Development of angiotensin II-induced hypertension: role of CGRP and its receptor

Abstract

Objective: To determine the role of endogenous calcitonin gene-related peptide (CGRP) and its receptor in development of angiotensin II (Ang II)-induced hypertension.

Design and methods: Seven-week-old male Wistar rats were given either Ang II (100 ng/kg per min) or saline via mini osmotic pumps with or without minoxidil (9 mg/kg per day) in their drinking water for 10 days. Mean arterial pressure (MAP) and its response to alpha-CGRP (1 microg/kg, iv) and its receptor antagonist, CGRP(8-37) (1 mg/kg, iv), were determined in conscious and unrestrained rats. Radioimmunoassay and Western blotting were employed, respectively, to determine CGRP levels in plasma and dorsal root ganglia (DRG) and CGRP receptor protein content in mesenteric arteries.

Results: After the 10-day treatment, MAP was higher in the Ang II group compared to control (Con), control plus minoxidil (Con-Min), and Ang II plus minoxidil (Ang II-Min) (P < 0.01). CGRP decreased MAP in the Ang II group compared to Con, Con-Min and Ang II-Min rats (P < 0.01). In contrast, CGRP8-37 increased MAP in Con-Min and Ang II-Min groups compared with Con and Ang II groups (P < 0.01). Radioimmunoassay showed that CGRP levels in plasma and DRG were not different among the four groups. Western blots showed that calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP1), which constitute a CGRP receptor, were significantly upregulated in mesenteric arteries in the Ang II group compared to the other three groups (P < 0.05).

Conclusion: These data indicate that long-term Ang II infusion is accompanied by an increase in CGRP receptor expression in mesenteric arteries but not in CGRP levels in plasma and DRG. The increase in mesenteric CGRP receptor expression appears to be pressure dependent and to enhance the blood pressure response to CGRP. Minoxidil enhances the hypertensive effect of CGRP8-37 to the same degree in control and Ang II-treated rats, indicating that this KATP channel activator sensitizes the blood pressure response regardless of the baseline pressure while CGRP receptors are blocked.