Vascular calcium channels and high blood pressure: pathophysiology and therapeutic implications

Abstract

Long-lasting Ca(2+) (Ca(L)) channels of the Ca(v)1.2 gene family are heteromultimeric structures that are minimally composed of a pore-forming alpha(1C) subunit and regulatory beta and alpha(2)delta subunits in vascular smooth muscle cells. The Ca(L) channels are the primary pathways for voltage-gated Ca(2+) influx that trigger excitation-contraction coupling in small resistance vessels. Notably, vascular smooth muscle cells of hypertensive rats show an increased expression of Ca(L) channel alpha(1C) subunits, which is associated with elevated Ca(2+) influx and the development of abnormal arterial tone. Indeed, blood pressure per se appears to promote Ca(L) channel expression in small arteries, and even short-term rises in pressure may alter channel expression. Membrane depolarization has been shown to be one stimulus associated with elevated blood pressure that promotes Ca(L) channel expression at the plasma membrane. Future studies to define the molecular processes that regulate Ca(L) channel expression in vascular smooth muscle cells will provide a rational basis for designing antihypertensive therapies to normalize Ca(L) channel expression and the development of anomalous vascular tone in hypertensive pathologies.

Fig. 1

(A) Proposed membrane topology of the L-type Ca²⁺ (Ca_L) channel. The central α₁ subunit is a single large polypeptide of 4 repeat domains (I–IV). The intracellular linkers and N- and C-termini of the α₁ subunit interact with β subunits and intracellular signaling molecules. Genes for four β subunits (β₁, β₂, β₃, β₄) have been identified, and four splice variants of the α₂δ subunit exist. A γ subunit has been detected in skeletal muscle and brain. Abbreviations: AID, alpha interactive domain; BID, beta interactive domain; CaM, calmodulin; PKA, protein kinase A; PKC, protein kinase C. (B) Linear model of amino acids in the domains of a β subunit. The β subunits possess a guanylate kinase (GK) region that contains the beta interactive domain (BID), and a Src homology 3 (SH3) domain that may interact with the GK region to permit binding between the α₁ and β subunits.

Fig. 2

Immunoblot showing that the α_1C subunit (200–240 kDa) is more highly expressed in the mesenteric, femoral and renal arteries of SHR compared to WKY rats. The doublet bands represent the long and short forms of the subunit. α-Actin was used as a loading control and appears as a 45-kDa band.

Fig. 3

Renal arteries of SHR show an increased expression and function of the Ca_L channel α_1C subunit. (A) The α_1C subunit is more highly expressed in renal arteries of SHR compared to WKY rats. (B) Whole-cell Ca²⁺ currents elicited by 8-mV steps from −70 mV to +20 mV were higher in renal VSMCs of SHR compared to WKY rats. (C) Tension-recording traces in isolated renal arteries of WKY and SHR maintained in drug-free physiological salt solution (PSS). The arteries of SHR developed more Ca²⁺-dependent tone, which was reversed by 1 μmol/L nifedipine. Adapted with permission from Pratt et al. (2002).

Fig. 4

Aortas of Sprague–Dawley rats were banded between the renal arteries to establish high blood pressure in the right renal circulation proximal to the banded site (inset). Four weeks later, renal arteries were microdissected from the right and left kidneys of the same animal for analysis. (A) The α_1C subunit was more highly expressed in the right renal (RR) arteries exposed to high blood pressure than in the left renal (LR) arteries. (B) Whole-cell Ca²⁺ currents elicited by 8-mV steps from −70 mV to +50 mV were higher in renal VSMCs of RR compared to LR arteries. (C) The RR arteries developed more Ca²⁺-dependent tone than the LR arteries in drug-free physiological salt solution (PSS), which was reversed by 1 μmol/L nifedipine. Adapted with permission from Pesic et al. (2004).

Fig. 5

Isolated renal arteries of control Sprague–Dawley rats were incubated for 48 h in control (Ctrl) or depolarizing (Depol.) media. (A) The Ca_L channel α_1C subunit was more highly expressed in the arteries depolarized for 48 h. (B) Whole-cell Ca²⁺ currents elicited by 8-mV steps from −70 mV to +50 mV were higher in renal VSMCs of depolarized compared to control arteries. (C) Cartoon suggesting that depolarization results in the upregulation of α_1C subunits in VSMC membranes. The mechanism has not been delineated. Adapted with permission from Pesic et al. (2004).