Rat Mesenteric Vascular Bed Research Articles

Alpha-Adrenoceptor- and Prostaglandin-Mediated Modulation of Vascular Adrenergic Neurotransmission in Spontaneously Hypertensive Rats

The modulation of vascular adrenergic neurotransmission in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) mediated by alpha-adrenoceptor and prostaglandin E2 (PGE2) were evaluated. The pressor responses of the perfused mesenteric vascular bed to perivascular adrenergic nerve stimulation (NS) and infusion of norepinephrine (NE) and the NS-induced 3H-efflux in preparations pretreated with 3H-norepinephrine were determined. In both SHR and WKY, a selective alpha2 agonist, B-HT 920 (30-300 nM), inhibited neurogenic vasoconstriction, and B-HT 920 (100-300 nM) potentiated the pressor response to NE in a dose-dependent manner. The effects of B-HT 920 did not significantly differ in SHR and WKY. Another alpha2 agonist, Clonidine (100 nM), decreased the 3H-efflux approximately by 30% both in SHR and WKY. A selective alpha2blocking agent, yohimbine (3-300 nM), potentiated the neurogenic vasoconstriction and inhibited the pressor response to NE equally in SHR and WKY. No difference in enhancement of 3H-efflux by yohimbine (30-300 nM) was seen between SHR and WKY either in the absence or presence of cocaine (10 μM) and metanephrine (20 μM). PGE2 (0.1-1 μM) potentiated pressor responses to NS. and NE in SHR and WKY, but this compound (1 μM) did not affect the NS-induced 3H-efflux in either group of rats. It appears that adrenergic neurotransmission is inhibited presynaptically via an alpha2 receptor mechanism and facilitated postsynaptically by PGE2 in the rat mesenteric vascular bed. The hypertensive state in SHR can not be accounted for by alteration of these modulator mechanisms.

Alpha-adrenoceptor- and prostaglandin-mediated modulation of vascular adrenergic neurotransmission in spontaneously hypertensive rats.

The modulation of vascular adrenergic neurotransmission in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) mediated by alpha-adrenoceptor and prostaglandin E2 (PGE2) were evaluated. The pressor responses of the perfused mesenteric vascular bed to perivascular adrenergic nerve stimulation (NS) and infusion of norepinephrine (NE) and the NS-induced 3H-efflux in preparations pretreated with 3H-norepinephrine were determined. In both SHR and WKY, a selective alpha 2 agonist, B-HT 920 (30-300 nM), inhibited neurogenic vasoconstriction, and B-HT 920 (100-300 nM) potentiated the pressor response to NE in a dose-dependent manner. The effects of B-HT 920 did not significantly differ in SHR and WKY. Another alpha 2 agonist, clonidine (100 nM), decreased the 3H-efflux approximately by 30% both in SHR and WKY. A selective alpha 2 blocking agent, yohimbine (3-300 nM), potentiated the neurogenic vasoconstriction and inhibited the pressor response to NE equally in SHR and WKY. No difference in enhancement of 3H-efflux by yohimbine (30-300 nM) was seen between SHR and WKY either in the absence or presence of cocaine (10 microM) and metanephrine (20 microM). PGE2 (0.1-1 microM) potentiated pressor responses to NS and NE in SHR and WKY, but this compound (1 microM) did not affect the NS-induced 3H-efflux in either group of rats. It appears that adrenergic neurotransmission is inhibited presynaptically via an alpha 2 receptor mechanism and facilitated postsynaptically by PGE2 in the rat mesenteric vascular bed. The hypertensive state in SHR can not be accounted for by alteration of these modulator mechanisms.

Effects of angiotensin-converting enzyme inhibitors on the vascular response to norepinephrine

The effects of three types of angiotensin-converting enzyme inhibitor, SQ 14225 (captopril), SQ 20881 (teprotide) and SA 446 (Santen, Osaka, Japan), on the vascular contraction induced by norepinephrine were studied in the perfused rat mesenteric vascular bed. (1) SQ 14225 attenuated the vascular contraction induced by norepinephrine, but SQ 20881 and SA 446 revealed no effect on vascular reactivity. (2) The effect of SQ 14225 was not altered in the presence of bradykinin or angiotensin II in the perfusate. On the basis of these results, it is suggested that the attenuating effect on the vascular response to norepinephrine may be limited to SQ 14225 and that its effect is not mediated through the renin-angiotensin or kalli-krein-kinin system.

Effects of magnesium on the vasoconstrictor responses to norepinephrine and potassium chloride in the rat mesenteric artery.

In the perfused rat mesenteric vascular bed, the effects of magnesium and calcium on the vasoconstrictor responses to norepinephrine or potassium chloride were studied. Higher concentrations of magnesium in the perfusate attenuated the vascular responses to norepinephrine and potassium chloride in a dose-related manner. Higher concentrations of calcium in the perfusate enhanced greatly the vascular responses to potassium chloride, while the response to norepinephrine was only slightly potentiated by increasing calcium concentration. The attenuating effect of magnesium on the responses to norepinephrine and to potassium chloride were reversed by elevation of calcium concentration in the perfusate. The potentiating effects of calcium on the responses to potassium chloride were also reversed by increasing the concentration of magnesium. However, an inhibitory effect of magnesium on the responses to norepinephrine was not observed in the presence of higher concentrations of calcium. These results indicate that magnesium acts antagonistically on calcium movement in vascular contractions due to potassium chloride, but that the relationship between magnesium and calcium is more complex in vascular contractions induced by norepinephrine.

Interactions between dopamine and prostaglandins on vascular reactivity to noradrenaline: Dopamine inhibits the action of PGE1

Interactions between dopamine and responses to noradrenaline as modulated by prostaglandins (PGs) were studied in the perfused rat mesenteric vascular bed. When perfused alone dopamine up to a concentration of 10 −7M neither changed baseline pressure nor modified the pressor response to noradrenaline. Dopamine at 10 −9 to 10 −7M significantly inhibited responses to noradrenaline which had been enhanced by the presence of 10 −10 to 10 −8 M PGEI. In preparations in which vascular responses to noradrenaline had been abolised by indomethacin and restored by adding PGEI, 10 −9 to 1 −7M dopamine significantly inhibited the restored responses. Dopamine also attenuated the inhibitory effects of prostacyclin on pressor responses to noradrenaline but it did not change the actions of either PGE2 or PGF2 alpha. Pimozide, a mainly centrally acting dopamine antagonist, did not interfere with these peripheral actions of dopamine. The dopamine effects were blocked by another dopamine antagonist, metoclopramide. Dopamine can inhibit the effects of PGEI and prostacyclin in the rat mesenteric vascular bed, possibly by interacting with specific dopamine receptors.

Spironolactone inhibits vascular reactivity by a prostaglandin-related mechanism unconnected with aldosterone

Effects of aldosterone and spironolactone on the vascular responses to noradrenaline and potassium were studied in the perfused rat mesenteric vascular bed. Aldosterone did not modify the response to either vascular agent. Spironolactone inhibited the vascular response to both pressor agents in a dose-dependent manner. The inhibitory effect of spironolactone was not altered by various concentrations of aldosterone and ouabain. However it was not apparent in preparations in which endogenous prostaglandin synthesis had been abolished by indomethacin. The observations suggest that spironolactone has actions on vascular reactivity which are not related to aldosterone or to sodium/potassium pumping. They may depend on modification of prostaglandin biosynthesis.

Effects of captopril and prostaglandin I2 on vasoconstrictor responses to norepinephrine and potassium ions in rat mesenteric artery.

In the perfused rat mesenteric vascular bed, the effects of captopril and prostaglandin I2 (PGI2) on the vasoconstrictor responses to norepinephrine or potassium chloride were studied. Captopril or PGI2 in the perfusate attenuated the vascular responses to norepinephrine in a dose-related manner, while these substances had no effect on the vascular contractions induced by potassium chloride. In preparations treated with indomethacin, the inhibitory effect of captopril on the vascular response to norepinephrine was similar to that found in the untreated preparations. These results suggest that, although the effects of captopril on the vascular reactivity is similar to that of PGI2, the direct vascular action of captopril is not mediated by the synthesis of prostaglandins in the vascular bed.

Vasodilation and aging evaluated in the isolated perfused rat mesenteric vascular bed: preliminary observations on the vascular pharmacology of dobutamine.

The influence of animal age of drug-induced vasodilation was investigated in the perfused rat mesentery constricted with norepinephrine. Responses to isoproterenol, a beta-receptor stimulant, decreased with increasing age. Also, there was a modest decline in the relaxation produced by papaverine. In contrast, dilation of the rat mesentery by acetylcholine, histamine, or nitroglycerin either did not change with age or the responses became somewhat larger. Dobutamine, a myocardial beta-receptor stimulant, produced a marked relaxation of the mesentery. A comparison of the action of isoproterenol and dobutamine revealed that isoproterenol stimulated vascular beta-receptors, whereas dobutamine relaxed the mesentery by antagonizing the tone produced by norepinephrine. The dilation resulting from the alpha-receptor-blocking action of dobutamine was unrelated to animal age.

Effect of mercuric chloride on the rat mesenteric vascular bed: Relevance to the mechanism of mercury toxicity

The effects of mercuric chloride on the vasculature were studied in the perfused rat mesenteric vascular bed. Mercuric chloride inhibited the vascular response to bolus injections of norepinephrine (100 ng) and potassium chloride (2 mg) even at a low concentration (3.7 × 10 −8 m) and the inhibition increased in a dose-dependent manner. Mercuric chloride at concentrations of 3.7 × 10 −7 m or more significantly increased the baseline perfusion pressure, an effect which was rapidly reversed probably as a result of severe damage to the vascular wall. This rise of baseline was in proportion to the calcium concentration of the perfusing buffer. In calcium-free buffer, mercuric chloride, even in high concentration (3.7 × 10 −5 m), had no effect on baseline pressure but the vascular responses to both pressor agents were inhibited almost in the same manner as in the case of normal calcium buffer. Prepefusing the preparation with 10 −5 m lanthanum chloride in calcium-containing buffer and then adding mercuric chloride to this buffer, with lanthanum still present, also prevented the rise of baseline pressure by mercury. Heavy metal antagonists ( d-penicillamine, N-acetyl- dl-penicillamine, dimercaprol) were effective in the treatment of early stage damage and in its prophylaxis. These results indicate that circulatory disturbances may play an important role in mercury toxicity and that the effects are in part related to modulation of calcium movements.

SQ 14, 225 attenuates the vascular response to norepinephrine in the rat mesenteric arteries

SQ 14, 225, a new angiotensin-converting enzyme inhibitor, attenuated the vascular contraction induced by norepinephrine in the perfused rat mesenteric vascular bed, while SQ 20, 881, an another converting enzyme inhibitor, did not have any effect on the vascular reactivity. Furthermore, this effect of SQ 14, 225 was not altered in the presence of bradykinin or angiotensin II in the perfusate. These results suggest that SQ 14, 225 may have a direct antihypertensive effect which is not mediated by the inhibition of angiotensin-converting enzyme.

Effects of potassium and ouabain on the vascular reactivity to norepinephrine in the rat mesenteric artery.

In the perfused rat mesenteric vascular bed, the effects of potassium and ouabain on the vascular response to norepinephrine were studied. Neither changing the concentration of potassium (1.9 to 7.9 mM) nor adding ouabain (8.6 × 10−7 to 2.2 × 10−4 M) to the perfusate changed the basal pressure. A slight increase in the potassium concentration in the perfusate attenuated the vascular response to norepinephrine, and a slight decrease in the potassium concentration potentiated this response. Ouabain in the perfusate potentiated the vascular response to norepinephrine in a dose-related manner. The effect of potassium on the vascular response was inhibited in the presence of ouabain. In preparations in which vascular reactivity had been abolished by indomethacin and then restored by prostaglandin E2, the effects of potassium and ouabain on the vascular reactivity to norepinephrine were similar to those found in the untreated preparations. These results indicate that a slight change in potassium concentration in the perfusate can affect the vascular response to norepinephrine by changing the activity of a Na+–K+-dependent ATPase. It is also suggested that the potentiating effect of low potassium concentration on the norepinephrine response is, at least in the rat mesenteric vascular bed, not mediated by the synthesis of prostaglandin E2 in the vascular wall.

Ultra-violet radiation and 8-methoxypsoralen have actions similar to those of known inhibitors of thromboxane A2 synthesis in rat mesenteric blood vessels

In the rat mesenteric vascular bed three structurally different agents (imidazole, benzydamine and N-0164) which have been reported to be inhibitors of thromboxane (TX) A2 synthesis at certain concentrations, all have a characteristic spectrum of action. They inhibit pressor responses to nor-adrenaline and angiotensin with equal potency and the inhibition can be reversed by exogenous PGE2: they do not inhibit responses to potassium. Ultra-violet (UV) radiation has a similar spectrum of action. The main difference between the action of imidazole and that of UV radiation is that the former is rapidly reversible while the latter is not. However irradiation administered to preparations inhibited by imidazole has no irreversible effect provided that the radiation is switched off before the imidazole is removed. The imidazole protects against radiation damage suggesting that the drug may stabilize the site affected by UV light. 8-methoxypsoralen, a light sensitizing agent used in treatment of psoriasis also inhibited noradrenaline and angiotensin but not potassium responses and seemed to make the preparation more sensitive to radiation damage. It is possible that UV radiation and 8-methoxypsoralen may inhibit TXA2 synthesis but this requires confirmation by direct methods.

Myo-inositol in physiological concentrations stimulates production of prostaglandin-like material

In physiological concentrations myo -inositol stimulated production of prostaglandin (PG)-like material in a rat mesenteric vascular bed preparation. There were five lines of evidence: 1. Inositol potentiated pressor responses to both norepinephrine and potassium in a manner similar to PGE2. 2. Inositol had no potentiating effect in preparations in which endogenous PG production was blocked by indomethacin. 3. Inositol caused no further potentiation in preparations already potentiated by arachidonic acid, the PG precursor. 4. The inhibitory effect of the PG antagonist chloroquine was reduced in an apparently competitive manner by inositol. 5. As indicated by rat stomach bioassay inositol caused a three fold rise in the outflow of PG-like material from the preparation.

Potentiation of pressor effects of noradrenaline and potassium ions in the rat mesenteric arteries by physiological concentrations of angiotensin II: effects of prostaglandin E2 and cortisol.

1. In the perfused rat mesenteric vascular bed, the effects of angiotensin II, cortisol and prostaglandin E2 on the vascular responses to noradrenaline or potassium chloride were studied. 2. Angiotensin II in subpressor concentrations potentiated the vasoconstrictor response to noradrenaline and potassium chloride. This effect of angiotensin II was inhibited in the presence of indomethacin and prostaglandin E2. 3. Cortisol in physiological concentrations inhibited the potentiating effect of angiotensin II. 4. Prostaglandin E2 enhanced the vasoconstrictor response to noradrenaline. This effect was not abolished by cortisol. 5. These results suggest that some actions of angiotensin II and cortisol in vivo are mediated by the regulation of prostaglandin synthesis or release.

Actions of the tricyclic antidepressant clomipramine on responses to pressor agents. Interactions with prostaglandin E2

Clomipramine inhibited pressor responses to potassium ions and vasopressin in the rat mesenteric vascular bed with an ID50 of about 1.8 μg/ml against both pressor agents and the actions of indomethacin and PGE2 on the clomipramine effect suggested that the drug may have been antagonising the action of an endogenous PG. This was supported by the inhibitory action of clomipramine on PGE2 actions on guinea-pig ileum. A lower concentration also inhibited pressor responses to noradrenaline and angiotensin (ID50 about 9 ng/ml): inhibition was increased by PGE2 and reduced by indomethacin. In this preparation potassium and vasopressin act primarily by stimulating calcium entry from the extracellular fluid whereas noradrenaline and angiotensin act primarily by releasing calcium from intracellular or membrane-bound stores. Our results can be explained by two actions: 1. a PG-antagonist action of clomipramine at the cell membrane and 2. a selective inhibitory effect on release of intracellular calcium. Clomipramine may prove useful in studying PG and calcium-dependent mechanisms.

Effects of prostaglandins on baseline pressure and responses to noradrenaline in a perfused rat mesenteric artery preparation: PGE1 as an antagonist of PGE2.

Concentrations of PGE1, PGE2, PGA1, PGA2 and PGF2α ranging from 10 to 10 5 pg/ml (2.8 × 10 −11 to 2.8 × 10 −7M) were perfused through a rat mesenteric vascular bed preparation and their effets on baseline pressure and responses to noradrenline noted. PGs A2 and F2α elevated baseline pressure at concentrations of 100 pg/ml and above but the other three PGs had little or no effect. PGs E 2, Al and F2 α markedly potentiated responses to noradrenaline at all concentrations studied. In contrast PGs E1 and A2 caused a clear potentiation at 10 pg/ml but at higher concentrations the effect disappeared and concentrations of above 10 4 pg/ml were actually inhibitory. E1 could antagonize the vascular effects of E2. These results offer possible explanations for some of the confusing findings reported in the literature.

Chloroquine, quinine, procaine, quinidine and clomipramine are prostaglandin agonists and antagonists

Chloroquine, quinine, procaine, quinidine and clomipramine behave as prostaglandin (PG) antagonists in a rat mesenteric vascular bed preparation. The ID50 concentrations were within the range of therapeutically effective human plasma levels in each case. Antagonism to PGE2 was studied in detail and seemed to be at least in part competitive. The drugs also antagonized the effects of PGs A1, A2, F2α and E1. Each drug also had weak prostaglandin agonist activity but only over a very narrow range of concentrations. It is possible that some of the clinical actions of these drugs may depend on blockade or imitation of natural PG effects. The findings suggest new approaches to the search for PG antagonists, a new screening technique for anti-inflammatory drugs and possible new uses for these established drugs. A preliminary study suggests that chloroquine may be successful in closing a patent ductus arteriosus in infants.

Indomethacin inhibits responses to all vasoconstrictors in the rat mesenteric vascular bed: Restoration of responses by prostaglandin E2

Indomethacin added to the perfusing buffer inhibited pressor responses to noradrenaline, angiotensin II, arginine vasopressin, histamine, serotonin, calcium ions and potassium ions in the male rat mesenteric vascular bed. For every pressor agent the indomethacin concentration which inhibited response amplitude by 50% was about 7 microg/ml (2.1 × 10 −5 M). With every pressor agent, prostaglandin (PG) E2 could restore normal responsiveness in indomethacin-blocked preparations even while the indomethacin was still present in the buffer. The concentration of PGE2 required was proportional to the concentration of indomethacin. Preparations completely inhibited by indomethacin needed about 5ng/ml PGE2 for complete restoration of normal responses. Aspirin and mefenamic acid could also inhibit responses to all pressor agents tested but with these drugs only a partial restoration could be achieved by PGE2.

Physiological cortisol levels block the inhibition of vascular reactivity produced by prolactin.

Cortisol in concentrations similar to the unbound levels of the hormone in human plasma can reverse the inhibition of vascular reactivity produced by prolactin. In the rat mesenteric vascular bed, cortisol alone in similar concentrations had no significant effect on the pressor responses to norepinephrine: the action of cortisol was seen only when prolactin was present. The relationships between the effects of different concentrations of prolactin and cortisol suggest that at some point there is a competitive interplay between the effects of the two hormones. There is indirect evidence that this interplay is at the level of prostaglandin synthesis or release. We suggest that cortisol has no effect on basal prostaglandin production but blocks the synthesis or release occurring in response to polypeptide hormone stimulation.

Hypothalamic stimulus effects on sympathetic nerve activity.

ARTICLESHypothalamic stimulus effects on sympathetic nerve activityI Ninomiya, WV Judy, and MF WilsonI Ninomiya, WV Judy, and MF WilsonPublished Online:01 Feb 1970https://doi.org/10.1152/ajplegacy.1970.218.2.453MoreSectionsPDF (3 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRole of posterior hypothalamus in hypobaric hypoxia induced pulmonary edemaRespiratory Physiology & Neurobiology, Vol. 205Organ and development related difference in tissue norepinephrine concentrations in Dahl ratsJournal of the Autonomic Nervous System, Vol. 71, No. 2-3Comparative effects of central administration of naloxone and clonidine on the blood pressure and heart rate response to anterior and posterior hypothalamic stimulationLife Sciences, Vol. 54, No. 22Effects of hypothalamic microinjection of PGE2 on body temperature and sympathetic nervous activities in the rabbitInternational Journal of Biometeorology, Vol. 37, No. 4Post-carotid endarterectomy hypertension: Association with elevated cranial norepinephrineJournal of Vascular Surgery, Vol. 9, No. 2Adrenergic stimulation of the rat mesenteric vascular bed: a combined micro- and macrocirculatory studyPflügers Archiv, Vol. 410, No. 3The effect of stimulation of the reticulo-hypothalamic-hippocampal systems on the cerebral blood flow and neocortical and hippocampal electrical activity in catsExperimental Brain Research, Vol. 60, No. 3Cardiovascular effects produced by injections of thyrotropin-releasing hormone in specific preoptic and hypothalamic nuclei in the ratPeptides, Vol. 5, No. 4Effects of adrenalectomy, propanolol and methylatropine on the increase in heart rate induced by injection of dermophin in the rat anterior hypothalamic nucleusBrain Research, Vol. 293, No. 1Neuronal Regulation of Blood PressureVisceromotor organization within descending spinal sympathetic pathways in the dog.Circulation Research, Vol. 37, No. 2Influence of electrical stimulation of the posterior hypothalamus on musculocutaneous and renal circulation in anesthetized dogsPflügers Archiv, Vol. 355, No. 2SociÉtÉ Belge De Physiologie Et De Pharmacologie27 September 2008 | Archives Internationales de Physiologie et de Biochimie, Vol. 83, No. 1Medullary sites involved in hypothalamic inhibition of reflex vagal bradycardia in the catBrain Research, Vol. 80, No. 1Activation of the central pathway of the baroreceptor reflex, a possible mechanism of the hypotensive action of clonidineNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 278, No. 3Responses of single units in the medial hypothalamus to electrical stimulation of the carotid sinus nerve in the catBrain Research, Vol. 44, No. 1Mechanism of Intraocular Pressure Response after Optic Nerve TransectionAmerican Journal of Ophthalmology, Vol. 72, No. 1 More from this issue > Volume 218Issue 2February 1970Pages 453-462 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.218.2.453PubMed5412461History Published online 1 February 1970 Published in print 1 February 1970 Metrics