The first evidence that CGRP plays a role in systemic hypertension was provided by studies using the DOC-salt rat (20,21). For these studies, we used DOC-salt rats during the onset stage (4 wk after the initiation of the protocol) and four groups of normotensive rats to control for pellet implantation, uninephrectomy, and/or salt administration. In our initial studies, we demonstrated that CGRP mRNA accumulation was significantly increased in DRG, and correspondingly, iCGRP levels were elevated in laminae I/II of the spinal cord compared to the control groups. Furthermore, this increase in neuronal CGRP expression in the DOC-salt rats was specific for the DRG, because we did not observe any alterations in the brain or in the brainstem. In order to determine if these changes in CGRP were playing an important hemodynamic role, groups of rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure, MAP) catheters surgically placed and were studied in the conscious, unrestrained state. As shown in Fig. 1, injection of saline did not alter MAP in any of the five groups, and CGRP8_37 (the CGRP receptor antagonist) administration did not significantly increase MAP in any of the four normotensive control groups. However, administration of the CGRP antagonist to the DOC-salt rats rapidly induced, in a dose-dependent manner, a further increase of the elevated MAP. The rapid onset of the hypertensive effects of CGRP8_37 and because of the antagonist probably does not penetrate the central nervous system, it is likely that the pressor activity of CGRP837 results from a direct interaction of the antagonist with vascular CGRP receptors. These data support the hypothesis that, in DOC-salt hypertension, CGRP is acting as a compensatory depressor to buffer the increased BP.
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