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The role of vasoactive intestinal peptide (VIP) in the control of pulmonary vascular tone was investigated by functional response, immunocytochemical localisation and receptor autoradiography in bovine pulmonary arteries. VIP-immunoreactive nerve fibres were present at the adventitial-medial junction and in the media of the vessels. Exposure of precontracted bovine pulmonary artery segments to VIP in vitro resulted in almost complete (86 +/- 3%; mean +/- s.e.mean) relaxation, the concentration needed for 50% relaxation being 4.47 +/- 0.37 X 10(-9)M. VIP effects did not depend on the presence of intact endothelial cells. The distribution of VIP receptors was studied by autoradiography using [125I]-VIP. A high density of VIP receptors was found in arterial vascular smooth muscle, with a gradient of density from adventitia to luminal surface. There were no receptors on endothelial cells. These data show that VIP is a potent vasodilator of bovine pulmonary arteries, via direct activation of VIP receptors in vascular smooth muscle. VIP-immunoreactive nerves may influence pulmonary vascular tone directly and could, therefore, be important in regulating pulmonary blood flow.

1 Ring segments of bovine left circumflex coronary artery were pre-contracted with 5-hydroxytryptamine or phenylephrine and then exposed to increasing concentrations of calcitonin gene-related peptide (CGRP) and other drugs. 2 CGRP administration resulted in dose-dependent inhibition of induced tone. Maximal relaxation to CGRP was 89 +/- 5% and the concentration required to achieve 50% maximal relaxation (EC50) was 2.11 +/- 1.35 X 10(-9)M. 3 CGRP-induced relaxation was not affected by removal of endothelial cells nor was it significantly altered by incubation of coronary vessels with atropine, propranolol, phentolamine (all 10(-6)M) or indomethacin (10(-5)M). 4 From these data we conclude that CGRP is a potent inhibitor of coronary artery vasomotor tone which appears to act directly on vascular smooth muscle rather than through the release of a secondary mediator. These data support the possibility that CGRP may play a role in non-adrenergic, non-cholinergic regulation of coronary artery tone.

An intravenous infusion of platelet activating factor (Paf) in the guinea-pig elicits an increase in bronchial responsiveness to the spasmogens, histamine and bombesin. Airways obstruction induced by bombesin in Paf-treated animals is poorly reversed by isoprenaline compared to comparable airways obstruction induced by bombesin in vehicle-treated animals. Isoprenaline induced a comparable dose-related relaxation in vitro of tracheal smooth muscle isolated from Paf- and vehicle-treated animals. No change in beta-adrenoceptor numbers or binding affinity was observed in lungs removed from Paf-treated animals in comparison with those from vehicle-treated animals, or after direct incubation with Paf in vitro. The reduced bronchodilator responsiveness to isoprenaline in Paf-treated animals is not related to changes in pulmonary beta-adrenoceptor function. These results suggest that non-spasmogenic elements may contribute to airways obstruction induced in hyper-responsive animals.

We studied the functional effects of vasoactive intestinal peptide (VIP) and the structurally related peptide histidine isoleucine (PHI) in segments of bovine and human intrapulmonary artery. In both species, VIP caused nearly complete relaxation of precontracted vessel segments. The EC50 was 1.3 ± 0.3 × 10–9 M (mean ± SD) in bovine and 3.4 ± 0.4 × 10–9 M in human pulmonary artery. The response to VIP was not endothelium-dependent and it was not affected by either adrenergic and cholinergic blockade or by cyclooxygenase inhibition. PHI also relaxed human and bovine vessels but this related peptide was significantly less effective than VIP. We conclude that VIP is a potent inhibitor of bovine and human pulmonary artery, which appears to act directly on vascular smooth muscle. These data support the concept that VIP may be a neurotransmitter which modulates pulmonary artery tone in both man and cow.

Although electrical field stimulation has been used to evoke neural responses in blood vessels this technique can also generate activated oxygen molecules which may affect the experimental preparation. We evaluated this by stimulating 10 cc of aerated Krebs-Henseleit solution for a period of 20 s and then transferring the fluid to a pre-contracted segment of bovine pulmonary artery. The parameters required to achieve 50% maximal relaxation were a voltage of 4.0 +/- 0.3 volts (mean +/- S.E.), a frequency of 1.6 +/- 0.1 Hz and a pulse duration of 0.37 +/- 0.02 ms. Exposure to stimulated fluid caused greater amounts of relaxation in vessels pre-contracted with serotonin than in those pre-contracted with either histamine or potassium chloride. Relaxation was not endothelial dependent and it was not inhibited by adrenergic or cholinergic blockade. Since both ascorbate and catalase but not superoxide dismutase inhibited relaxation, it appears that hydrogen peroxide is involved. We conclude that even low intensity electrical field stimulation generates activated oxygen molecules in oxygenated physiologic buffer solution and that these molecules can relax blood vessels both directly and by altering the response to drugs in the muscle bath. These effects must be considered when using electrical field stimulation to study blood vessels.