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 stu died in the guinea-pig isolated trachea, main bronchi and pulmonary ar tery in vitro and compared to the effects of calcitonin gene-related p eptide (CGRP). 2 In tracheal rings, CGRP (1 nM to 1 mu M) potentiated the cholinergic contractions induced by electrical field stimulation ( EFS) at 5 Hz in a concentration-dependent manner. At a concentration o f 1 mu M, 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 concen tration-response curves to acetylcholine (ACh). In contrast, adrenomed ullin (1 nM to 1 mu M) not alter either EFS-induced cholinergic or ACh -induced contractions. 3 In bronchial strips, CGRP (1 nM to 1 mu M) sl ightly reduced both the non-adrenergic non-cholinergic (NANC) contract ion induced by EFS at 10 Hz and the substance P (1 mu M)-induced contr action in a concentration-dependent manner, whereas adrenomedullin (1 nm to 1 mu M) was without effect. 4 Neither CGRP (1 mu M) nor adrenome dullin (1 mu M) altered NANC relaxation induced by EFs at 5 Hz in trac heal rings precontracted with histamine (10 mu M).5 Adrenomedullin (1 nM to 1 mu M) and CGRP (1 nM to 1 mu M) induced a concentration-depend ent relaxation of the histamine (10 mu M)- and prostaglandin F-2 alpha (10 mu M)-precontracted pulmonary arterial rings with intact endothel ium with a similar potency. 6 Neither removal of the endothelium nor N -G-nitro-L-arginine methyl ester (100 mu M) altered the vasorelaxant e ffects of adrenomedullin (1 nM to 1 mu M) and CGRP (1 nM to 1 mu M). 7 The putative CGRP receptor antagonist CGRP(8-37) (1 mu M to 10 mu M) concentration-dependently attenuated the CGRP (3 nM to 30 nM)-induced vasorelaxant actions, whereas it had no effect on the relaxation of ve ssel rings induced by adrenomedullin (3 nM to 30 nM). 8 These results suggest that adrenomedullin is a potent vasodilator of the pulmonary a rtery without any bronchomotor effect in the guinea-pig lung, and that the vasorelaxant actions of adrenomedullin are not mediated via the a ctivation of CGRP(1) receptors.