Abstract-Calcitonin gene-related peptide (CGRP) and substance P are known to play a counterregulatory role in acquired models of salt-dependent hypertension. In contrast, neuronal production of these peptides is decreased in the spontaneously hypertensive rat, which may contribute to the elevated blood pressure. To determine the role played by CGRP and substance P in Dahl-salt hypertension, 4-to 6-week-old male salt-resistant (DR) and salt-sensitive (DS) rats were divided into 4 groups (nϭ5/group) and pair-fed low-salt (0.2% NaCl) (DR/LS and DS/LS) and high-salt (8% NaCl) diets (DR/HS and DS/HS) for 3 weeks. After 3 weeks, all the rats had venous (for drug administration) and arterial (for blood pressure monitoring) catheters surgically implanted and were studied in the conscious and unrestrained state. Mean arterial pressure was significantly higher in the DS/HS rats animals (185.8Ϯ1.6 mm Hg, PϽ0.001). Intravenous administration of CGRP and SP receptor antagonists was without effect in any of the groups studied. CGRP and SP mRNA content from dorsal root ganglia were not significantly different between the groups. Whereas immunoreactive CGRP was decreased in the DS groups (DS/HS, 9.4Ϯ0.4 pg/g protein; DS/LS, 11.1Ϯ0.8 pg/g protein; PϽ0.01) compared with the DR groups (DR/HS, 13.9Ϯ0.6 pg/g protein; DR/LS, 14.6Ϯ0.6 pg/g protein), neuronal SP production was similar between all the groups. Thus, CGRP and substance P do not play a counterregulatory role in Dahl-salt hypertension. The decrease in neuronal CGRP expression in DS rats appears to be genetically determined as in SHR, however, and may contribute to the increase in blood pressure following salt-loading. Key Words: rats Ⅲ neuropeptides Ⅲ hypertension, genetic Ⅲ blood pressure Ⅲ RNA Ⅲ radioimmunoassay C alcitonin gene-related peptide (CGRP), a 37 amino acid peptide, is produced by the alternate splicing of the calcitonin/CGRP gene. 1,2 CGRP is the most potent vasodilator discovered to date and has markedly positive chronotropic and inotropic effects. 3 There are 2 CGRP genes, which are called ␣-CGRP and -CGRP in the rat and I and II humans. 3 In the rat and in humans, the 2 peptides differ by 1 amino acid and 3 amino acids, respectively, and their biological activities are similar in most vascular beds. Substance P (SP) is a member of the tachykinin family and, like CGRP, is involved in numerous physiological activities such as neuromodulation, smooth muscle contraction, and vasodilation. 4,5 A prominent site for CGRP and SP synthesis is the dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons that terminate centrally in the spinal cord and peripherally on blood vessels. 3 We have demonstrated that the neuronal expression of CGRP is decreased in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). 6 Also, reduced levels of SP have been reported in essential hypertension in humans and in stroke-prone SHR. 7,8 Therefore, in these settings both CGRP and SP could contribute to elevated blood pressure through the decre...