Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

Michal Behuliak,Michal Bencze,Ivana Vaněčková,Josef Zicha,Jaroslav Kuneš

doi:10.1155/2017/8029728

Abstract

Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry—spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.

Highlights

Increased vascular tone and elevated peripheral resistance are the hallmarks of human and experimental hypertension
In rats with intact endogenous renin-angiotensin system (RAS) and sympathetic nervous system (SNS), the administration of fasudil caused dose-dependent blood pressure reduction in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats (Figure 2(a)) and similar findings were obtained in transgenic rats (TGR) and Hannover Sprague Dawley (HanSD) rats (Figure 2(b))
When fasudil-induced MAP changes were expressed in percentage of initial MAP values, this strain difference was abolished in SHR (Figure 2(d)) but not in TGR (Figure 2(e))

Summary

Introduction

Increased vascular tone and elevated peripheral resistance are the hallmarks of human and experimental hypertension. The degree of resistance vessel constriction is determined by cytosolic calcium level and the sensitivity of contractile apparatus to it. The latter mechanism, which is called calcium sensitization, is enhancing vascular contraction at a given level of cytosolic calcium. It is partially signaled via RhoA/Rho kinase pathway that inhibits the dephosphorylation of myosin light chain through the inactivation of myosin light chain phosphatase [1,2,3,4,5]. RhoA/Rho kinase pathway is a constitutively active mechanism which is involved in the regulation of vascular tone and BP in normotensive animals under physiological conditions [12,13,14,15]

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