Sympathetic Denervation Facilitates L‐Type Ca 2+ Channel Activation in Renal Resistance Arteries by Depolarization of Vascular Smooth Muscle Cells (VSMCs)

Abstract

Sympathetic denervation sensitizes renal resistance arteries (RA) to norepinephrine (NE) as well as to Rho kinase (Rock) and L-type Ca2+ channel inhibition. Since Rock-dependent Ca2+ sensitization and Ca2+ entry mutually interact in VSMCs, we tested if sympathetic denervation enhances Rock activation or L-type Ca2+ channel-dependent signaling. RA from sympathectomized rats showed higher pD2 values for NE than control RA (pD2 6.61±0.16 vs. 6.10±0.09, respectively, p<0.01). Nifedipine lowered pD2 and Emax for NE to similar values in both groups. Additional Rock inhibition did not affect pD2 but reduced Emax for NE by further 20% in both groups. NE did not significantly increase Rock substrate phosphorylation in RA of both groups. There was no evidence for group differences in IP3- and RyR-dependent Ca2+ release. While L-Type Ca2+ channel protein expression was similar in RA of both groups, the L-type Ca2+ channel activator S-(-)-BayK8644 contracted RA from sympathectomized but not from control rats. Rock inhibition or KATP channel activation blocked and depolarization enhanced S-(-)-BayK8644-induced contractions in RA from sympathectomized rats. Depolarization also gave rise to S-(-)-BayK8644-induced contractions in control RA. Resting membrane potential in VSMC from RA was lower in sympathectomized rats than in controls (-57.5 ± 2.0 mV vs. -64.3 ± 0.3 mV, p < 0.01). Sympathetic denervation depolarizes VSMC resting potential in RA thereby enhancing L-type Ca2+ channel activation and NE sensitivity. Sympathetic innervation supports hyperpolarizing currents in RA VSMCs.