Prevention of endothelin-1-induced increases in blood pressure: role of endogenous CGRP

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Abstract
To determine the role of endothelin-1 (ET-1) and its receptors in the regulation of calcitonin gene-related peptide (CGRP) release, male Wistar rats were divided into six groups and subjected to the following treatments for 1 wk with or without ABT-627 (an ETAreceptor antagonist, 5 mg·kg−1·day−1in drinking water) or A-192621 (an ETB-receptor antagonist, 30 mg·kg−1·day−1by oral gavage): control (Con), ET-1 (5 ng·kg−1·min−1iv), Con + ABT-627, Con + A-192621, ET-1 + ABT-627, and ET-1 + A-192621. Baseline mean arterial pressure (MAP, mmHg) was higher ( P < 0.05) in Con + A-192621 (122 ± 4) and ET-1 + A-192621 (119 ± 4) groups compared with Con (104 ± 6), ET1 (106 ± 3), Con + ABT-627 (104 ± 3), and ET1 + ABT-627 (100 ± 3) groups. Intravenous administration of CGRP8–37(a CGRP receptor antagonist, 1 mg/kg) increased MAP ( P < 0.05) in ET-1 (13 ± 1), Con + A-192621 (12 ± 1), and ET-1 + A-192621 (15 ± 3) groups compared with Con (4 ± 1), Con-ABT-627 (4 ± 1), and ET-1 + ABT-627 (5 ± 1) groups. Plasma CGRP levels (in pg/ml) were increased ( P < 0.05) in ET-1 (57.5 ± 6.1), Con + A-192621 (53.9 ± 3.4), and ET-1 + A-192621 (60.4 ± 3.0) groups compared with Con (40.4 ± 1.6), Con + ABT-627 (40.0 ± 2.9), and ET-1 + ABT-627 (42.6 ± 1.9) groups. Plasma ET-1 levels (in pg/ml) were higher ( P < 0.05) in ET-1 (2.8 ± 0.2), ET-1 + ABT-627 (3.2 ± 0.4), Con + A-192621 (3.3 ± 0.4), and ET-1 + A-192621 (4.6 ± 0.3) groups compared with Con (1.1 ± 0.2) and Con-ABT-627 (1.3 ± 0.2) groups. Therefore, our data show that ET-1 infusion leads to increased CGRP release via activation of the ETAreceptor, which plays a compensatory role in preventing ET-1-induced elevation in blood pressure.