-Kinase Function in the Cerebral Circulation In Vivo Stroke, September 1, 2004; 35(9): 2200 - 2205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Budzyn, P. D. Marley, and C. G. Sobey Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R342 - R348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Schiff and J. P. Mulhall The Link Between LUTS and ED: Clinical and Basic Science Evidence J Androl, July 1, 2004; 25(4): 470 - 478. [Full Text] [PDF]
|
|
|
|
|
|
E. A. Wehrwein, C. A. Northcott, R. D. Loberg, and S. W. Watts Rho/Rho Kinase and Phosphoinositide 3-Kinase Are Parallel Pathways in the Development of Spontaneous Arterial Tone in Deoxycorticosterone Acetate-Salt Hypertension J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1011 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Bailly, A. J. Ridley, S. M. Hall, and S. G. Haworth RhoA Activation by Hypoxia in Pulmonary Arterial Smooth Muscle Cells Is Age and Site Specific Circ. Res., May 28, 2004; 94(10): 1383 - 1391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, Y. Hirooka, T. Kishi, Y. Kimura, K. Kaibuchi, H. Shimokawa, and A. Takeshita Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition Hypertension, February 1, 2004; 43(2): 156 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-C. Tosello-Trampont, K. Nakada-Tsukui, and K. S. Ravichandran Engulfment of Apoptotic Cells Is Negatively Regulated by Rho-mediated Signaling J. Biol. Chem., December 12, 2003; 278(50): 49911 - 49919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, Y. Hirooka, K. Sakai, T. Kishi, K. Kaibuchi, H. Shimokawa, and A. Takeshita Rho/Rho-Kinase Pathway in Brain Stem Contributes to Blood Pressure Regulation via Sympathetic Nervous System: Possible Involvement in Neural Mechanisms of Hypertension Circ. Res., June 27, 2003; 92(12): 1337 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Noma, Y. Higashi, D. Jitsuiki, K. Hara, M. Kimura, K. Nakagawa, C. Goto, T. Oshima, M. Yoshizumi, and K. Chayama Smoking Activates Rho-Kinase in Smooth Muscle Cells of Forearm Vasculature in Humans Hypertension, May 1, 2003; 41(5): 1102 - 1105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Seko, M. Ito, Y. Kureishi, R. Okamoto, N. Moriki, K. Onishi, N. Isaka, D. J. Hartshorne, and T. Nakano Activation of RhoA and Inhibition of Myosin Phosphatase as Important Components in Hypertension in Vascular Smooth Muscle Circ. Res., March 7, 2003; 92(4): 411 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Randriamboavonjy, R. Busse, and I. Fleming 20-HETE-Induced Contraction of Small Coronary Arteries Depends on the Activation of Rho-Kinase Hypertension, March 1, 2003; 41(3): 801 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mohri, H. Shimokawa, Y. Hirakawa, A. Masumoto, and A. Takeshita Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm J. Am. Coll. Cardiol., January 1, 2003; 41(1): 15 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cavarape, N. Endlich, R. Assaloni, E. Bartoli, M. Steinhausen, N. Parekh, and K. Endlich Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo J. Am. Soc. Nephrol., January 1, 2003; 14(1): 37 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Masumoto, M. Mohri, H. Shimokawa, L. Urakami, M. Usui, and A. Takeshita Suppression of Coronary Artery Spasm by the Rho-Kinase Inhibitor Fasudil in Patients With Vasospastic Angina Circulation, April 2, 2002; 105(13): 1545 - 1547. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||