CALCITONIN-GENE-RELATED PEPTIDE DOES NOT MEDIATE THE ABNORMAL VASCULAR REACTIVITY OBSERVED IN A RAT MODEL OF ACUTE PSEUDOMONAS-PNEUMONIA

Abnormal systemic and pulmonary vascular reactivity has been demonstra ted in numerous models of sepsis and pneumonia. Furthermore, the atten uated hypoxic pulmonary presser response observed in these animals pro bably is responsible for the ventilation/perfusion (V/Q) mismatching a nd consequent arterial hypoxemia. We hypothesized that excess release of endogenous vasodilators such as calcitonin gene-related peptide (CG RP) in pneumonia was responsible for the diminished hypoxic presser re sponse; Using the CGRP receptor antagonist CGRP((8-37)), we examined t he role of CGRP in at-tenuated hypoxic pulmonary response iii a rat mo del of acute Pseudomonas pneumonia. Sixteen Sprague-Dawley rats were i nstrumented for chronic hemodynamic monitoring and subsequently random ized to either Pneumonia (n = 8), induced by the instillation of 0.2 m l broth containing 2 x 10(8) colony-forming units (CFU)/ml Pseudomonas aeruginosa into the right lower lobe, or Sham (n = 8) procedure. Hemo dynamic measurements and the hypoxic (FiO(2) = 0.08) pulmonary presser response were recorded at baseline, 48 h after the pneumonia or sham procedure and after the administration of 250 mu g CGRP((8-37)) (post- CGRP((8-37))). The regional distribution of pulmonary blood flow was d etermined by the injection of radioactive microspheres. Forty-eight ho urs after the instillation of Pseudomonas, Pneumonia animals had signi ficantly increased cardiac output (CO) as compared with Sham (193 +/- 7 vs. 154 +/- 7 ml/min, p < 0.05), slightly decreased mean arterial pr essure (MAP 109 +/- 4 vs. 118 +/- 3 mm Hg, p = NS), and reduced total systemic vascular resistance (TSVR 0.57 +/- 0.03 vs, 0.78 +/- 0.05 mm Hg . min . ml(-1), p < 0.05). Pneumonia animals were further character ized by increased mean pulmonary artery pressure (MPAP) as compared wi th Sham (24 +/- 2 vs. 20 +/- 1 mm Hg, p < 0.05) animals, and an increa sed alveolar-arterial (A-a) oxygen gradient (31 +/- 3 vs. 20 +/- 4 mm Hg, p < 0.05). The administration of CGRP((8-37)) did not alter baseli ne hemodynamic variables and did not change the presser response to hy poxia in either group. Furthermore, CGRP receptor blockade did not alt er the distribution of blood flow in the lung during normoxia or hypox ia. These data suggest that although this model of acute pneumonia is characterized by an attenuated hypoxic presser response, the mechanism does not appear to be mediated by excess release of the vasodilator C GRP.