Attenuated Noradrenaline-Induced Contraction of Pulmonary Arteries from Rats Treated with Monocrotaline: Role of Rho Kinase

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Abstract

Noradrenaline-induced pulmonary artery contraction was reduced in monocrotaline-treated rats. The possibility that this could be due to alterations in the rho kinase pathway was examined in this study. A combination of nifedipine (10–6 M) and thapsigargin (10–6 M) attenuated noradrenaline-induced contraction significantly more in artery segments from monocrotaline-treated rats than in artery segments from control rats indicating a reduced role for calcium sensitization in artery segments from monocrotaline-treated rats. In artery segments permeabilized with ionomycin, CaCl2 (1.25 mmol/l) produced significantly greater contraction in monocrotaline treated rats compared with control rats. Addition of noradrenaline (10–5 M) to the bath produced further contractions in both groups. However, noradrenaline-induced contraction was less in monocrotaline-treated rats compared with controls. Y-27632 concentration dependently relaxed ring segments of pulmonary artery pre-contracted with noradrenaline (10–5 M). The pIC50 values were 6.46 ± 0.09 (n = 5) 5.81 ± 0.06 (n = 5) in control and pulmonary hypertensive rings, respectively. The maximum relaxation to Y-27632 was significantly higher in monocrotaline-treated rats. ROCK II was the predominant isoform of rho kinase expressed in the pulmonary artery. The level of expression was increased in rats treated with monocrotaline. These results would suggest that while basal rho kinase activity was elevated in monocrotaline-induced pulmonary hypertension, noradrenaline-induced contraction was attenuated, suggesting poor coupling of the receptor activation to rho kinase activation.

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Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle.

Lawrence H Le, P Pacaud, G Loirand … (2000)

The potent vasodilator action of cyclic GMP-dependent protein kinase (cGK) involves decreasing the Ca(2+) sensitivity of contraction of smooth muscle via stimulation of myosin light chain phosphatase through unknown mechanisms (Wu, X., Somlyo, A. V., and Somlyo, A. P. (1996) Biochem. Biophys. Res. Commun. 220, 658-663). Myosin light chain phosphatase activity is controlled by the small GTPase RhoA and its target Rho kinase. Here we demonstrate cGMP effects mediated by cGK that inhibit RhoA-dependent Ca(2+) sensitization of contraction of blood vessels and actin cytoskeleton organization in cultured vascular myocytes. Ca(2+) sensitization and actin organization were inhibited by both 8-bromo-cGMP and sodium nitroprusside (SNP). SNP also caused translocation of activated RhoA from the membrane to the cytosol. SNP-induced actin disassembly was lost in vascular myocytes in culture after successive passages but was restored by transfection of cells with cGK I. Furthermore, cGK phosphorylated RhoA in vitro, and addition of cGK I inhibited RhoA-induced Ca(2+) sensitization in permeabilized smooth muscle. 8-Bromo-cGMP-induced actin disassembly was inhibited in vascular myocytes expressing RhoA(Ala-188), a mutant that could not be phosphorylated. Collectively, these results indicate that cGK phosphorylates and inhibits RhoA and suggest that the consequent inhibition of RhoA-induced Ca(2+) sensitization and actin cytoskeleton organization contributes to the vasodilator action of nitric oxide.

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Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.

Yutaka Nakashima, Yasuharu Matsumoto, Hiroaki Shimokawa … (2004)

Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.

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Fiber type and temperature dependence of inorganic phosphate: implications for fatigue.

R Fitts, Shaival Davé, E Debold (2004)

Elevated levels of P(i) are thought to cause a substantial proportion of the loss in muscular force and power output during fatigue from intense contractile activity. However, support for this hypothesis is based, in part, on data from skinned single fibers obtained at low temperatures (< or =15 degrees C). The effect of high (30 mM) P(i) concentration on the contractile function of chemically skinned single fibers was examined at both low (15 degrees C) and high (30 degrees C) temperatures using fibers isolated from rat soleus (type I fibers) and gastrocnemius (type II fibers) muscles. Elevating P(i) from 0 to 30 mM at saturating free Ca(2+) levels depressed maximum isometric force (P(o)) by 54% at 15 degrees C and by 19% at 30 degrees C (P < 0.05; significant interaction) in type I fibers. Similarly, the P(o) of type II fibers was significantly more sensitive to high levels of P(i) at the lower (50% decrease) vs. higher temperature (5% decrease). The maximal shortening velocity of both type I and type II fibers was not significantly affected by elevated P(i) at either temperature. However, peak fiber power was depressed by 49% at 15 degrees C but by only 16% at 30 degrees C in type I fibers. Similarly, in type II fibers, peak power was depressed by 40 and 18% at 15 and 30 degrees C, respectively. These data suggest that near physiological temperatures and at saturating levels of intracellular Ca(2+), elevated levels of P(i) contribute less to fatigue than might be inferred from data obtained at lower temperatures.

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Author and article information

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2005

Publication date (Print): October 2005

Publication date (Electronic): 28 September 2005

Volume: 42

Issue: 5

Pages: 433-440

Affiliations

Departments of ^aBiochemistry and ^bPharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait

Article

Publisher ID: 87901 Other ID: J Vasc Res 2005;42:433–440

DOI: 10.1159/000087901

PubMed ID: 16127279

SO-VID: b6783705-9087-49ae-9c31-c7d0649d870b

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 08 April 2005

Date accepted : 25 June 2005

Page count

Figures: 6, References: 32, Pages: 8

Attenuated Noradrenaline-Induced Contraction of Pulmonary Arteries from Rats Treated with Monocrotaline: Role of Rho Kinase

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Karger: Cardiovascular System

Most cited references 20

Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle.

Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.

Fiber type and temperature dependence of inorganic phosphate: implications for fatigue.

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