Songping Han

Inhibition of periarterial nerve stimulation-induced vasodilation of the mesenteric arterial bed by CGRP (8-37) and CGRP receptor desensitization.

We provide the first functional evidence that calcitonin gene-related peptide (8-37) induces a direct vasoconstriction and reversibly antagonizes vasodilation of the mesenteric arterial bed induced by calcitonin gene-related peptide (CGRP) suggesting that CGRP (8-37) is a competitive antagonist of vascular CGRP receptors. Vasodilation induced by periarterial nerve stimulation was inhibited both by CGRP (8-37) and by desensitization of CGRP receptors. These results further support the evidence that the periarterial nerve stimulation-induced nonadrenergic noncholinergic vasodilation of the mesenteric vasculature is mediated by endogenous CGRP and its receptors.

Direct evidence for the role of neuropeptide Y in sympathetic nerve stimulation-induced vasoconstriction

Neuropeptide Y (NPY) is a vasoconstrictor peptide and a cotransmitter with norepinephrine (NE) in sympathetic nerve terminals and is thought to be involved in sympathetic nerve stimulation (SNS)-induced vasoconstriction. Using BIBP-3226, a Y1 receptor selective antagonist, we examined this hypothesis in the isolated and perfused mesenteric vascular bed. SNS produced a frequency-dependent increase in perfusion pressure and concomitant overflow of NPY immunoreactivity in the perfusate. [Leu31,Pro34]NPY potentiated NE-induced and ATP-induced vasoconstriction, indicating the presence and biological action of Y1 receptors in this vascular bed. The potentiation effect of [Leu31,Pro34]NPY of the increase in perfusion pressure by NE, ATP, or SNS was prevented by BIBP-3226. In addition, SNS-induced vasoconstriction at both high and low frequencies was significantly attenuated by BIBP-3226 at a concentration that completely blocked the [Leu31,Pro34]NPY-induced potentiation of the NE- or ATP-induced vasoconstrictor effect. These results suggest that approximately 30% of vasoconstriction produced by SNS depends on NPY in the mesenteric vascular bed.Neuropeptide Y (NPY) is a vasoconstrictor peptide and a cotransmitter with norepinephrine (NE) in sympathetic nerve terminals and is thought to be involved in sympathetic nerve stimulation (SNS)-induced vasoconstriction. Using BIBP-3226, a Y1 receptor selective antagonist, we examined this hypothesis in the isolated and perfused mesenteric vascular bed. SNS produced a frequency-dependent increase in perfusion pressure and concomitant overflow of NPY immunoreactivity in the perfusate. [Leu31,Pro34]NPY potentiated NE-induced and ATP-induced vasoconstriction, indicating the presence and biological action of Y1 receptors in this vascular bed. The potentiation effect of [Leu31,Pro34]NPY of the increase in perfusion pressure by NE, ATP, or SNS was prevented by BIBP-3226. In addition, SNS-induced vasoconstriction at both high and low frequencies was significantly attenuated by BIBP-3226 at a concentration that completely blocked the [Leu31,Pro34]NPY-induced potentiation of the NE- or ATP-induced vasoconstrictor effect. These results suggest that ∼30% of vasoconstriction produced by SNS depends on NPY in the mesenteric vascular bed.

Role of Neuropeptide Y in Cold Stress-Induced Hypertension

Chronic cold stress (4 degrees C) produced a sustained increase in mean arterial pressure in both normotensive and borderline hypertensive rats (BHR). The high blood pressure in BHRs was significantly reversed by a neuropeptide Y (NPY) Y1 receptor antagonist suggesting that NPY is involved in mediating stress-induced hypertension. Corresponding increases in adrenal NPY messenger RNA and NPY immunoreactivity were found during the stress; furthermore, chronic cold stress also potentiated the pressor response of rats to a subsequent acute stress test in which NPY has been shown to play a role. These results suggest that chronic cold stress-induced hypertension is mediated by elevated NPY release and vascular tone as a result of increased NPY gene expression and storage.

Cardiac and vascular actions of sarafotoxin S6b and endothelin-1

Snake venom-derived sarafotoxin S6B (SRT) and porcine endothelium-derived endothelin-1 (ET) have striking structural similarities. In conscious, freely-moving rats, ET (0.67 nmol/kg) produced a transient tachycardia and fall in arterial blood pressure which was followed by a long-lasting increase in arterial pressure, bradycardia, decrease in cardiac output (CO) and marked increase in total peripheral resistance. In contrast, SRT (0.67 nmol/kg) produced only the sustained cardiovascular responses. The sustained cardiovascular effects of SRT or ET were similarly attenuated by nifedipine. SRT and ET (30 nM) produced vasoconstriction in the isolated perfused mesenteric vascular bed without initial vasodilation. SRT and ET had potent positive inotropic and negative chronotropic effects on isolated perfused hearts and induced toxic reactions including coronary vasospasm, arrhythmias, A-V block and ventricular fibrillation. In addition to SRT lacking the initial depressor response in vivo, several differences in the activities of the peptides were also observed. ET produced greater and longer-lasting actions than SRT in producing pressor and vasoconstrictor responses in all 3 preparations, and in its ability to induce toxic effects on the heart.

Elevated Neuropeptide Y Gene Expression and Release During Hypoglycemic Stress

Our previous studies show that neuropeptide Y (NPY) is involved in mediating sympathetic nerve stimulation-induced vasoconstriction. Insulin hypoglycemia is known to produce increased sympathetic output and elevated arterial pressure. The present study examined the role of NPY in the hypertensive response to insulin by examining the effects of insulin on NPY gene expression, tissue content and release. Subcutaneous injection of insulin produced an immediate increase in plasma NPY immunoreactivity (NPYir) and delayed increases in adrenal and neuronal NPY mRNA and adrenal NPYir in rats. These results suggest that NPY may play a role in insulin-induced hypertension.

Endothelin and sarafotoxin S6b have similar vasoconstrictor effects and postsynaptically mediated mechanisms

In the isolated perfused mesenteric vascular bed, porcine endothelin (ET) and sarafotoxin S6b produced direct vasoconstriction and potentiated nerve stimulation-induced vasoconstriction. ET also enhanced the vasoconstrictor response to exogenous norepinephrine (NE). Basal or stimulated endogenous NE release was not affected either by ET or sarafotoxin S6b. Qualitatively similar responses to ET and sarafotoxin S6b were always observed, although, in many cases, the response to ET was greater and longer lasting than to sarafotoxin S6b. These results indicate that vasoconstrictor responses to ET or sarafotoxin S6b are mediated primarily by postsynaptic mechanisms. No initial vasodilator response to ET or sarafotoxin S6b was observed in this mesenteric vascular preparation.

Influence of cold stress on neuropeptide Y and sympathetic neurotransmission

Chronic cold stress of rats (4 degrees C; 1-3 weeks) induced a marked increase in gene expression (adrenal medulla; superior cervical ganglia), tissue content (mesenteric arterial bed) and nerve stimulation-induced overflow of NPY-immunoreactivity (NPYir) from the perfused mesenteric arterial bed. In contrast increased NPY neurotransmission was offset by an apparent decrease in the evoked overflow of norepinephrine (NE) due to a presumed deactivation of NE by nitric oxide (NO), despite increased sympathetic nerve activity. The net effect of these offsetting system was no change in basal or the evoked increase in perfusion pressure (sympathetic tone). It is concluded that differences in NPY and NE transmission act as an important compensatory mechanism preventing dramatic changes in arterial pressure when sympathetic nerve activity is high during cold stress.

Presynaptic Peptide Receptors and Hypertension

Vascular smooth muscle is subject to control from a variety of neuronal, hormonal, and autacoidal influences. Among the various chemical mediators that exert important actions on the cardiovascular system are a variety of vasoactive peptides stored and released from perivascular nerves or from components of blood vessels such as smooth muscle and endothelium. Two peptides of great interest include neuropeptide Y (NPY) which has been shown to be colocalized and coreleased with norepinephrine from noradrenergic nerves’,’ and calcitonin gene-related peptide (CGRP) located in a variety of sensory and perivascular nerves.’.‘‘ The purpose of this paper is to summarize recent studies on the preand postjunctional actions of NPY and CGRP at the vascular neuroeffector junction of normotensive and the spontaneously hypertensive rat (SHR). The perfuscd mesenteric arterial bed of the rat has bccn utilized as a model of the vascular neuroeKector junction.

Effects of neuropeptide Y at sympathetic neuroeffector junctions.

Publisher Summary Evidence for the existence of these three cotransmitters—norepinephrine(NE), neuropeptide Y (NPY), and adenosine triphosphate (ATP)—has come from studies showing that they are located in sympathetic nerves and that they can be released under appropriate conditions. In addition, the application of each transmitter mimics a phase of sympathetic nerve stimulation and each phase can be blocked with appropriate antagonists. Earliere studies included the perfused mesenteric arterial bed of the rat and the nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cell. Both preparations were set up and utilized as previously described. The release of mediators was induced by periarterial nerve stimulation of the mesenteric arterial bed or depolarization with high K + (50 mM) of the PC12 cell. Nerve stimulation of the perfused mesenteric arterial bed resulted in the release of NE, ATP, and NPY. The release of NE was inhibited by NPY and NPY analogues. The ability of NPY to inhibit the evoked release of NE from the perfused mesenteric arterial bed of 8- to 10-week-old spontaneous hypertensive rat (SHRs) was attenuated compared with WKY rats while the postjunctional potentiation of the contractile effect induced by nerve stimulation or the exogenous administration of NE or ATP was enhanced. These results are consistent with alterations in the normal function of NPY playing a role in the development of hypertension in the SHR.