5-Hydroxytryptamine receptor profile in healthy and diseased human epicardial coronary arteries

STUDY OBJECTIVE--The aim of the study was to investigate the receptor events that mediate the vascular effects of 5-hydroxytryptamine (5-HT) on human coronary arteries, since 5-HT has long been thought to play a role in coronary artery vasospasm. DESIGN--Recently available selective receptor agonists and antagonists were used to examine the 5-HT receptor subtypes present in human epicardial coronary arteries using in vitro organ baths. EXPERIMENTAL MATERIAL--138 segments of coronary arteries were obtained from 21 patients aged 2-66 years undergoing heart transplantation. MEASUREMENTS AND MAIN RESULTS--5-HT produced only concentration dependent contractions of coronary artery segments. No evidence was obtained for 5-HT receptors mediating either endothelium dependent or endothelium independent vasorelaxation. In tissue from patients without ischaemic heart disease, 5-HT effects were mimicked by (+/-)-alpha-methyl-5-HT (alpha-me-5-HT), a selective agonist at 5-HT2 receptors. In addition, the selective 5-HT1-like receptor agonist GR43175 produced contractions which achieved 30% of the maximum response to 5-HT. Responses to alpha-me-5-HT were surmountably antagonised by the non-selective antagonist methiothepin (0.1 mumol.litre-1) as well as the 5-HT2 receptor antagonist ketanserin (0.1 mumol.litre-1). In contrast GR43175 effects were resistant to blockade by ketanserin, but remained sensitive to methiothepin. Responses to the two agonists were not antagonised by the 5-HT3 receptor antagonist MDL72222 (1.0 mumol.litre-1). Vessel segments from ischaemic heart disease patients also contracted to alpha-me-5-HT and GR43175. Diseased arteries contracted with a decrease in the maximal response induced by both alpha-me-5-HT and by 90 mM K+ depolarisation compared to "normal" vessels, but the effect of GR43175 was preserved in the diseased arteries. Vascular rings adjacent to an atheromatous lesion were more reactive to GR43175 than serial segments taken distal to the lesion. CONCLUSIONS--These results show that both 5-HT1-like and 5-HT2 receptors mediate contraction of human epicardial coronary arteries and indicate that effects mediated by 5-HT1-like receptors but not 5-HT2 receptors are preserved in patients with ischaemic heart disease

Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro

Human airway smooth muscle possesses an inhibitory nonad-renergic noncholinergic neural bronchodilator response me-diated by nitric oxide (NO). In guinea pig trachea both endoge-nous NO and vasoactive intestinal peptide (VIP) modulate cholinergic neural contractile responses. To identify whether endogenous NO or VIP can modulate cholinergic contractile responses in human airways in vitro, we studied the effects of specific NO synthase inhibitors and the peptidase a-chymo-trypsin on contractile responses evoked by electrical field stimu-lation (EFS) at three airway levels. Endogenous NO, but not VIP, was shown to inhibit cholinergic contractile responses at all airway levels but this inhibition was predominantly in tra-chea and main bronchus and less marked in segmental and subsegmental bronchi. To elucidate the mechanism ofthis mod-ulation we then studied the effects ofendogenous NO on acetyl-choline (ACh) release evoked by EFS from tracheal smooth muscle strips. We confirmed that release was neural in origin, frequency dependent, and that endogenous NO did not affect ACh release. These findings show that endogenous NO, but not VIP, evoked by EFS can inhibit cholinergic neural responses via functional antagonism ofACh at the airway smooth muscle and that the contribution of this modulation is less marked in lower airways. (J. Clin. Invest. 1993.92:736-743.) Key words: acetylcholine release * functional antagonism * bronchodilation * parasympathetic innervation * inhibitory nonadrenergic non-cholinergic (i-NANC