The effects of
calcitonin gene-related peptide (CGRP) (6 x 10(-8) M) on hemodynamics and on pulmonary microvascular permeability were investigated in isolated, perfused rabbit lungs by measuring the arterial, capillary and venous pressures and the capillary filtration coefficient (Kf,c). CGRP was administered alone or in combination with
capsaicin (10(-4) M),
acetylcholine (ACh) (10(-11) M to 10(-7) M),
substance P (SP) (10(-10) M to 10(-6) M) and
serotonin (10(-4) M). The influence of a specific antagonist of
CGRP receptors,
CGRP8-37 (10(-8) M), on the
pulmonary edema induced by these mediators was also considered. CGRP had no direct effect on the vascular pressures or on Kf,c.
Capsaicin and
serotonin induced an increase in Kf,c of 271 +/- 49% and 676 +/- 147% of base line, respectively. ACh and SP also increased the microvascular permeability, in proportion to the concentration. The effects of
capsaicin, ACh and SP have been related to the activation of neurokinin NK1 receptors. Co-administration of CGRP with
capsaicin and ACh enhanced the increase in Kf,c induced by these two drugs. By contrast, when co-injected with SP, CGRP inhibited the Kf,c increase induced by 10(-8) M and 10(-7) M of SP (P < .05) and significantly decreased the arterial and capillary pressures. CGRP also partly prevented the
pulmonary edema induced by
serotonin (P < .05). Pretreatment with
CGRP8-37 partly prevented the effects of
capsaicin and ACh on Kf,c but bestowed no protection against SP-induced
pulmonary edema. These data suggest that CGRP is co-released with SP from the C-fibers upon the action of
capsaicin and ACh in the rabbit lung. Because CGRP potentiated the
pulmonary edema induced in
capsaicin and ACh, but decreased the effects of SP, we hypothesize that CGRP exerts a positive retro-control on the release of
neuropeptides by these fibers but can attenuate their effects on the target cells.