Background: Calcium entry through nifedipine-sensitive L-type voltage-dependent calcium channels (L-VDCC) is augmented in spontaneously hypertensive rats (SHR) characterized by enhanced sympathetic vasoconstriction. However, the changes of calcium sensitization mediated by RhoA/Rho kinase pathway are less understood.
Methods and results: The participation of calcium entry and calcium sensitization in the control of blood pressure (BP) and vascular contraction was studied in SHR and normotensive Wistar–Kyoto (WKY) rats. The acute administration of fasudil (Rho kinase inhibitor) caused BP decrease which lasted longer in SHR. Fasudil also attenuated adrenergic contraction in femoral or mesenteric arteries of WKY and SHR. BP reduction elicited by fasudil in WKY was more pronounced than that induced by L-VDCC blocker nifedipine (−33 ± 2 vs. −15 ± 3% of baseline BP, P < 0.001), whereas both inhibitors were similarly effective in SHR (−36 ± 4 vs. −41 ± 2%). Fasudil pretreatment also attenuated BP elevation elicited by L-VDCC agonist BAY K8644 more in WKY than in SHR (−63 ± 4 vs. −42 ± 5%, P < 0.001), indicating reduced calcium sensitization in SHR. Moreover, fasudil pretreatment shifted norepinephrine dose–response curves to the right more in WKY than in SHR. The additional nifedipine pretreatment shifted these curves further to the right but this shift was more pronounced in SHR than in WKY. Thus adrenergic vasoconstriction is more dependent on L-VDCC in SHR and on RhoA/Rho kinase pathway in WKY rats.
Conclusion: Ca2+ sensitization mediated by RhoA/Rho kinase pathway is attenuated in SHR compared with normotensive WKY rats. This might be a part of the compensation for enhanced Ca2+ entry through L-VDCC in genetic hypertension.
aInstitute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
bInstitute of Pharmacology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
*Michal Behuliak and Mária Pintérová contributed equally to the writing of this article.
Correspondence to Dr Josef Zicha, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-142 20 Prague 4, Czech Republic. Tel: +420 24106 2438; fax: +420 24106 2488; e-mail: firstname.lastname@example.org
Abbreviations: ANOVA, analysis of variance; BP, blood pressure; EC50, half-maximal effective concentration; Emax/2, half-maximal contraction; L-VDCC, L type voltage-dependent calcium channels; MAP, mean arterial pressure; RAS, renin–angiotensin system; SHR, spontaneously hypertensive rats; SNS, sympathetic nervous system; VSM, vascular smooth muscle; WKY, Wistar–Kyoto rats
Received 7 December, 2012
Revised 6 March, 2013
Accepted 27 April, 2013