Modifications by stretches of the mechanical response of isolated cerebral and extracerebral arteries to vasoactive agents

Summary Length-tension relationship was compared in helically cut strips of canine cerebral, coronary, mesenteric, renal, and femoral arteries. Tension developed progressively by increasing the stretch; with the same strain, a greater passive tension developed in cerebral than in extracerebral arteries. The peak active tension developed by serotonin (cerebral, coronary), norepinephrine (mesenteric, renal and femoral) or K⁺ (coronary) was obtained at a resting tension of 1.5 g (other than coronary) or 2.0 g (coronary). Papaverine (10^–4 M) caused a relaxation in cerebral arterial strips contracted with serotonin to a level lower than that prior to the addition of serotonin, the relexation from the initial level of tension being related directly to the stretch applied. The relaxing effect of adenosine was related directly to stretches of cerebral arterial strips. It seems likely that a rise of intra-arterial pressure effects a greater increase in the wall stiffness in cerebral than in extracerebral arteries. The responsiveness to vasoconstricting and vasodilating agents of both cerebral and extracerebral arteries appears to increase when the arteries are distended.     

Role of dopaminergic and adrenergic receptors in the pathogenesis of arterial lesions induced by fenoldopam mesylate and dopamine in the rat.

Fenoldopam mesylate (FM), a selective, postjunctional, dopaminergic (DA1) vasodilator, causes a novel lesion of large caliber splanchnic arteries (100 to 800 microns) in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (less than 100 microns) of the splanchnic, cerebral, coronary, and renal vascular beds. Dopamine, an alpha- and beta-adrenoceptor and dopaminergic agonist, is used clinically, principally as a pressor agent. Because these arterial lesions were believed to result from the pharmacologic activity of these two compounds, the role of vascular receptor subtypes in their pathogenesis was investigated. Rats were coexposed to either FM or dopamine and a variety of receptor antagonists (alpha, beta, DA1, DA2, and 5HT2). In rats coexposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions of large caliber arteries were increased; PBZ, however, prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. SK&F 83566-C, a selective DA1 dopaminergic receptor antagonist, prevented the induction of FM and dopamine-induced hemorrhagic lesions of large caliber arteries. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. The other receptor antagonists tested did not prevent arterial injury. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and FM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA1 receptors. Activation of the postjunctional, dopaminergic (DA1) receptor is causally associated with the induction of novel hemorrhagic lesions of large caliber splanchnic arteries in the rat.     

Isolated human coronary arteries in response to vasoconstrictor substances

In helical strips of human epicardial coronary arteries, norepinephrine produced a concentration-related contraction; the contractions relative to those induced by 30 mM K+ were greater in the proximal portion of the arteries than in the distal portion. The amine-induced contraction was suppressed by treatment with phentolamine. Acetylcholine contracted human coronary arteries but, in contrast, relaxed the monkey coronary arteries (both freshly excised and cadaver) previously contracted with prostaglandin F2 alpha. Both the contraction and relaxation induced by acetylcholine were suppressed by atropine. Removal of the endothelium abolished the relaxation of monkey arteries but did not significantly alter the contraction of human arteries. Human coronary arteries responded to histamine with contractions, which were reversed to relaxations following treatment with chlorpheniramine. It is concluded that, as far as the portions of human coronary arteries used in the present study are concerned, the arterial contraction mediated via alpha-adrenoceptors is inversely related to the distance from the coronary artery orifice. Acetylcholine produces contractions of human coronary arteries, possibly due to activation of muscarinic receptors on smooth muscle cells. Histamine-induced contractions appear to be mediated via H1-receptors.     

Relaxant responses to transmural stimulation and nicotine of dog and monkey cerebral arteries

In helical strips of dog and monkey cerebral arteries contracted with prostaglandin F2 alpha, transmural stimulation and nicotine produced relaxations that were abolished by tetrodotoxin and hexamethonium, respectively. These responses were attenuated by quinidine, whereas relaxations of dog coronary arteries to transmural stimulation and isoproterenol were unaffected. Treatment with vasoactive intestinal polypeptide (VIP) and substance P (SP) abolished the relaxant response of cerebral arteries to repeated applications of VIP and SP, respectively; however, after VIP or SP, a normal relaxant response to transmural stimulation or nicotine was produced. Aminophylline suppressed relaxations induced by ATP but not by nerve stimulation. VIP, SP, and adenosine 5'-triphosphate (ATP) relaxed dog cerebral arteries; the responses were unaffected by quinidine. However, only VIP and ATP relaxed monkey cerebral arteries, and SP contracted the arteries. Acetylcholine contracted monkey arteries, in which transmural stimulation produced a relaxation. It may be concluded that nerves innervating the cerebrospinal wall are stimulated electrically and chemically by nicotine, resulting in the arterial relaxation. However, a vasodilator transmitter was not identified. Quinidine appears to selectively antagonize the action of the transmitters on cerebroarterial smooth muscle.     

Release of gastrin on stimulation of the sciatic and brachial nerves of the cat

The vasomotor response of dopamine and dopaminergic agonists was studied in vitro on middle cerebral arteries from cat and pial arteries from humans. The action of various inhibitors was tested in order to define the receptors involved. A contractile response could be obtained by epinine, apomorphine and dopamine in the mentioned order of potency. The effect was blocked by alpha-receptor as well as serotonin receptor antagonists. The mode of inhibition suggested that serotonin receptors rather than alpha-adrenoceptors mediated the dopamine-induced contraction. A dose-dependent dilatation could be evoked by the dopaminergic agonists on actively contracted pial arteries. The relative potency was epinine > dopamine > apomorphine. The order of potency for the agonists, together with blocking experiments (including a parallel shift in the log dose-response curve induced by bulbocapnine), indicated that the vasodilatation is mediated by specific dopamine receptors.     

Potassium-induced relaxation in isolated cerebral arteries contracted with prostaglandin F2α

Summary In helically cut strips of canine cerebral arteries exposed to 5.4 mM [K⁺]_o and contracted with prostaglandin F₂, the addition of K⁺ in concentrations ranging from 0.5–5 mM caused a dose-related relaxation. The relaxing effect of K⁺ was potentiated at reduced [K⁺]_o and suppressed at reduced [Na⁺]_o. Reduction of Cl^– from bathing media failed to alter the effect of K⁺. Removal of external Ca²⁺ markedly attenuated the K⁺-induced relaxation and increase in [Ca²⁺]_o also attenuated the relaxation. Similar relaxation was induced by K⁺ in cerebral arteries from other species including humans, puppies, cats and rabbits. The addition of K⁺ also elicited a relaxation in peripheral arteries, including coronary, femoral, mesenteric and renal, contracted with prostaglandin, but this relaxation was markedly less than in cerebral arteries. The content of Na⁺ in freshly excised cerebral arteries was significantly greater than that of peripheral arteries, while the content of K⁺ in these arteries was not significantly different.The present study provides further evidence to support the hypothesis that an electrogenic Na⁺ pump is involved in the genesis of K⁺-induced relaxation. The Na⁺ pump does not appear to be fully activated at normal [K⁺]_o of 5.4 mM in cerebral arteries.     

Regional differences in endothelium-dependent relaxation in the rat: contribution of nitric oxide and nitric oxide-independent mechanisms

Relaxant effects of acetylcholine (ACh), histamine, calcitonin gene-related peptide (CGRP) and the calcium ionophore A23187 were examined in rat femoral (Ø ? 0.2 mm), mesenteric (0.2 mm), intrarenal (0.2 mm) and hepatic (0.3 mm) arteries, and aorta (2 mm). Acetylcholine elicited an endothelium-dependent relaxation in all arteries. Histamine induced an endothelium-dependent relaxation in aorta, and mesenteric and intrarenal arteries, whereas a partly endothelium-dependent and mainly endothelium-independent relaxation was observed in hepatic and femoral arteries, respectively. In hepatic, mesenteric and intrarenal arteries, CGRP induced an endothelium-independent relaxation, whereas either small or no relaxation was obtained in aorta and femoral arteries respectively. A23187 induced an endothelium-dependent relaxation in the aorta and hepatic artery, whereas A23187 had no relaxant effect in femoral, mesenteric and intrarenal arteries. Nω-nitro-l -arginine (l -NOARG, 0.3 mM) reduced the maximum ACh-induced relaxation (in the presence of 10 μM indomethacin) by 66% in the aorta, and abolished the relaxation in femoral and intrarenal arteries. A marked l -NOARG/indomethacin-resistant relaxation was obtained in mesenteric and hepatic arteries. Levcromakalim induced a concentration-dependent and almost complete relaxation in all arteries. When contracted by a 60 mM K⁺ solution, all arteries responded to ACh with a relaxation that was abolished by l -NOARG. These results demonstrate marked regional differences with regard to the vascular effects of ACh, histamine, CGRP and A23187. Whereas nitric oxide appears to mediate endothelium- dependent relaxation regardless of the vascular region, an l -NOARG/indomethacin-resistant relaxation, presumably mediated by an endothelium-derived hyperpolarizing factor, was observed only in mesenteric and hepatic arteries, and aorta.     

Regional and species differences in vascular reactivity to extracellular potassium

In-vitro vasoreactivity to extracellular potassium (Ko+) was tested in isolated human pial and mesenteric arteries as well as basilar and mesenteric arteries from rabbits and rats. Contractions were induced by stepwise increases in [K+]o and were measured isometrically with a force-displacement transducer, in small-volume organ baths. Significant differences between species as well as between regions were found. The threshold of [K+]o for eliciting contraction in human cerebral arteries in hyperosmotic solutions was 10 mM, in rabbit cerebral arteries 17 mM and in rat cerebral arteries 27 mM. The threshold concentration for contraction in mesenteric arteries was significantly higher compared to cerebral arteries in humans and rabbits, but lower in rats: 20 mM in humans, 26 mM in rabbits and 25 mM in rats. In all species the contractile amplitudes were significantly higher in both cerebral and mesenteric arteries when [K+]o was increased under isotonic conditions in the buffer solution than when hyperosomolality was created. This difference increased with increasing hyperosmolality. In hyperosmotic solutions, the EC50 for [K+]o was lower in cerebral and mesenteric arteries from man than in vessels from rabbit and rat. When the solutions were isotonic, this pattern was seen only in mesenteric arteries. It is concluded that significant species and regional differences in vascular responses to [K+]o exist. Considering that [K+]o is increased in cerebral ischaemia, the observed significantly lower threshold for K+-induced contractions in human cerebral arteries may be of importance, especially in human cerebral ischaemic events.     

Effect of intrarenal administration of dopamine on renin release in conscious dogs

We investigated the effect of intrarenal administration of dopamine on renin release in conscious dogs. Dopamine in doses ranging from 0.28 to 3.0 micrograms . kg(-1) . min(-1) produced a significant increase in systemic plasma renin activity (PRA) and renin secretion rate without altering systemic blood pressure. Dopamine also induced renal vasodilatation and natriuresis within this dose range. To determine if the dopamine-induced renin release is related to its vasodilatory action, two other vasodilators, papaverine and acetylcholine, were infused into the renal artery, but neither, in doses that produced a rise in renal blood flow similar to that of dopamine, had any effect on PRA. As dopamine can activate alpha- and beta-adrenergic receptors in addition to dopaminergic receptors, experiments were also performed to characterize the type of receptors involved in dopamine-induced renin release. Intrarenal infusion of sulpiride and haloperidol, dopamine antagonists, significantly inhibited dopamine-induced renin release and renal vasodilatation. In contrast, intrarenal infusion of propranolol failed to alter dopamine-induced rise in PRA or renal blood flow. Simultaneous infusion of phentolamine and dopamine, on the other hand, produced a significant potentiation of dopamine-induced renin release and renal vasodilatation. In conclusion, our studies demonstrate that dopamine is capable of inducing renin release and renal vasodilatation in conscious dogs. Moreover, such actions of dopamine are mediated through activation of specific dopamine receptors in the kidney. Finally, we present evidence for the existence of the intrarenal alpha-adrenergic mechanism that is inhibitory to renin release.     

Dopamine induces contraction in the proximal,but relaxation in the distal rat isolated small intestine

In the gut, dopamine is released by enteric neurons and modulates motility of small intestine smooth muscle cells. Here, we systematically analyzed the dopamine-induced effects on the longitudinal smooth muscle of different sections of the rat isolated small intestine. We found that exogenous dopamine had biphasic effects and could lead to both an early contraction and a late relaxation, depending on the region of small intestine. Thus, dopamine-induced early contractions were commonly observed in the duodenum, but less frequently in the jejunum, and rarely in the ileum. The amplitudes of these early contractions showed a striking regional dependence (duodenum > jejunum > ileum) and were significantly blocked by SCH23390 and raclopride. Conversely, dopamine-induced late relaxations were regularly obtained in the ileum and in the jejunum, but less frequently in the duodenum. Interestingly, the amplitudes of these relaxations showed an inverse regional dependence (ileum > jejunum > duodenum), and were insensitive to dopamine receptor antagonists. Rather, they were significantly inhibited by propranolol and prazosin. We conclude that dopamine exerts differential effects on smooth muscle motility in different regions within the rat small intestine. In proximal parts, dopamine predominantly causes D₁ and D₂ dopamine receptor-dependent contraction, whereas it leads to α and β adrenoceptor-dependent relaxation in more distal parts.     

Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy

We recently reported vascular dysfunction in adult offspring of rats fed a fat-rich (animal lard) diet in pregnancy. This study reports further characterization of constrictor and dilator function in mesenteric and caudal femoral arteries from 180-day-old offspring of dams fed the high fat diet (OHF). Endothelium-dependent relaxation in response to acetylcholine (10⁻⁹–10⁻⁵ m ) was impaired in mesenteric small arteries from male and female OHF compared with offspring of dams fed normal chow (males (maximum percentage relaxation): OHF 67.92 ± 2.89, n = 8 versus control 92.08 ± 2.19, n = 8, P < 0.01). Substantial relaxation in response to acetycholine in control mesenteric arteries remained after inhibition of nitric oxide synthase, soluble guanylate cyclase and cyclo-oxygenase but was blocked by 25 m m potassium. This component of relaxation, attributed to EDHF, was significantly reduced in OHF mesenteric arteries compared with controls. However, EDHF played a minor role in acetylcholine-induced relaxation in both control and OHF femoral caudal arteries (male and female). In these arteries, in contrast to mesenteric vessels, acetylcholine-induced relaxation was significantly enhanced in OHF but only in males (ACh (maximum percentage relaxation): OHF 58.40 ± 4.39, n = 8 versus male controls 32.18 ± 6.36, P < 0.05). This was attributable to enhanced nitric oxide-mediated relaxation. In conclusion, reduced endothelium-dependent relaxation in OHF mesenteric arteries is due to impaired EDHF-mediated relaxation. This defect was not apparent in femoral arteries in which EDHF has a less prominent role.     

Heterogeneity in the response to histamine of isolated dog arteries

Arterial rings were used to evaluate the differences in the effect of histamine (HIS) on canine dorsal pedal (DPA) and coronary arteries. Moreover, the responses of intact coronary arteries (IA) to HIS were compared with those of arteries isolated from sham operated dogs (SA) and from dogs in the late postinfarction period (PA). DPA responded to HIS added cumulatively with contraction which was potentiated by cimetidine (CIM) and reversed by mepyramine (MEP). IA responded with relaxation potentiated by MEP and reversed by CIM. Under resting conditions, coronary arteries responded to a single concentration of HIS with contraction or relaxation (in IA, SA). In PA, only contractions were seen. Responses of PA were significantly higher than those of IA and SA. It appears that in PA the ratio of H₁- and H₂-receptors is changed.     

KIR channels function as electrical amplifiers in rat vascular smooth muscle

Strong inward rectifying K(+) (K(IR)) channels have been observed in vascular smooth muscle and can display negative slope conductance. In principle, this biophysical characteristic could enable K(IR) channels to 'amplify' responses initiated by other K(+) conductances. To test this, we have characterized the diversity of smooth muscle K(IR) properties in resistance arteries, confirmed the presence of negative slope conductance and then determined whether K(IR) inhibition alters the responsiveness of middle cerebral, coronary septal and third-order mesenteric arteries to K(+) channel activators. Our initial characterization revealed that smooth muscle K(IR) channels were highly expressed in cerebral and coronary, but not mesenteric arteries. These channels comprised K(IR)2.1 and 2.2 subunits and electrophysiological recordings demonstrated that they display negative slope conductance. Computational modelling predicted that a K(IR)-like current could amplify the hyperpolarization and dilatation initiated by a vascular K(+) conductance. This prediction was consistent with experimental observations which showed that 30 mum Ba(2+) attenuated the ability of K(+) channel activators to dilate cerebral and coronary arteries. This attenuation was absent in mesenteric arteries where smooth muscle K(IR) channels were poorly expressed. In summary, smooth muscle K(IR) expression varies among resistance arteries and when channel are expressed, their negative slope conductance amplifies responses initiated by smooth muscle and endothelial K(+) conductances. These findings highlight the fact that the subtle biophysical properties of K(IR) have a substantive, albeit indirect, role in enabling agonists to alter the electrical state of a multilayered artery.     

Involvement of cyclo-oxygenase-1-mediated prostacyclin synthesis in the vasoconstrictor activity evoked by ACh in mouse arteries

This study was to determine whether the endothelium of mouse major arteries produces prostacyclin (PGI(2)) and, if so, to determine how PGI(2) affects vasomotor reactivity and whether cyclo-oxygenase-1 (COX-1) contributes to PGI(2) synthesis. Abdominal aortas, carotid and femoral arteries were isolated from wild-type mice and/or those with COX-1 or -2 deficiency (COX-1(-/-); COX-2(-/-)) for biochemical and/or functional analyses. The PGI(2) metabolite 6-keto-PGF(1α) was analysed with high-performance liquid chromatography-mass spectroscopy, while vasoreactivity was determined with isometric force measurement. Results showed that in the abdominal aorta, ACh evoked endothelium-dependent production of 6-keto-PGF(1α), which was abolished by COX-1(-/-), but not by COX-2(-/-). Interestingly, COX-1(-/-) enhanced the dilatation in response to ACh, while PGI(2), which evoked relaxation of the mesenteric artery, caused contraction that was abolished by antagonizing thromboxane prostanoid (TP) receptors in the abdominal aorta. However, the TP receptor agonist U46619 evoked similar contractions in the abdominal aorta and mesenteric artery. Also, antagonizing TP receptors enhanced the relaxation in response to PGI(2) in mesenteric arteries. Real-time PCR showed that the PGI(2) (IP) receptor mRNA level was lower in the abdominal aorta than in mesenteric arteries. In addition, COX-1(-/-) not only abolished the contraction in response to ACh following NO inhibition in abdominal aorta, but also those in the carotid and femoral arteries. These results demonstrate an explicit role for endothelial COX-1 in PGI(2) synthesis and suggest that in given mouse arteries, PGI(2) mediates not dilatation but rather vasoconstrictor activity, possibly due to a low expression or functional presence of IP receptors, which enables PGI(2) to act mainly on TP receptors.     

Vasomotor changes in isolated coronary arteries from diabetic rats

Contractile responses to prostaglandin F2 alpha, serotonin, noradrenaline, and potassium were examined in isolated intramyocardial arteries of Wistar rats 8 weeks after the induction of diabetes mellitus by administration of streptozotocin (STZ). The concentration-response curves obtained were compared with those noted in vessels both from age- and from weight-matched control rats. Light and electron microscopy did not reveal any major change in coronary artery wall thickness or morphology. There was no difference in the pattern of vasomotor responses between the two control groups. Contractile responses to prostaglandin F2 alpha, and potassium were significantly reduced, while contractile responses to serotonin and noradrenaline were unaltered in coronary arteries from diabetic rats. The vasomotor responses to noradrenaline and potassium showed a biphasic pattern in control vessels, i.e. contraction noted at high agonist concentrations was preceded by slight, but reproducible relaxation at lower concentrations. In diabetic vessels these relaxant responses were absent. The contraction produced by noradrenaline was markedly enhanced by the presence of propranolol in both diabetic and control vessels. Dilator responses to verapamil, diltiazem, nifedipine, papaverine and magnesium were studied in serotonin-precontracted coronary arteries; the concentration-response curves obtained by verapamil and diltiazem were shifted to the right in diabetic vessels. It appears justified to use vessels from age-matched rats as controls when vasomotor reactivity in coronary arteries from STZ-diabetic rats is investigated. The reduction in contractile responses to prostaglandin F2 alpha and potassium, and the reduction or lack of relaxant responses to noradrenaline, potassium, verapamil and diltiazem, in diabetic coronary arteries, indicate a selective modification of the coronary circulation by the diabetic disease.     

Dilatory responses to acetylcholine, calcitonin gene-related peptide and substance P in the congestive heart failure rat

It was examined to what extent congestive heart failure (CHF) in rats, induced by ligation of the left coronary artery, affects the vascular responses to the vasodilatory substances acetylcholine (ACh), calcitonin gene-related peptide (CGRP), and substance P (SP). After induction of CHF status, the basilar, mesenteric and renal arteries and the iliac vein were studied in vitro. Dilatory responses were determined in relation to pre-contraction by the thromboxane mimetic U46619. Sham-operated animals (Sham) served as controls. U46619 induced stronger contraction in CHF basilar and renal arteries compared with the corresponding segments in Sham. ACh induced concentration-dependent dilations in all vessels examined with no difference of maximum relaxation or potency between CHF and Sham. SP induced weak dilations in all arteries examined while the response was markedly attenuated in CHF iliac veins compared with Sham (Emax% 12.2 +/- 3.4 vs. 32.3 +/- 4.8, P = 0.01). The CGRP induced dilation in the CHF basilar artery was weaker (Emax% 18.6 +/- 6.5 vs. 66.9 +/- 5.0, P < 0.001) and less potent (pEC50: 8.2 +/- 0.2 vs. 9.0 +/- 0.2, P = 0.01) compared with Sham. Further, CGRP was less potent in the renal artery of CHF rats compared with Sham (pEC50: 8.1 +/- 0.2 vs. 9.5 +/- 0.3, P < 0.01). In the CHF iliac vein, CGRP was more potent compared with Sham (pEC50: 9.7 +/- 0.4 vs. 8.3 +/- 0.4, P < 0.05). It can be concluded CHF is accompanied by alterations in the vascular response to the dilatory substances studied. The changes differ between vascular beds and between the different substances.     

Angiotensin II-induced modulation of endothelium-dependent relaxation in rabbit mesenteric resistance arteries

The role of local endogenous angiotensin II (Ang II) in endothelial function in resistance arteries was investigated using rabbit mesenteric resistance arteries. First, the presence of immunoreactive Ang II together with Ang II type-1 receptor (AT₁R) and angiotensin converting enzyme (ACE) was confirmed in these arteries. In endothelium-intact strips, the AT₁R-blocker olmesartan (1 μ m ) and the ACE-inhibitor temocaprilat (1 μ m ) each enhanced the ACh (0.03 μ m )-induced relaxation during the contraction induced by noradrenaline (NA, 10 μ m ). Similar effects were obtained using CV-11974 (another AT₁R blocker) and enalaprilat (another ACE inhibitor). The nitric-oxide-synthase inhibitor N ^G-nitro- l -arginine ( l -NNA) abolished the above effect of olmesartan. In endothelium-denuded strips, olmesartan enhanced the relaxation induced by the NO donor NOC-7 (10 n m ). Olmesartan had no effect on cGMP production (1) in endothelium-intact strips (in the absence or presence of ACh) or (2) in endothelium-denuded strips (in the absence or presence of NOC-7). In β-escin-skinned strips, 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP, 0.01–1 μ m ) concentration dependently inhibited the contractions induced (a) by 0.3 μ m Ca²⁺ in the presence of NA+GTP and (b) by 0.2 μ m Ca²⁺+GTPγS. Olmesartan significantly enhanced, while Ang II (0.1 n m ) significantly inhibited, the 8-Br-cGMP-induced relaxation. We propose the novel hypothesis that in these arteries, Ang II localized within smooth muscle cells activates AT₁Rs and inhibits ACh-induced, endothelium-dependent relaxation at least partly by inhibiting the action of cGMP on these cells.     

Endothelium-independent potentiation by neuropeptide Y of vasoconstrictor responses in isolated arteries from rat and rabbit

An endothelium-dependent action of neuropeptide Y (NPY) has been implicated in studies on various vascular beds. In the present study, the requirement of an intact endothelium for NPY-evoked potentiation of the response to sympathetic nerve stimulation was determined in the small mesenteric arteries of the rat and in the central ear artery of the rabbit. Further, NPY-mediated inhibition of relaxing influences was determined in small mesenteric arteries of the rat. Vascular segments were mounted in a double myograph, where one of the two suspended vessels was denuded of endothelium by gently rubbing the intimal surface. Removal of endothelium was verified by en-face silver staining. In both species, the response to bursts of transmural field stimulation eliciting 10% of maximal contraction was potentiated 2-4 times in the presence of 10 nM NPY, whether the endothelium was present or not. In small mesenteric arteries precontracted with noradrenaline, addition of acetylcholine (I microM) caused relaxation only in vessels with an intact endothelium. Subsequent addition of 10 nM NPY enhanced vasoconstriction in both intact and endothelium-denuded vessels. The endothelium-independent beta-adrenergic agonist isoprenaline (I microM) relaxed both intact and denuded small mesenteric arteries, and in both further addition of 10 nM NPY increased the contraction to about the same extent. The results demonstrate that NPY potentiates the responses to sympathetic field stimulation in small mesenteric arteries from the rat and in central ear artery from rabbit whether the endothelium is present or not. NPY inhibits both endothelium-dependent and -independent relaxations in small mesenteric arteries from rat.     

The Influence of Erythropoietin on the Vascular Responses of Rat Resistance Arteries

This study examined the effect of erythropoietin (EPO) on resting tension and on the responses of rat mesenteric and renal arcuate arteries in vitro to a number of agonists as a possible cause of its blood pressure elevating properties when used therapeutically. Noradrenaline and potassium chloride induced concentration-dependent vasoconstrictions in both vessel types but the basal tension, maximum tension, and the -log concentration producing half-maximal response (pEC50) were altered in the presence of 0.1 or 20 U ml-1 EPO. The thromboxane A2 receptor agonist U46619 induced a constriction of the renal arcuate arteries which was enhanced by EPO at 20 U ml-1, from 1.68 +/- 0.34 to 2.64 +/- 0.39 mN mm-1 (P < 0.01), but which was unchanged by NG-nitro-L-arginine methyl ester (10-4 m). Serotonin (10-9-10-5 M) caused a concentration-related vasoconstriction in renal arcuate arteries which was shifted to the right in the time control study (P < 0.001) but this was abolished by both 0.1 and 20 U ml-1 of EPO. Acetylcholine induced a relaxation of precontracted mesenteric arteries, by 95.4 +/- 1.64 % with an EC50 of 7.08 +/- 0.08 M which was reduced (P < 0.001) by 20 U ml-1 EPO to 81.7 +/- 3.56 % and 6.10 +/- 0.11 M, respectively. The sodium nitroprusside-induced relaxations were unaffected by EPO. The acetylcholine-mediated relaxations in renal arcuate arteries were unchanged by EPO. Bradykinin-induced relaxations in mesenteric and renal arcuate arteries were unaffected by both EPO concentrations. Together these data showed that EPO over a large concentration range had only minor effects on basal tension and the vascular responsiveness of both mesenteric and renal arcuate arteries. The mechanism whereby EPO causes a chronic elevation in blood pressure is unlikely to be due to acute interactions with agonist-mediated responses.     

Transmitter characteristics of small mesenteric arteries from the rat

We have studied the neurogenic response of small mesenteric arteries from the rat to evaluate the involvement of possible co-transmitters under various modes of stimulation. Segments of small branches of the mesenteric artery were mounted in a myograph and the intramural nerves were activated with transmural electrical stimulation. A single stimulation of the nerves caused a contraction that was reduced by only 20% in the presence of adrenergic blocking agents (prazosin or phenoxybenzamine), whereas the steady-state response to continuous nerve stimulation of high frequency was reduced by 90-95%. In contrast, all responses to applied noradrenaline in doses up to at least 1 mM were eliminated by phenoxybenzamine treatment. The stable ATP analogue, alpha,beta-methylene ATP, reduced the response to a single nerve stimulation by 70%, but reduced the contraction caused by continuous high-frequency nerve stimulation by only 10%. None of these agents affected the response to applied neuropeptide Y (NPY). The response of relaxed vessels to nerve stimulation was totally blocked by the combination of an adrenoceptor-blocking agent and alpha,beta-methylene ATP, although even in this situation a further neurogenic response could be revealed in vessels precontracted with vasopressin. Responses to either single stimuli or brief burst stimulations were potentiated after high-frequency stimulation. Both the adrenergic and non-adrenergic components were enhanced to roughly the same extent. Also the potentiated response was eliminated by the combined application of prazosin and alpha,beta-methylene ATP. The non-adrenergic transmitter in the sympathetic nerves of small arteries thus appears to be the dominant transmitter during low-frequency nerve stimulation, causing rapid but phasic activation. Noradrenaline is the most important transmitter for higher frequencies, exerting slower but sustained contractions. The post-stimulatory potentiation affects both the adrenergic and the non-adrenergic part of the neurogenic response.