Increase in Functional Ca²⁺ Channels in Cerebral Smooth Muscle With Renal Hypertension

From the Departments of Neurosurgery and Physiology, University of Maryland School of Medicine, Baltimore, Md.

Abstract—The hypothesis that availability of functional Ca²⁺ channels in vascular smooth muscle is augmented in hypertension was tested in basilar artery cells from Wistar rats exhibiting stable systolic blood pressure (BP_sys) for 2 to 11 weeks after partial renal artery ligation (Goldblatt 2-kidney 1-clip [2K1C] model). Cells were freshly isolated and patch-clamped using a nystatin–perforated patch method. BP_sys ranged from 110 to 280 mm Hg and correlated with normalized kidney mass. Macroscopic current-voltage curves were fit to a Boltzmann function to obtain maximum conductance (g_max), steepness and midpoint potential for the voltage dependence of activation (k and E_1/2, respectively), and extrapolated reversal potential for the chord conductance (E_rev). Linear regression of normalized conductance (ng_max=g_max/cell capacitance) versus BP_sys for 103 cells indicated a strong relationship, with a slope of 0.0019 nS · pF^-1 · mm Hg^-1 (P<0.0001). Similar analysis of data from 35 other cells exposed to 500 nmol/L Bay K 8644 gave a slope of 0.0041 nS · pF^-1 · mm Hg^-1 (P=0.001). Voltage-dependent parameters, k, E_1/2, and E_rev, were not significantly related to BP_sys. Single-channel measurements in cell-attached patches revealed that the number of channels in 32 patches was significantly related to BP_sys (P=0.0024) but that slope conductance, open dwell times at 0 mV, and distribution between 2 open states were not. Finally, in a subgroup of 61 cells from animals made hypertensive (180 mm Hg<BP_sys<200 mm Hg) for 1/2 to 6 weeks, we found that elevation of ng_max depended on duration of hypertension (P=0.003), with no elevation at 1/2 week. We conclude that in the 2K1C model, availability of functional Ca²⁺ channels increases with BP_sys with no change in channel properties and that measurable BP_sys elevation occurs before the increase in functional channels.

Key Words: hypertension • Goldblatt model • two-kidney one-clip model • Ca²⁺ channel • smooth muscle cell

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