Contractile and dilatory action of neuropeptides on isolated human mesenteric blood vessels

doi:10.1016/0196-9781(87)90099-4

Peptides

Volume 8, Issue 2, March–April 1987, Pages 251-256

https://doi.org/10.1016/0196-9781(87)90099-4 Get rights and content

Abstract

Neuropeptide Y (NPY), substance P (SP), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), lysyl-bradykinin, somatostatin, Met- and Leu-enkephalin were tested for their smooth muscle activity in isolated human mesenteric arteries and veins. Only NPY regularly contracted both arteries and veins. Alpha-adrenergic and 5-HT₂ antagonists did not affect the response. Somatostatin contracted the veins, but not the arteries, in a variable but concentration-dependent way. The other neuropeptides were without contractile effect. CGRP, bradykinin, and SP regularly dilated, in a concentration-dependent way, both arteries and veins precontracted with prostaglandin F_2α or uridine triphosphate. CGRP and bradykinin were the most potent dilators. VIP and somatostatin usually caused a moderate dilatation in the arteries, whereas in the veins, somatostatin was without dilatory effect and the VIP-induced dilatation was irregular. In both types of vessels Met-enkephalin seldom gave any significant dilatation, and no response occurred in the presence of Leu-enkephalin or NPY. The SP-antagonist (D-Arg¹, D-Trp^7.9, Leu¹¹)-SP (spantide) caused a dextal shift of the concentration-response curves for SP, in the case of the arteries also including a reduced maximum effect.

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In this study, we compared the mesenteric arteries of humans, pigs, rabbits and rats in terms of the i) evolutionary changes in the amino acid sequences of α₁ and β2 adrenoceptors; M₁, M₂, and M₃ muscarinic receptors; and bradykinin (BKR) and thromboxane-prostanoid (TP) receptors, through bioinformatics tools; ii) expression of α₁, β₂, M1, M3 and TP receptors in each tunica, as assessed by immunofluorescence; and iii) reactivity to receptor-dependent and independent contractile agonists and relaxants, by performing organ bath assays. Phylogenetically, pigs showed the highest degree of evolutionary closeness to humans for all receptors, and with the exception of BKR, rabbits presented the greatest evolutionary difference compared to humans, pigs and rats. The expression of the measured receptors in the three vascular tunica in pigs was most similar to that in humans. Using a one-way ANOVA to determine the differences in vascular reactivity, we found that the reactivity of pigs was the most similar to that of humans in terms of sensitivity (pD2) and maximum effect of vascular reactivity (Emax) to KCl, phenylephrine, isoproterenol and carbachol.
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Citation Excerpt :
The wide expression of tachykinins, tachykinin receptors and NEP in the SV suggested that the tachykinin system may have both physiologic and pathophysiologic interests at this richly innervated portion of the vascular system [23], which we further investigated with functional studies. SP is known to induce an endothelium-dependent relaxation in numerous human vascular preparations [3–8,11–13], and endothelial NK1-receptors have been shown to mediate the relaxation of human pulmonary arteries and veins [11,12]. In pre-constricted SV segments from patients undergoing coronary artery bypass surgery, SP produced a relaxation which was markedly attenuated after the removal of the endothelium [32].
Substance P (SP) and neurokinin A (NKA) are members of the tachykinin peptides family. SP causes endothelial-dependant relaxation but the contractile response to tachykinins in human vessels remains unknown. The objective was to assess the expression and the contractile effects of tachykinins and their receptors in human saphenous veins (SV). Tachykinin expression was assessed with RT-PCR, tachykinin receptors expression with RT-PCR and immunohistochemistry, and functional studies were performed in organ bath. Transcripts of all tachykinin and tachykinin receptor genes were found in SV. NK₁-receptors were localized in both endothelial and smooth muscle layers of undistended SV, whereas they were only found in smooth muscle layers of varicose SV. The expression of NK₂- and NK₃-receptors was limited to the smooth muscle in both preparations. NKA induced concentration-dependent contractions in about half the varicose SV. Maximum effect reached 27.6 ± 5.5% of 90 mM KCl and the pD₂ value was 7.3 ± 0.2. NKA also induced the contraction of undistended veins from bypass and did not cause the relaxation of these vessels after precontraction. The NK₂-receptor antagonist SR48968 abolished the contraction induced by NKA, and a rapid desensitization of the NK₂-receptor was observed. In varicose SV, the agonists specific to NK₁- or NK₃-receptors did not cause either contraction or relaxation. The stimulation of smooth muscle NK₂-receptors can induce the contraction of human SV. As SV is richly innervated, tachykinins may participate in the regulation of the tone in this portion of the low pressure vascular system.
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Effect of somatostatin on rabbit isolated coronary arteries
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Somatostatin analogues are capable of inhibiting vascular smooth muscle and endothelial cell proliferation. However, little is known about the effect of somatostatin on vascular responses in endothelium-denuded coronary arteries in vitro. The aim of this work was to determine whether or not somatostatin prevented the contractile response induced by 5-hydroxytryptamine and acetylcholine in endothelium-denuded rabbit coronary arteries. Somatostatin attenuated the contraction produced by 5-hydroxytryptamine in both proximal (PC) and distal coronary (DC) arteries (contraction induced by 10^-4 M 5-hydroxytryptamine was inhibited by 10^-6 M somatostatin by 90.8 ± 11.0% (P<0.001, n = 9) and by 46.2 ± 14.0% (P<0.05, n = 9) in DC and PC, respectively), but concentration-dependently decreased the contraction induced by U46619 (11α-epoxy-methanoprostaglandin F_2α) only in PC arteries, suggesting that the response of PC and DC arteries to somatostatin were qualitatively different. Furthermore, we suggest that somatostatin may enhance acetylcholine-induced relaxation by combination of increasing endothelium-dependent relaxation (by a NO-dependent mechanism) and blocking contraction at the muscle level.

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Contractile and dilatory action of neuropeptides on isolated human mesenteric blood vessels

Abstract

Eur J Pharmacol

Regul Pept

Regul Pept

Trends Pharmacol Sci

Neurosci Lett

Life Sci

Eur J Pharmacol

Brain Res

Peptides

Neurosci Lett

J Pharmacol Exp Ther

Calcitonin gene-related peptide is a potent vasodilator

Nature

Effect of trigeminal denervation on in vitro responses of rabbit iris sphincter muscle to bradykinin and substance P

J Physiol (Lond)

Regulatory substances in clinically non-functioning gastrointestinal carcinoids

Molecular forms of VIP in normal tissue

Neuropeptide Y potentiates the effect of various vasoconstrictor agents on rabbit blood vessels

Br J Pharmacol

An unidentified depressor substance in certain tissue extracts

J Physiol (Lond)

Peptide hormones in various types of gastro-entero-pancreatic tumors: Immunohistochemical patterns and evolutionary background

Stimulation of noradrenergic sympathetic outflow by calcitonin gene-related peptide

Nature