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 generelated peptide (CGRP).2 In tracheal rings, CGRP (1 nM to 1 gM) potentiated the cholinergic contractions induced by electrical field stimulation (EFS) at 5 Hz in a concentration-dependent manner. At a concentration of 1 gM, 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 gM) did not alter either EFS-induced cholinergic or ACh-induced contractions. 3 In bronchial strips, CGRP (1 nm to 1 pM) slightly reduced both the non-adrenergic non-cholinergic (NANC) contraction induced by EFS at 10 Hz and the substance P (1 gM)-induced contraction in a concentration-dependent manner, whereas adrenomedullin (1 nM to 1 pM) was without effect.4 Neither CGRP (1 gM) nor adrenomedullin (1 gM) altered NANC relaxation induced by EFS at 5 Hz in tracheal rings precontracted with histamine (10 gM). Adrenomedullin (1 nm to 1 gM) and CGRP (1 nM to 1 pM) induced a concentration-dependent relaxation of the histamine (10 pM)-and prostaglandin F2a (10 gM)-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 pM) altered the vasorelaxant effects of adrenomedullin (1 nM to 1 pM) and CGRP (1 nM to 1 gM). 7 The putative CGRP receptor antagonist, CGRP8-37 (1 MM to 10 gM) 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.

Intermedin Is a Calcitonin/Calcitonin Gene-related Peptide Family Peptide Acting through the Calcitonin Receptor-like Receptor/Receptor Activity-modifying Protein Receptor Complexes

“…The increase in heart rate by intermedin and related peptides could be a reflex response to the hypotensive effect; however, the exact mechanisms remain to be investigated because the CRLR gene has been shown to be expressed in cardiac myocytes (35) in addition to the cardiac vasculature (34,36). Furthermore, intermedin could have cardioprotective and antibronchial constriction activities that are important for the regulation of cardiac and respiratory homeostasis (27,37). Because intermedin is not detected in proximity to the vasculature system using immunohistochemical analysis, further studies are needed to reveal whether intermedin represents an endocrine hormone involved in the regulation of cardiac and vasculature systems.…”

Bronchoprotector Properties of Calcitonin Gene–related Peptide in Guinea Pig and Human Airways

“…Thus, in contrast to the conflicting data currently reported on the myotropic effect of CGRP, our results would suggest that there are no interspecies variations in this capability of CGRP to act as a modulatory agent in mammalian isolated airways. In fact, our findings are not altogether unprecedented: recently CGRP has been shown to produce a concentration-dependent inhibition on both the nonadrenergic, noncholinergic contraction induced by EFS and the SPevoked contractile response in guinea pig bronchi in vitro (19) and to prevent leukotriene D 4 -elicited increase in airway resistance in guinea pig in vivo (24). Previously, we showed that CGRP also prevents in a concentration-related manner contractions elicited by carbamylcholine and 5-hydroxytryptamine in rat isolated airways (10).…”

“…For example, in human isolated airways, evidence has been provided for (3) and against (9) a bronchoconstrictor action of CGRP. Similarly, Luts and coworkers (17), Bhogal and coworkers (18), and Pinto and coworkers (19) showed that CGRP does not exert any contractile or re- laxant effect in guinea pig trachea, whereas Hamel and FordHutchinson (20) and Tschirhart and coworkers (21) reported that CGRP is one of the most potent contractile agents on guinea pig trachea yet identified. On the other hand, CGRP has been found to have no effect on hilus bronchi and parenchyma in the guinea pig in vitro (9,19,20) and to cause no changes in airway resistance in guinea pig in vivo (7,9,(22)(23)(24).…”

“…More recently CGRP has been reported to potentiate the cholinergic contractions elicited by electrical field stimulation (EFS) in guinea pig trachea (19), to produce no bronchoconstriction in isolated and perfused guinea pig lung (25), to induced relaxations in guinea pig trachea precontracted with KCl and prostaglandin F 2␣ (PGF 2␣ ) (18), but to be without any relaxant effect in human and guinea pig bronchi precontracted with NKA (9) and in guinea pig trachea precontracted with histamine (19). In other animal species, CGRP has been shown to have no contractile effect on the airway smooth muscle in the rabbit (26), pig (27,28), rat (10,20), and mouse (29) in vitro and in the sheep in vivo (30).…”

Relaxant effect of the calcitonin gene-related peptide (CGRP) on the nonpregnant and pregnant rat uterus. Comparison with vascular tissue

“…Hence, we assume that our treatment eliminates the uterotonic effect of substance P released by electrical stimulations and that could have counteracted the effect of CGRP . It is also known that CGRP facilitates the release of acetylcholine from cholinergic nerves and thus may counteract its own relaxant effect on smooth muscle (Pinto et al 1996). Inhibiting cholinergic effects on the smooth muscle cells with atropine or TTXpotentiates the effect of CGRP on myometrial muscle cells.…”