Local neurogenic regulation of rat hindlimb circulation: CO2-induced release of calcitonin gene-related peptide from sensory nerves

1 The mechanism of release of calcitonin gene-related peptide (CGRP) from sensory nerves in response to skeletal muscle contraction was investigated in the rat hindlimb in vivo and in vitro. 2 In the anaesthetized rat, sciatic nerve stimulation at 10 Hz for 1 min caused a hyperaemic response in the hindlimb. During the response, partial pressure of CO2 in the venous blood effluent from the hindlimb significantly increased from 43+/-3 to 73+/-8 mmHg, whereas a small decrease in pH and no appreciable change in partial pressure of O-2 were observed. 3 An intra-arterial bolus injection of NaHCO3 (titrated to pH 7.2 with HCl), which elevated PCO2 of the venous blood, caused a sustained increase in regional blood flow of the iliac artery. Capsaicin (0.33 mu mol kg(-1), i.a.) and a specific calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP(8-37), (100 nmol kg(-1) min(-1), i.v.) significantly suppressed the hyperaemic response to NaHCO3. Neither NDomega-nitro-L-arginine methyl ester (1 mu mol kg(-1) min(-1), i.v.) nor indomethacin (5 mg kg(-1), i.v.) affected the response. 4 The serum level of CGRP-like immunoreactivity in the venous blood was significantly increased by a bolus injection of NaHCO3 (pH = 7.2) from 50+/-4 to 196+/-16 fmol ml(-1). 5 In the isolated hindlimb perfused with Krebs-Ringer solution, a bolus injection of NaHCO3 (pH = 7.2) caused a decrease in perfusion pressure which was composed of two responses, i.e., an initial transient response and a slowly-developing long-lasting one. CGRP(8-37) significantly inhibited the latter response by 73%. 6 These results suggest that CO2 liberated from exercising skeletal muscle activates capsaicin-sensitive perivascular sensory nerves locally, which results in the release of CGRP from their peripheral endings, and then the released peptide causes local vasodilatation.