Calcitonin Gene-related Peptide mRNA In Dorsal Root Ganglia Research Articles

Calcitonin Gene-Related Peptide-Mediated Depressor Effect and Inhibiting Vascular Hypertrophy of Rutaecarpine in Renovascular Hypertensive Rats

Calcitonin gene-related peptide (CGRP), the predominant neurotransmitter in capsaicin-sensitive sensory nerves, is a potent vasodilator and inhibits proliferation of vascular smooth muscle cells. Previous investigations have demonstrated that the hypotensive effect of rutaecarpine (Rut) is associated to stimulation of CGRP synthesis and release via activation of the vanilloid receptor subtype 1 (VR1) in the phenol-induced hypertensive rat. This study tested whether the depressor effect and inhibiting vascular hypertrophy of Rut is mediated by endogenous CGRP in 2-kidney, 1-clip (2K1C) hypertensive rats. Systolic blood pressure (SBP) was measured by tail-cuff method in conscious. Mesenteric arteries were isolated for examination of morphological changes. The concentration of CGRP in the plasma and the expression of CGRP mRNA in dorsal root ganglia (DRG) were measured. Chronic administration of Rut (10, 20, or 40 mg/kg/day, respectively) for 4 weeks caused a depressor effect and significantly regressed the lumen diameter and decreased the medium thickness of mesenteric arteries in hypertensive rats concomitantly with an increase in the plasma concentration of CGRP and the expression of CGRP mRNA in DRG. In conclusion, chronic administration of Rut can reduce blood pressure and relieve mesenteric artery hypertrophy in the 2K1C hypertensive rats, and the effects of Rut may be related to stimulation of CGRP synthesis and release.

An increase in the synthesis and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats

Previous investigations have indicated that capsaicin-sensitive sensory nerves play an important role in modulation of the peripheral resistance of the circulation system. In the present study, we examined the role of capsaicin-sensitive sensory nerves in two-kidney, one-clip (2K1C) renovascular hypertension rats. Systolic blood pressure (BP) was monitored by the tail-cuff method throughout the experiment. Concentrations of calcitonin gene-related peptide (CGRP) in the plasma, the level of CGRP mRNA in dorsal root ganglia (DRG) and the density of CGRP immunoreactive (CGRP-ir) fibers in mesenteric artery were measured. Blood pressure was significantly elevated at day 10 postoperation (BP was 143±10 and 114±7 mm Hg for 2K1C and Sham groups, respectively, p<0.05). Treatment with capsaicin, which selectively depletes neurotransmitters in sensory nerves, enhanced hypertensive responses to clipping (BP was 168±7 and 143±10 mm Hg at day 10 postoperation for Cap1+2K1C and 2K1C groups, respectively, p<0.05), and BP in the rats treated with a second injection of capsaicin was greater than that in the rats treated with a single injection of capsaicin (At day 30 postoperation, BP was 199±7 and 166±9 mm Hg for Cap2+2K1C and 2K1C groups, respectively, p<0.01; mean arterial pressure was 185.2±6.6 and 150.5±4.1 mm Hg for Cap2+2K1C and 2K1C groups, respectively, p<0.01). The expression of α-CGRP mRNA in DRG (122.87±3.67 arbitrary units, p<0.05), the level of CGRP in the plasma (75.40±4.99 pg/ml, p<0.01) and the density of CGRP-ir fibers in mesenteric artery (525.67±31.42 intersections, p<0.05) were significantly increased in 2K1C rats. Treatment with capsaicin, a single injection or a second injection, prevented the increased in the expression of CGRP mRNA in DRG. However, the decreased level of CGRP was only observed in the rats treated with a second capsaicin. These results suggest that in 2K1C hypertensive rats, the activity of capsaicin-sensitive sensory nerves is increased, which is playing a compensatory depressor role to partially counteract the increase in blood pressure, and that the cardiovascular actions of CGRP is mediated by the α-CGRP isoform.

Chronic Angiotensin II Inhibition Increases Levels of Calcitonin Gene-Related Peptide mRNA of the Dorsal Root Ganglia in Spontaneously Hypertensive Rats.

We previously reported that the vasodilation mediated by calcitonin gene-related peptide (CGRP)-containing nerves and level of CGRP mRNA in the dorsal root ganglia (DRG) in spontaneously hypertensive rats (SHR) decreased with age, and that the reduced function of CGRP nerves was restored by chronic inhibition of angiotensin II. The present study was performed to investigate the effect of long-term treatment with angiotensin II type-1 receptor antagonists (L-158,809 and olmesartan), an angiotensin converting enzyme inhibitor (temocapril) and hydralazine on levels of CGRP mRNA in DRG of SHR and the contents of CGRP in the mesenteric artery and atrium. The level of CGRP mRNA and degree of CGRP-like immunoreactivities (CGRP-LI) were measured by Northern blot hybridization assay and enzyme-linked immunosorbent assay, respectively. Seven week-treatment of 8 week-old SHR with temocapril (0.005%), L-158,809 (0.001%), olmesartan (0.01%) or hydralazine (0.01%) administered in drinking water significantly lowered the systolic blood pressure of SHR. The level of CGRP mRNA in the DRG of control SHR was significantly lower than that in normotensive Wistar Kyoto rats (WKY), whereas the level of CGRP-LI in the mesenteric artery and atrium of SHR were significantly greater than those in WKY. Treatment of SHR with temocapril, L-158,809, or olmesartan, but not hydralazine, significantly elevated the levels of CGRP mRNA in DRG, markedly increased the level of CGRP-LI in the mesenteric artery, and slightly increased the CGRP-LI level in the atrium. These results suggest that long-term inhibition of angiotensin II restores the reduced expression of CGRP mRNA in DRG and may facilitate neurotransmission of CGRP-containing vasodilator nerves in SHR.

Increase of calcitonin gene-related peptide (CGRP) release and mRNA levels in endotoxic rats.

Previously we showed that calcitonin gene-related peptide (CGRP) is released into the circulation during pathogenesis of septic shock in humans and endotoxicosis in rats and pigs. The present study examines the changes of both CGRP release and synthesis during endotoxicosis in rats. Endotoxin was administered as a bolus (5 mg/kg,i.v.) to rats lightly anesthetized with ether. Blood samples and lumbar dorsal root ganglia (DRG), neuronal cell bodies synthesizing CGRP, were taken from rats at 0, .5, 3, or 8 h after endotoxin administration. CGRP levels in plasma and the steady-state levels of mRNA for CGRP in DRG were determined by methods of radioimmunoassay and semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR), respectively. Endotoxin elevated plasma CGRP by 62%, but not mRNA at .5 h. Endotoxin increased plasma CGRP by 142% and CGRP mRNA in DRG by 36% at 3 h, and further increased plasma CGRP by 216% and CGRP mRNA in DRG by 88% at 8 h. The data suggest that both CGRP expression and release in sensory nerves are increased during development of endotoxicosis in rats. CGRP synaptic transmission may be maintained during the course of endotoxicosis in rats. DRG undergo an elevation of CGRP expression in response to endotoxicosis, presumably as an adaptation of CGRP release during the inflammation. CGRP, because of its extremely high potency in hypotensive, tachycardiac and immunosuppressive effects, may play an important role in the pathogenesis of septic shock.