Vascular Reactivity to Calcitonin Gene Related-Peptide Is Enhanced in Subtotal Nephrectomy-Salt Hypertension.
We previously demonstrated that CGRP plays a counterregulatory role to attenuate the BP increase in subtotal nephrectomy-(SN)-salt-induced hypertension. This effect was observed in the absence of any increase in neuronal CGRP expression in this hypertensive model, suggesting that the mechanism of this compensatory vasodilator response is enhanced vascular reactivity to CGRP. To test this hypothesis, hypertension was induced in Sprague-Dawley rats (150-175 g, n=5) by SN and 1% saline drinking water. Controls (n=5) were sham operated and given tap water to drink. After eleven days, systolic BP was significantly higher in the SN compared to the control rats (220±7 vs 140±4 mmHg). Vascular reactivity was then examined in isolated endothelium-intact superior mesenteric arterial strips. Phenylephrine (10-9-3×5-5 M)-induced contraction was not different between the two groups. CGRP (10-11-5×10-8 M)-induced maximum relaxation in phenylephrine-contracted arteries was not altered between the SN and control arteries, however, CGRP was significantly more potent in the arteries from the SN group (EC50, 0.7±0.2 vs 2.5±0.8 nM). Phenylephrine-contracted arteries were also treated with forskolin (10-9-10-6 M) since increased intracellular cAMP levels is a prominant mechanism linked to CGRP-mediated vasodilation. While no change in efficacy was observed, there was a marked decrease in response to forskolin in SN arteries (EC50, 327±146 vs 20±8 nM). To examine the BP response to exogenous CGRP in vivo, identical groups of SN and control rats (n=6/group) had i.v. (for CGRP administration) and arterial (for continous BP monitoring) catheters surgically placed and were studied in a concious, unrestrained state. Baseline mean BP was higher in the SN rats compared to the controls (173±5 vs 125±4 mmHg). Administration of CGRP (0.25μg/kg i.v.) resulted in a significantly greater decrease in mean BP in the SN rats compared to controls (-19±4 vs -9±1 mmHg). These data suggest that the counterregulatory effects of CGRP observed in SN-hypertension result, at least in part, from a cAMP-independent enhancement in vascular reactivity to this potent vasodilator.