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

Abstract

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 microM) potentiated the cholinergic contractions induced by electrical field stimulation (EFS) at 5 Hz in a concentration-dependent manner. At a concentration of 1 microM, 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 microM) did not alter either EFS-induced cholinergic or ACh-induced contractions. 3. In bronchial strips, CGRP (1 nM to 1 microM) slightly reduced both the non-adrenergic non-cholinergic (NANC) contraction induced by EFS at 10 Hz and the substance P (1 microM)-induced contraction in a concentration-dependent manner, whereas adrenomedullin (1 nM to 1 microM) was without effect. 4. Neither CGRP (1 microM) nor adrenomedullin (1 microM) altered NANC relaxation induced by EFS at 5 Hz in tracheal rings precontracted with histamine (10 microM). 5. Adrenomedullin (1 nM to 1 microM) and CGRP (1 nM to 1 microM) induced a concentration-dependent relaxation of the histamine (10 microM)- and prostaglandin F2 alpha (10 microM)-precontracted pulmonary arterial rings with intact endothelium with a similar potency. 6. Neither removal of the endothelium nor NG-nitro-L-arginine methyl ester (100 microM) altered the vasorelaxant effects of adrenomedullin (1 nM to 1 microM) and CGRP (1 nM to 1 microM). 7. The putative CGRP receptor antagonist, CGRP8-37 (1 microM to 10 microM) 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 CGRP1 receptors.