Effects of adrenomedullin and calcitonin gene-related peptide on airway and pulmonary vascular smooth muscle in guinea-pigs

1. The airway and pulmonary vascular effects of adrenomedullin were studied in the guinea-pig isolated trachea, main bronchi and pulmonary artery in vitro and compared to the effects of calcitonin gene-related peptide (CGRP). 2. In tracheal rings, CGRP (1 nM to 1 μM) potentiated the cholinergic contractions induced by electrical field stimulation (EFS) at 5 Hz in a concentration-dependent manner. At a concentration of 1 μM, CGRP slightly decreased the responses to log EFS frequency, producing 50% of the maximum contraction from a control value of 0.77 ± 0.10 Hz to 0.54 ± 0.05 Hz without a significant effect on the concentration-response curves to acetylcholine (ACh). In contrast, adrenomedullin (1 nM to 1 μM) did not alter either EFS-induced cholinergic or ACh-induced contractions. 3. In bronchial strips, CGRP (1 nM to 1 μM) slightly reduced both the non-adrenergic non-cholinergic (NANC) contraction induced by EFS at 10 Hz and the substance P (1 μM)-induced contraction in a concentration-dependent manner, whereas adrenomedullin (1 μM to 1 μM) was without effect. 4. Neither CGRP (1 μM) nor adrenomedullin (1 μM) altered NANC relaxation induced by EFS at 5 Hz in tracheal rings precontracted with histamine (10 μM). 5. Adrenomedullin (1 nM to 1 μM) and CGRP (1 nM to 1 μM) induced a concentration-dependent relaxation of the histamine (10 μM)- and prostaglandin F(2α) (10 μM)-precontracted pulmonary arterial rings with intact endothelium with a similar potency. 6. Neither removal of the endothelium nor N(G)-nitro-L-arginine methyl ester (100 μM) altered the vasorelaxant effects of adrenomedullin (1 nM to 1 μM) and CGRP (1 nM to 1 μM). 7. The putative CGRP receptor antagonist, CGRP_8-37 (1 μM to 10 μM) concentration-dependently attenuated the CGRP (3 nM to 30 nM)-induced vasorelaxant actions, whereas it had no effect on the relaxation of vessel rings induced by adrenomedullin (3 nM to 30 nM). 8. These results suggest that adrenomedullin is a potent vasodilator of the pulmonary artery without any bronchomotor effect in the guinea-pig lung, and that the vasorelaxant actions of adrenomedullin are not mediated via the activation of CGRP(I) receptors.