STIMULATION OF CGRP SYNTHESIS AND RELEASE: MECHANISMS FOR A NOVEL ANTIHYPERTENSIVE DRUG, RUTAECARPINE

【Author】

Pan-Yue DENG;Feng YE;Wei-Jun CAI;Gui-Shan TAN;Chang-Pin HU;Han-Wu DENG;Yuan-Jian LI Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China

【Abstract】

<正> AIMS: To examine the depressor effect of rutaecarpine and explore whether theantihypotensive effect of rutaecarpine is related to stimulation of the synthesis and release ofendogenous calcitonin gene-related peptide (CGRP) in the hypertensive rats.MOTHEDS: Hypertension was appeased by injecting 50μL of 10% phenol in the lower poleof the left kidney of the male Sprague-Dawley. Control rats received 50μL of normal saline inthe lower pole of the kidney as a normotension control for hypertensive rats. The first series ofexperiments was designed to evaluate the hypotensive effect of a single bolus injection ofrutaecarpine in the hypertensive rats. Fifteen days after treatment of phenol, the right jugularvein and carotid artery of rats were cannulated for administration of drugs or for monitoringof the mean arterial pressure (MAP). When the depressor effect of rutaecarpine approachedthe lowest point, the rats were decapitated for collection of blood for measurement of plasmaCGRP concentration by radioimmunoassay. The second series of experiments was designed toevaluate the depressor effect of chronic treatment with rutaecarpine in the hypertensive rats.Fifteen days after intrarenal injection of phenol, the rats were treated with rutaecarpine bygastrogavage twice per day with a total dose of 3 or 6 mg/kg for 12 days. MAP,concentrations of CGRP in the plasma and the content of CGRP in the dorsal root ganglia(DRG), the level of CGRP mRNA in the DRG, and the density of CGRP immunoreactivenerve fibers in the mesenteric artery and the CGRP content in the dorsal horn of spinal cordwere determined by a pressure transducer coupled to computerized recorder,radioimmunoassay, RT-PCR, and immunohistochemistry followed by image analysis,respectively.RESULTS: Acute intravenous administration of rutaecarpine (30, 100, or 300μg/kg) causedan increase in the plasma concentration of CGRP concomitantly with a depressor effect in adose-dependent manner, which was blocked by capsaicin (used to deplete CGRP fromcapsaicin-sensitive sensory nerves) or capsazepine (the competitive vanilloid receptor subtype1 antagonist) by ≈85% and ≈80% in the changes of MAP, respectively, and by ≈90% in therelease of CGRP by each of them. In the chronic study, rutaecarpine at the dose of 3 or6mg/kg per day significantly decreased blood pressure and caused a sustained hypotensiveeffect from day 6 on (tail-cuff systolic blood pressure was 179 ±8, 159 ±8 and 136 ±10mmHg for the hypertensive rats and rats treated with rutaecarpine at dose of 3 or 6mg/kg,respectively, P < 0.01). Pretreatment with capsaicin blocked the depressor effect ofrutaecarpine by ≈65% (P < 0.01). The synthesis and release of CGRP were decreased in thehypertensive rats. Treatment with rutaecarpine significantly elevated the synthesis and releaseof this peptide, as shown by the increase in the levels of CGRP mRNA and peptide in theDRG, the density of CGRP immunoreactive nerve fibers in the mesenteric artery, the CGRPcontent in the spinal cord and the plasma concentration of CGRP, which were markedly attenuated by pretreatment with capsaicin.CONCLUSIONS: In summary, the present study suggests, for the first time, that theantihypotensive effect of rutaecarpine is mediated by stimulation of CGRP synthesis andrelease via activation of vanilloid receptor subtype 1 in the phenol-induced hypertensive rats.

【Keywords】

rutaecarpine;;vanilloid receptor;;hypertension;;calcitonin gene-related peptide (CGRP)

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