title: Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice.
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 alpha-calcitonin gene-related peptide (alpha-CGRP) gene. Although the beta-calcitonin gene-related peptide (beta-CGRP) gene is intact in these mice, alpha-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 alpha-CGRP on baseline BP and beta-CGRP and substance P mRNA expression. Systolic BP was significantly higher in the knockout mice (n=7) compared with wild-type in both male (160+/-6.1 vs 125+/-4.8 mm Hg) and female (163+/-4.8 vs 135+/-33 mm Hg) mice. Next, groups (n=7) 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 (139+/-4.9 vs 118+/-4.9 mm Hg) and female (121+/-3.4 vs 107+/-3.1 mm Hg) mice. Northern blot analysis of DRG RNA samples confirmed the absence of alpha-CGRP mRNA in the knockout mice. Substance P mRNA content in DRG was unchanged between the 2 groups; however, beta-CGRP mRNA levels were reduced 2-fold in the knockout mice. These results indicate for the first time that alpha-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.
authors.affiliation: Departments of Obstetrics and Gynecology, Internal Medicine, and Anatomy and Neurosciences, The University of Texas Medical Branch, Galveston, TX 77555-1062, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Gangula
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: S C
authors.initials: SC
authors.lastname: Supowit
authors.forename: S J
authors.initials: SJ
authors.lastname: Wimalawansa
authors.forename: D J
authors.initials: DJ
authors.lastname: Dipette
authors.forename: K N
authors.initials: KN
authors.lastname: Westlund
authors.forename: R F
authors.initials: RF
authors.lastname: Gagel
authors.forename: C
authors.initials: C
authors.lastname: Yallampalli
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D015152:Blotting, Northern; D002116:Calcitonin / Q000235:genetics*; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D013373:Substance P / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D013373:Substance P; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide