Enhanced Neuropeptide Y Immunoreactivity and Vasoconstriction in Mesenteric Small Arteries from Spontaneously Hypertensive Rats

Abstract

Enhanced sympathetic nerve activity is thought to play a role in the pathogenesis of hypertension. The purpose of the present study was to investigate the mechanisms underlying the enhanced vasocontractile response to perivascular stimulation of mesenteric arteries isolated from female spontaneously hypertensive rats (SHR). Innervation of mesenteric small arteries was evaluated by immunohistochemistry and confocal microscopy while functional studies were conducted in a microvascular myograph. The distribution of nerve terminals immunoreactive for tyrosine hydroxylase (TH) and neuropeptide Y (NPY) was similar in mesenteric small arteries from Wistar-Kyoto (WKY) and SHR rats. However, immunointensity of TH or NPY immunoreactivities were much higher in small arteries from SHR compared to WKY. Expressed as percentage of contractions elicited by 124 mM K⁺, concentration-response curves for noradrenaline (NA) and NPY were shifted leftward in SHR compared with WKY rats. The combination of noradrenaline (1 µM) and NPY (10 nM) contracted mesenteric arteries from WKY and SHR to higher levels than compared to either contractile agent added alone. The NPY Y₁ receptor antagonist, BIBP 3226, inhibited these contractions with 87 ± 0.7 and 80 ± 1.3% (p < 0.05, n = 6) in arteries from WKY and SHR rats, respectively. In arteries incubated with the α₁-adrenoceptor antagonist, prazosin, and preactivated with vasopressin, electrical field stimulation evoked contractions which were more pronounced in mesenteric arteries from SHR compared to WKY rats. BIBP 3226 partially inhibited these contractions. In vasopressin-activated arteries BIBP 3226 caused rightward shifts of the concentration-response curves for NPY in mesenteric arteries from SHR rats, but in addition it also abolished the maximal NPY contraction in arteries from WKY rats. In the presence of BIBP 3226, low concentrations (1 pM to 10 nM) of NPY caused relaxations in arteries from WKY, but not in segments from SHR rats. Mechanical removal of the endothelium abolished NPY relaxation in arteries from WKY. In arteries activated with vasopressin and exposed to either forskolin or sodium nitroprusside, the addition of NPY evoked contractions which were more pronounced in arteries from SHR compared to WKY arteries. The present study suggests that enhanced NPY content and vasoconstriction to NPY in arteries from hypertensive rats can contribute to the enhanced sympathetic nerve activity and vascular resistance in female hypertensive rats. Endothelial cell dysfunction as well as alterations in smooth muscle response to NPY seem to contribute to the enhanced vasoconstriction in arteries from hypertensive animals.

Functional Antagonism between Endogenous Neuropeptide Y and Calcitonin Gene-Related Peptide in Mesenteric Resistance Arteries

“…NPY that is stored in the vicinity of CGRP has been shown to enhance vasoconstrictor responses and to reduce vasodilator responses to stimulation of adenylyl cyclase (Doods et al, 2000;Gradin et al, 2003). Our observations with NPY during K ϩ -induced contraction and forskolin-induced relaxation are in line with these earlier findings.…”

“…It also Coalescence and functional antagonism of CGRP and NPY suggest that Y1 receptor blockade may be considered to enhance the efficacy of endogenous CGRP. In spontaneously hypertensive rats, which display an increased density of periarterial NPY-containing but not CGRP-containing nerves (Gradin et al, 2003;Luff et al, 2005), BIBP3226 does not lower blood pressure even during stress-induced stimulation of the sympathetic nervous system (Zhao et al, 1997). However, in this model BIBP3226 displays an age-dependent reducing effect on the enhanced neurogenic renovascular constriction (Vonend et al, 2005;Dubinion et al, 2006).…”

“…Our protocol was inspired by a previous study of Simonsen et al (Gradin et al, 2003). We used a high concentration of phenylephrine to cause contraction and to saturate the postjunctional ␣ 1 -adrenoceptors that play a major role in neurogenic vasoconstriction.…”

Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries

“…However, evidence has emerged recently suggesting a vasodilator role for the peptide in certain vascular beds both in vivo and in vitro models. Thus, NPY relaxes precontracted renal arteries of diabetic and nondiabetic rats (Torffvit & Edvinsson, 1997), human subcutaneous arteries and mesenteric small arteries (Gradin et al, 2003), and induces vasodilatation in cerebral arteries from different species (Kobari et al, 1993;You et al, 2001). In the present study, several results provide evidence for the existence of NPY vasodilator receptors.…”

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

“…26,27 Our Western blot analysis showed decreased levels of NPY at sites of MI and at sites distant from MI in the RDN group. The neurotransmitter NPY, a marker of sympathetic activity, has been demonstrated to be decreased after RDN.…”