Abstract-Nerves that contain calcitonin gene-related peptide (CGRP) are components of the sensory nervous system.Although these afferent nerves have traditionally been thought to sense stimuli in the periphery and transmit the information centrally, they also have an efferent vasodilator function. Acute administration of a CGRP receptor antagonist increases the blood pressure (BP) in several models of hypertension, which indicates that this potent vasodilator plays a counterregulatory role to attenuate the BP increase in these settings. To determine the role of this peptide in the long-term regulation of cardiovascular function, including hypertension, we obtained mice that have a deletion of the ␣-calcitonin gene-related peptide (␣-CGRP) gene. Although the ␤-calcitonin gene-related peptide (␤-CGRP) gene is intact in these mice, ␣-CGRP is by far the predominant species of CGRP produced in dorsal root ganglia (DRG) sensory neurons. Initially, we examined the effect of deletion of the ␣-CGRP on baseline BP and ␤-CGRP and substance P mRNA expression. Systolic BP was significantly higher in the knockout mice (nϭ7) compared with wild-type in both male (160Ϯ6.1 vs 125Ϯ4.8 mm Hg) and female (163Ϯ4.8 vs 135Ϯ33 mm Hg) mice. Next, groups (nϭ7) of knockout and wild-type mice had catheters surgically placed in the right carotid artery for mean arterial pressure recording. With the animals fully awake and unrestrained, the knockout mice displayed an elevated mean arterial pressure compared with wild-type in both male (139Ϯ4.9 vs 118Ϯ4.9 mm Hg) and female (121Ϯ3.4 vs 107Ϯ3.1 mm Hg) mice. Northern blot analysis of DRG RNA samples confirmed the absence of ␣-CGRP mRNA in the knockout mice. Substance P mRNA content in DRG was unchanged between the 2 groups; however, ␤-CGRP mRNA levels were reduced 2-fold in the knockout mice. These results indicate for the first time that ␣-CGRP may be involved in the long-term regulation of resting BP and suggest that these mice are particularly sensitive to challenges to BP homeostasis because of the loss of a compensatory vasodilator mechanism. Key Words: peptides Ⅲ blood pressure Ⅲ mice Ⅲ genes C alcitonin gene-related peptide (CGRP) is a 37-amino acid vasoactive neuropeptide that is widely distributed in the central and peripheral nervous systems in mammals. 1,2 ␣-CGRP is produced by the tissue-specific alternative splicing of the primary transcript of the calcitonin/␣-CGRP gene and is synthesized almost exclusively in neuronal tissues. 3,4 There is a second CGRP gene, ␤-CGRP, which does not produce calcitonin. 5 Again, expression of ␤-CGRP is limited almost exclusively to specific neuronal sites. 4,5 The 2 CGRP genes, ␣ and ␤ in the rat and I and II in humans, differ in their protein sequences by 1 and 3 amino acids, respectively, and their biological activities are quite similar in most vascular beds. 6,7 The dorsal root ganglia (DRG) is a prominent site of CGRP synthesis that contains the cell bodies of primary afferent neurons that terminate peripherally on blood vessels and other tissue...

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