Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation

Abstract

Blood pressure is regulated by a number of key molecules involving G-protein-coupled receptors, ion channels and monomeric small G-proteins. The relative contribution of these different signaling pathways to blood pressure regulation remains to be determined. Tamoxifen-induced, smooth musclespeci®c inactivation of the L-type Ca v 1.2 Ca 2+ channel gene in mice (SMAKO) reduced mean arterial blood pressure (MAP) in awake, freely moving animals from 120 6 4.5 to 87 6 8 mmHg. Phenylephrine (PE)-and angiotensin 2 (AT2)-induced MAP increases were blunted in SMAKO mice, whereas the Rho-kinase inhibitor Y-27632 reduced MAP to the same extent in control and SMAKO mice. Depolarization-induced contraction was abolished in tibialis arteries of SMAKO mice, and development of myogenic tone in response to intravascular pressure (Bayliss effect) was absent. Hind limb perfusion experiments suggested that 50% of the PE-induced resistance is due to calcium in¯ux through the Ca v 1.2 channel. These results show that Ca v 1.2 calcium channels are key players in the hormonal regulation of blood pressure and development of myogenic tone.

Cardiac ion channels

“…27 In mice, global and cardiac-specific deletion of Cav1.2 is lethal, whereas smooth muscle specific knockout lowered blood pressure and reduced myogenic tone and contractility in isolated small-diameter arteries. 28 A role for Cav1.3 in modulating heart rate has only recently been appreciated. Relative to other L-type calcium channels, Cav1.3 activates rapidly and at more hyperpolarized voltages; key attributes that support the role of Cav1.3 in pace making.…”

Unchanged β-Adrenergic Stimulation of Cardiac L-type Calcium Channels in Cav1.2 Phosphorylation Site S1928A Mutant Mice

“…Antibodies-The anti-Ca v 1.2 and -Ca v ␤2 a antibodies have been described previously (20,21). Antibodies against the catalytic (PKAc) and regulatory subunits (RII␣ and RII␤) of cAMP-dependent protein kinase were purchased from BD Biosciences.…”

“…Proteins were separated on 10% SDS-polyacrylamide gels, blotted, and probed with antibodies by using a chemiluminescence detection system or nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate as described in Ref. 20. To quantitatively evaluate Ser 1928 phosphorylation, blots were first probed with anti-phospho-Ser 1928 antibody and subsequently with anti-Ca v 1.2 antibody to correct for variability in the amount of total Ca v 1.2.…”

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

“…L-type Ca 2+ channels play a dominant role in blood pressure regulation as suggested by the fall in mean arterial blood pressure in mice with selective ablation of the channel gene (CACN1C) in vascular smooth muscle cells (VSMCs) (Moosmang et al, 2003), the increased CACN1C gene expression in VSMCs in rodent models of hypertension (Pesic et al, 2004;Rhee et al, 2009), the anti-hypertensive effect of L-type Ca 2+ channel blockers (CaBs) (Mancia et al, 2007) and the relationship between an autoantibody against vascular L-type Ca 2+ channels and clinical characteristics of hypertensive patients (Zhou et al, 2008). Transcripts and protein expression of CACN1C are found widely in the cardiovascular system, where the ion channels serve the time-and voltage-dependent influx of Ca 2+ ions to initiate muscle contraction (Akata, 2007;Bers, 2002).…”