Stimulation of calcitonin gene-related peptide synthesis and release: mechanisms for a novel antihypertensive drug, rutaecarpine.

Abstract

Previous investigations have demonstrated that capsaicin-sensitive primary sensory nerves play an important role in modulation of the peripheral resistance of the circulation system. The vanilloid receptor subtype 1 (VR1) is expressed almost exclusively in the primary sensory nerves and cell bodies of these sensory neurons. Rutaecarpine (Rut) can relax vascular smooth muscle via stimulation of calcitonin gene-related peptide (CGRP) release by activation of VR1. In the present study, we examined the depressor effect of Rut and the possible mechanisms in the phenol-induced hypertensive rats, in which hypertension was induced by injecting 50 microl of 10% phenol in the lower pole of the left kidney. Acute administration of Rut (30, 100 or 300 microg/kg, i.v.) caused a depressor effect concomitantly with an increase in the plasma concentration of CGRP in a dose-dependent manner, which was blocked by capsaicin (used to deplete the CGRP from sensory nerves) or capsazepine (a competitive VR1 antagonist), causing an approximately 85% and approximately 80% change in mean arterial pressure, respectively, and by either of them, causing an approximately 90% elevation of plasma CGRP. In the chronic study, Rut at a dose of 3 or 6 mg/kg per day significantly lowered tail-cuff systolic blood pressure to 159 +/- 8 and 136 +/- 10 mmHg, respectively, compared with hypertensive rats (179 +/- 8 mmHg), and caused a sustained hypotensive effect from day 6 on. Pretreatment with capsaicin blocked the depressor effect of Rut by approximately 65%. Treatment with Rut significantly increased the synthesis and release of CGRP, as shown by the increase in the levels of CGRP mRNA and peptide in the dorsal root ganglia, the density of CGRP immunoreactive nerve fibers in the mesenteric artery, the CGRP content in the spinal cord and the plasma concentration of CGRP, which was markedly attenuated by pretreatment with capsaicin. These results suggest, for the first time, that the hypotensive effect of Rut is mediated by stimulation of CGRP synthesis and release via activation of VR1 in the phenol-induced hypertensive rat.