Acute Rho-kinase inhibition improves coronary dysfunction in vivo, in the early diabetic microcirculationReport as inadecuate




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Cardiovascular Diabetology

, 12:111

First Online: 01 August 2013Received: 29 July 2013Accepted: 30 July 2013

Abstract

ObjectivesActivation of RhoA-Rho-kinase ROCK is increasingly implicated in acute vasospasm and chronic vasoconstriction in major organ systems. Therefore we aimed to ascertain whether an increase in ROCK activity plays a role in the deterioration of coronary vascular function in early stage diabetes.

MethodsSynchrotron radiation microangiography was used to determine in vivo coronary responses in diabetic 3 weeks post streptozotocin 65 mg-kg ip and vehicle treated male Sprague–Dawley rats n = 8 and 6. Changes in vessel number and calibre during vasodilator stimulation before and after blockade of nitric oxide synthase and cyclooxygenase were compared between rats. Acute responses to ROCK inhibitor, fasudil 10 mg-kg iv was evaluated. Further, perivascular and myocardial fibrosis, arterial intimal thickening were assessed by histology, and capillary density, nitrotyrosine and ROCK1-2 expressions were evaluated by immunohistochemical staining.

ResultsDiabetic rats had significantly elevated plasma glucose P < 0.001 vs control, but did not differ in fibrotic scores, media to lumen ratio, capillary density or baseline visible vessel number or calibre. Responses to acetylcholine and sodium nitroprusside stimulation were similar between groups. However, in comparison to control rats the diabetic rats showed more segmental constrictions during blockade, which were not completely alleviated by acetylcholine, but were alleviated by fasudil. Further, second order vessel branches in diabetic rats were significantly more dilated relative to baseline 37% vs 12% increase, P < 0.05 after fasudil treatment compared to control rats, while visible vessel number increased in both groups. ROCK2 expression was borderline greater in diabetic rat hearts P < 0.053.

ConclusionsWe found that ahead of the reported decline in coronary endothelial vasodilator function in diabetic rats there was moderate elevation in ROCK expression, more widespread segmental constriction when nitric oxide and prostacyclin production were inhibited and notably, increased calibre in second and third order small arteries-arterioles following ROCK inhibition. Based on nitrotyrosine staining oxidative stress was not significantly elevated in early diabetic rats. We conclude that tonic ROCK mediated vasoconstriction contributes to coronary vasomotor tone in early diabetes.

AbbreviationsAChAcetylcholine

BGBlood glucose

BWBody weight

COXCyclo-oxygenase

EDHFEndothelium derived hyperpolarising factors

eNOSEndothelial nitric oxide synthase

ET1Endothelin 1

HRHeart rate

IDInternal diameter

L-NAMENω-nitro-l-arginine methyl ester

LVLeft ventricle

MAPMean arterial pressure

NONitric oxide

NOSNitric oxide synthase

PGI2Prostacyclin

PKCProtein kinase C

ROCKRhoA-Rho-kinase

SEMStandard error of the mean

SNPSodium nitroprusside

SRSynchrotron radiation

STZStreptozotocin.

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2840-12-111 contains supplementary material, which is available to authorized users.

James T Pearson, Mathew J Jenkins contributed equally to this work.

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Author: James T Pearson - Mathew J Jenkins - Amanda J Edgley - Takashi Sonobe - Mandar Joshi - Mark T Waddingham - Yutaka Fujii

Source: https://link.springer.com/article/10.1186/1475-2840-12-111







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