Chemical sympathectomy reveals pre- and postsynaptic effects of neuropeptide Y (NPY) in the cardiovascular system

Intravenous injection of neuropeptide Y (NPY) caused short-lasting dose-dependent pressor responses in anesthetized rats. NPY was equipotent with noradrenaline in producing proportional pressor effects. Chemical sympathectomy, following the administration of 100 mg/kg 6-hydroxydopamine (6-OHDA), significantly potentiated the systemic pressor effects elicited by NPY or noradrenaline. Pretreatment with 2 nmol NPY enhanced the noradrenaline-induced pressor response in control rats. NPY did not change the basal tension of isolated rat aortic strips but significantly potentiated the contractile activity induced by 16 nM noradrenaline. This effect of NPY was not observed in aortic strips from rats pretreated with 6-OHDA. The presence of pre- and postsynaptic sites of action for NPY in the cardiovascular system of the rat is discussed.     

Catecholamine metabolism in the vas deferens and the adrenal gland with special reference to the central catecholamine-depleted state.

Experiments were carried out to elucidate the role of central catecholamines in regulating catecholamine metabolism in the vas deferens and adrenal gland of the rat. Rats were injected intracerebroventricularly (i.c.v.) with either vehicle or 6-hydroxydopamine (6-OHDA). Groups of animals pretreated with vehicle or 6-OHDA (i.c.v.) were injected intraperitoneally (i.p.) with alpha-methyl-para-tyrosine (AMT), a tyrosine hydroxylase inhibitor. Catecholamine turnover rates were estimated by determining norepinephrine or epinephrine content after administering AMT. Central norepinephrine and dopamine contents decreased significantly (p less than 0.05) after treatment with 6-OHDA and AMT. The norepinephrine content of the vas deferens of rats pretreated with 6-OHDA was markedly reduced (p less than 0.001) after administration of AMT, whereas that of the vehicle-treated rats remained unchanged. Administration of 6-OHDA had no effect on the norepinephrine or epinephrine content of the adrenal gland. The present results indicate that central monoaminergic neurons have an inhibitory effect on the adrenergic neurons of the vas deferens. In contrast, this inhibitory regulation does not appear to be exerted on the adrenal glands.     

Catecholamine metabolism in the vas deferens and the adrenal gland with special reference to the central catecholamine-depleted state

Experiments were carried out to elucidate the role of central catecholamines in regulating catecholamine metabolism in the vas deferens and adrenal gland of the rat. Rats were injected intracerebroventricularly (i.c.v.) with either vehicle or 6-hydroxydopamine (6-OHDA). Groups of animals pretreated with vehicle or 6-OHDA (i.c.v.) were injected intraperitoneally (i.p.) with alpha-methyl-para-tyrosine (AMT), a tyrosine hydroxylase inhibitor. Catecholamine turnover rates were estimated by determining norepinephrine or epinephrine content after administrating AMT.Central norepinephrine and dopamine contents decreased significantly (p<0.05) after treatment with 6-OHDA and AMT. The norepinephrine content of the vas deferens of rats pretreated with 6-OHDA was markedly reduced (p<0.001) after administration of AMT, whereas that of the vehicle-treated rats remained unchanged. Administration of 6-OHDA had no effect on the norepinephrine or epinephrine content of the adrenal gland.The present results indicate that central monoaminergic neurons have an inhibitory effect on the adrenergic neurons of the vas deferens. In contrast, this inhibitory regulation does not appear to be exerted on the adrenal glands.     

Vascular reactivity in chronic Goldblatt two kidney-one clip hypertensive rats

We studied the possible contribution of increased vascular reactivity in the chronic phase of Goldblatt two kidney-one clip hypertension. Vascular reactivity was evaluated in aortic strips from hypertensive rats (16 weeks after inducing hypertension) and age-matched control rats. The findings were: a) increased sensitivity to vasopressin in the aortic tissue of hypertensive rats, b) a similar response to angiotensin II, noradrenaline and KCl in hypertensive and control rats, and c) reduced maximal response to angiotensin II compared with other vasoconstrictors in both groups of rats. These results suggest a possible role for vasopressin in the chronic phase of this model of hypertension.     

Vascular reactivity in chronic Goldblatt two kidney-one clip hypertensive rats

Summary We studied the possible contribution of increased vascular reactivity in the chronic phase of Goldblatt two kidney-one clip hypertension. Vascular reactivity was evaluated in aortic strips from hypertensive rats (16 weeks after inducing hypertension) and age-matched control rats. The findings were: a) increased sensitivity to vasopressin in the aortic tissue of hypertensive rats, b) a similar response to angiotensin II, noradrenaline and KCl in hypertensive and control rats, and c) reduced maximal response to angiotensin II compared with other vasoconstrictors in both groups of rats. These results suggest a possible role for vasopressin in the chronic phase of this model of hypertension.The authors thank Ms Karen Shashok for revising the English style.     

The influence of 6-OHDA on hypothermia produced by intrahypothalamically-injected carbachol in the pigeon

Summary The involvement of the noradrenergic system in hypothermia induced by intrahypothalamically-injected carbachol (CCh) was studied by depleting hypothalamic noradrenaline (NA) with the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) and repeating the CCh injections after 6-OHDA treatment. The results suggest that noradrenergic neurons may be involved in hypothermia produced by CCh in the pigeon.     

Influence of nocloprost on the vascular responses to various stimuli in the isolated perfused rabbit kidney

Nocloprost, a new synthetic prostanoid, elicited a vasodilator action when given through the renal artery of the isolated perfused rabbit kidney. Lower concentrations of the compound inhibited the pressor response to sympathetic stimulation or to angiotensin II, but potentiated the pressor effect of exogenous noradrenaline. These results were taken as an evidence that nocloprost prevents the release of neurotransmitter by a presynaptic mechanism.     

Influence of nocloprost on the vascular responses to various stimuli in the isolated perfused rabbit kidney

Summary Nocloprost, a new synthetic prostanoid, elicited a vasodilator action when given through the renal artery of the isolated perfused rabbit kidney. Lower concentrations of the compound inhibited the pressor response to sympathetic stimulation or to angiotensin II, but potentiated the pressor effect of exogenous noradrenaline. These results were taken as an evidence that nocloprost prevents the release of neurotransmitter by a presynaptic mechanism.This work was supported by a grant from the Turkish Scientific and Technical Research Council (TAG-578). Nocloprost is the gift of Dr E. Schillinger, Head of Biochemical Pharmacology, Schering AG Research Laboratories, Berlin, FRG.     

Effects of polysorbates and Cremophor EL on vascular responses in rat aorta

The effects of Tween 20, Tween 80, and Cremophor EL, surface active agents which are used for dispersion of water-insoluble substances, on vascular responsiveness were investigated using rat aortic rings. In high concentrations all these agents produced persistent contractions in aortic rings independent of the presence of endothelium. These contractions were not influenced by inhibitors of known endogenous contractile mediators. Incubation with these agents caused a concentration-dependent inhibition of the endothelium-dependent relaxant responses to acetylcholine in intact precontracted aortic rings. Endothelium-independent relaxations produced by sodium nitroprusside were not inhibited, but rather potentiated in the presence of Tween 80 (10^–1 ml/l). On the other hand, Tween 80 inhibited the contractile effects of 5-hydroxytryptamine, phenylephrine, and bradykinin significantly. The data suggests that these substances affect both endothelial cells and vascular smooth muscle.     

Pharmacologic study of several alpha-adrenolytics

Six alpha-adrenoceptor blocking agents have been investigated in dogs and rats. 170 150 and 170 153 have been found the most potent of these agents. At low doses (0,1 microgram/kg) they reversed the pressor response to low doses of adrenaline (0,1 and 0,3 microgram/kg) and suppressed the response to high doses of adrenaline. They reduced the pressor response to noradrenaline. In addition, in dogs 170 150 increased the tachycardia caused by stimulation of the cardiac nerve. The compound prevented and reversed the inhibition caused by clonidine on the effects of cardiac nerve stimulation. 170 153 did not increase the tachycardia caused by cardiac nerve stimulation, but it prevented and reversed the inhibitory effects of clonidine on this stimulation. The results show that 170 150 and 170 153 are potent alpha-adrenoceptor blocking agents acting on both pre and post-synaptic alpha-adrenoceptors which could be interesting pharmacological tools.     

Extraneuronal serotonin accumulation in peripheral arteries of the rat

Accumulations of serotonin (5-HT) and norepinephrine (NE) were compared in control and 6-hydroxydopamine (6-OHDA) pretreated rat aorta, mesenteric and tail arteries. The distribution of these amines was corrected by subtracting tissue uptake of tritiated sorbitol in the extracellular space. 5-HT greatly accumulated both in control and 6-OHDA pretreated arteries. In contrast, NE accumulation in mesenteric and tail arteries was substantially decreased after 6-OHDA treatment. In the aorta 6-OHDA pretreatment did not affect the accumulation of both amines. These findings suggest that 5-HT accumulation in these arteries is mainly extraneuronal, and NE mainly neuronal. Since the accumulation of 5-HT in the aorta was not influenced by pretreatment with 10 microM NE, the extraneuronal uptake mechanisms for 5-HT and NE appear to be different.     

Influence of hypoxia on contractility and calcium uptake in rabbit aorta

Summary The influence of hypoxia on noradrenaline (NA)-induced contractions and⁴⁵Ca uptake has been studied on isolated rabbit aortae. Hypoxia significantly decreased the contractility of aortic strips. NA stimulation resulted in increased or decreased⁴⁵Ca uptake by normoxic or hypoxic specimens, respectively. Relating⁴⁵Ca movement with mechanical activity, the results suggest that decrease in Ca⁺⁺ uptake may be mechanism for hypoxic relaxation of aortic smooth muscle.The author acknowledges facilities at the Wellcome Surgical Research Institute, University of Glasgow, U.K. Much of this work was in collaboration with Drs Sheila Jennett and J.D. Pickard.     

Ethanol reduces Ca2+ concentrations in arterial and venous smooth muscle.

The present results, using isolated rat aortic strips and portal vein segments, demonstrate that ethanol (170--430 mM) significantly inhibits calcium uptake in these 2 different types of vascular smooth muscle.     

Effects of 6-hydroxydopamine on rat carotid body chief cells

Summary Administration of 6-hydroxydopamine (6-OHDA) in concentrations high enough to cause degeneration of perivascular adrenergic nerve terminals has no morphological effect on the catecholamine-storing cells of the rat carotid body. Uptake of 6-OHDA by carotid body chief cells may be more selective than that exhibited by small-intenselyfluorescent cells and other catecholamine-storing cells which are affected by 6-OHDA. Alternatively, the sustentacular cells which envelope the chief cells may provide an effective barrier against the uptake of 6-OHDA.Supported by a Grant-in-Aid from the American Heart Association (77 630) and with funds contributed in part by the Texas Affiliate.     

Ethanol reduces Ca2+ concentrations in arterial and venous smooth muscle

Summary The present results, using isolated rat aortic strips and portal vein segments, demonstrate that ethanol (170–430 mM) significantly inhibits calcium uptake in these 2 different types of vascular smooth muscle.Supported by NIH grant No. HL-18015 and NIMH grant No. MH-26236. Request for reprints should be addressed to B.M. Altura.     

Wirkungsverstärkung von Adrenalin und Noradrenalin durch Azetylcholin am isolierten Irisdilatator des Kaninchens

Summary Radial strips of the isolated iris of rabbits were suspended in streaming Tyrode's solution and their contractions were registered isometrically. The contractions produced by adrenaline or noradrenaline were increased after the administration of eserine or neostigmine. Acetylcholine in a concentration 5.10^–7–5.10^–6 M enhanced the effect of adrenaline and noradrenaline on both, the normal and the chronically denervated dilator muscle. Acetylcholine did not enhance the contractions by adrenaline and noradrenaline in the presence of atropine. Choline in a concentration of 5.10^–6 M had no effect whereas concentrations of 5.10^–5 M were slightly effective.     

Sympatho-inhibitory mechanisms acting at sympathetic ganglia to attenuate hypothalamic-induced pressor effect in the cat

Summary Pressor and tachycardic effects induced in the cat by stimulation of a lateral hypothalamic (LH) site, are shown to be mediated by sympathetic ganglia nicotinic receptor, and potentiated under atropine methyl nitrate sympathetic ganglia blockage. It is postulated that a sympatho-inhibitory pathway muscarinic ganglionic mechanism, co-activated by the LH stimulation, attenuates the pressor and tachycardic effects, the potentiation presumably being a manifestation of blockage of that mechanism.     

Sympatho-inhibitory mechanisms acting at sympathetic ganglia to attenuate hypothalamic-induced pressor effect in the cat

Pressor and tachycardic effects induced in the cat by stimulation of a lateral hypothalamic (LH) site, are shown to be mediated by sympathetic ganglia nicotinic receptor, and potentiated under atropine methyl nitrate sympathetic ganglia blockage. It is postulated that a sympatho-inhibitory pathway muscarinic ganglionic mechanism, co-activated by the LH stimulation, attenuates the pressor and tachycardic effects, the potentiation presumably being a manifestation of blockage of that mechanism.     

The endothelium-dependent relaxation of human middle cerebral artery: effects of activated neutrophils.

Neutrophils, activated by 4 beta-phorbol-12 beta-myristate-13 alpha-acetate, decreased acetylcholine-induced relaxation of strips of human middle cerebral artery precontracted with noradrenaline. This effect was prevented by catalase, but not by superoxide dismutase. Nifedipine, propranolol and, less markedly, captopril reduced the decrease in acetylcholine-induced relaxation. Aspirin and dipyridamole did not reduce it.     

Stress-induced increase in noradrenaline release in the rat hypothalamus assessed by intracranial microdialysis

Summary The hypothalamic microdialysis of conscious rats was used to investigate the effects of immobilization stress (20 min) on extracellular noradrenaline(NA) levels. The stress significantly increased NA levels relative to basal efflux by 106% and this elevation continued for 40 min after release from stress.