Nitric oxide synthase in the pig autonomic nervous system in relation to the influence of NG-nitro-L-arginine on sympathetic and parasympathetic vascular control in vivo (original) (raw)
Related papers
Neuroscience, 1997
The hypothesis was tested that the activation of postganglionic sympathetic neurons contributes to the peripheral vasoconstriction and the blood pressure increase which are observed in rats after systemic blockade of nitric oxide synthase by substituted -arginine analogues. Single and multifibre postganglionic sympathetic activity supplying hindlimb hairy skin and the activity in the caudal lumbar sympathetic trunk supplying mainly hindlimb skeletal muscle were recorded in anaesthetized, paralysed and artificially ventilated Wistar rats before, during and up to 1 h after intravenous injection of a supramaximal dose (10 or 35 mg/kg) of N G -nitro--arginine methyl ester. This elicited a sustained rise of arterial blood pressure, a long-lasting decrease in heart rate and vasoconstriction in hindlimb skin and skeletal muscle as measured by laser Doppler flowmetry. With intact buffer nerves all sympathetic neurons analysed responded with a decrease in their ongoing activity in parallel with the vasoconstriction and the increased blood pressure, except for one neuron which was unresponsive. These responses were probably mediated by the arterial baroreceptors, since it was shown that N G -nitro--arginine methyl ester did not impair the function of both the afferent and the efferent limb of the reflex. Furthermore, baroreceptor denervation almost abolished the inhibitory responses in sympathetic neurons. In baroreceptor denervated animals, with a latency of about 15 min after N G -nitro--arginine methyl ester there was an increase in sympathetic activity without a further increase in blood pressure.
Role of Nitric Oxide in Central Sympathetic Outflow
2001
The central effects of NO as assessed by intracerebroventricular, intracisternal, or direct injection within the specific central areas is also discussed. Our studies demonstrating specific medullary and hypothalamic sites involved in sympathetic outflow are summarized. The review will be concluded with a discussion of the role of central NO mechanisms in the altered sympathetic outflow in disease states such as hypertension and heart failure.
Inhibition of Nitric Oxide Synthase Specifically Enhances Adrenergic Vasoconstriction in Rabbits
Clinical and Experimental Pharmacology and Physiology, 1992
1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (NOLA) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of NOLA (15 mg/ kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 pg/ kg per min) were significantly attenuated in the presence of NOLA. In contrast, NOLA significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 pg/ kg per min) in vivo. 3. Infusion of noradrenaline (1-4 pg/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 pg/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of NOLA, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, NOLA (10 pmol/ L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. NOLA enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, NOLA causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, NOLA enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.
Nitric Oxide, 2001
The object of the present study was to investigate the involvement of nitric oxide (NO) in the regulation of renal vasoconstrictor responses to sympathetic nerve activation, and each of the known sympathetic cotransmitters separately, in the pig in vivo. Renal vasoconstrictor responses were elicited by sympathetic nerve stimulation, the ␣ 1adrenoceptor agonist phenylephrine (10 nmol kg ؊1 , injected iv), neuropeptide Y (NPY, 120 pmol kg ؊1 , iv) acting on the NPY Y 1 receptor, and the stable ATPanalogue ␣,-methylene ATP (mATP, 10 nmol kg ؊1 ) presumably acting on the P2X 1 purinoceptor. Infusion of the NO-donor sodium nitroprusside, at a dose (0.1 mg kg ؊1 h ؊1 , iv) that elevated renal blood flow (by 14 ؎ 7%) and lowered mean arterial pressure (by 30 ؎ 5%), inhibited renal vasoconstrictor responses to sympathetic nerve stimulation, phenylephrine, and NPY, but not to mATP. In contrast, injection of the NO synthase inhibitor N-nitro-Larginine methyl ester, at a dose (10 mg kg ؊1 , iv) that lowered renal blood flow (by 47 ؎ 4%) and elevated mean arterial pressure (by 28 ؎ 8%), potentiated the renal vasoconstriction evoked by sympathetic nerve stimulation, phenylephrine, and NPY, but not mATP. It is concluded that endogenous NO may function as an inhibitory modulator of vasoconstrictor responses to the sympathetic cotransmitters norepinephrine and NPY. In contrast, NO seems not to modify vasoconstrictor responses to the sympathetic cotransmitter ATP, a discrepancy that may be due to differences in the types of receptors and intracellular effector mechanisms.
British Journal of Pharmacology, 1994
1 We aimed to determine whether nitric oxide (NO) and/or the endothelium is involved in cholinergic neurogenic vasodilatation in the rat isolated hindquarters. 2 The abdominal aorta was cannulated for perfusion of the rat hindquarters with Krebs bicarbonate solution containing phenylephrine, to induce basal constrictor tone. In the presence of noradrenergic neurone blockade with guanethidine (200 mg kg', i.p.) electrical stimulation of peri-aortic nerves induced frequency-dependent decreases in hindquarters perfusion pressure, indicating vasodilatation. Both the endothelium-dependent vasodilator, acetylcholine (ACh) and the endothelium-independent vasodilator, sodium nitroprusside (SNP) induced dose-dependent decreases in perfusion pressure. In each experiment, responses to either nerve stimulation, ACh or SNP were recorded before and after treatment with saline vehicle, atropine (1 gLM), NG-nitro-L-arginine (L-NOARG, 100 JM), L-arginine (1 mM), L-arginine plus L-NOARG, or 3-3 cholamidopropyl dimethylammonio 1-propanesulphonate (CHAPS, 30 mg). Hindquarters dilatation after each treatment was expressed as a percentage of the control response. 3 Following treatment with saline, responses to nerve stimulation and ACh were 99 ± 9% and 107 ± 10% of control, respectively demonstrating the reproducibility of these responses. Nerve stimulation-induced dilatation was abolished by atropine (0 ± 0% of control, P <0.05) or reduced to 14 ± 10% of control by NO synthase inhibition with L-NOARG (P <0.05). Dilator responses to ACh were also abolished by atropine (0 ± 0% of control, P<0.05) or inhibited by L-NOARG (59 ± 10% of control, P<0.05), indicating that the neurogenic dilatation is cholinergic and is mediated by NO. The administration of the NO precursor, L-arginine, prevented the inhibitory effect of L-NOARG on dilator responses to nerve stimulation and ACh (L-arginine plus L-NOARG: 89 ± 13% and 122 ± 24% of control, respectively). In addition CHAPS, which removes endothelial cells, inhibited responses to both nerve stimulation (0 ± 0% of control, P <0.05) and ACh (33 ± 8% of control, P <0.05). In contrast, no treatment significantly reduced the vasodilator responses to SNP. 4 These observations suggest that cholinergic neurogenic vasodilatation in the rat isolated hindquarters requires the synthesis and release of NO from the endothelium.
HAEMODYNAMIC RESPONSES TO N-NITRO-l-ARGININE IN CONSCIOUS RABBITS
Clinical and Experimental Pharmacology and Physiology, 1991
1. The effect of N-nitro-L-arginine (NOLA) on mean arterial pressure (AP), hindlimb vascular resistance (HVR) and heart rate (HR) was examined in conscious rabbits. 2. NOLA (15 mg/kg, i.v.) increased AP (A A P = 14+3 mmHg) and HVR (AHVR = 0.8+0.3 U) and decreased HR (A H R =-66 k 8 beatslmin). A P remained elevated for at least 2 h following NOLA infusion but had returned to control levels after 24 h. In contrast, the hindlimb vasoconstriction and bradycardia were sustained for at least 48 h but had returned to control levels after 12 h. 3. In the presence of total autonomic blockade (hexamethonium 30 mg/kg; propranolol 1 mg/kg and atropine 0.1 mg/kg) NOLA continued to have a pressor (AAP = 33t-9 mmHg) and hindlimb vasoconstrictor action (AHVR = 0.4kO.l U) but did not affect HR (AHR =-1 f 3 beats/min). 4. NOLA has a prolonged pressor and vasoconstrictor action which is independent of any action in the central nervous system and which results in a marked reflex bradycardia. These results suggest that the peripheral biosynthesis of nitric oxide is important in regulation vascular tone and arterial pressure.
European Journal of Pharmacology, 1991
The effects of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine (NOLA), have been examined in perfused segments of rat tail artery. NOLA (1 and 10/.tM) significantly enhanced the vasoconstrictor responses to perivascular nerve stimulation (5 Hz, I0 s) and noradrenaline (10 ng). The enhancing effects of NOLA were prevented by L-arginine, but not by o-arginine, and were absent in endothelium-denuded artery segments. The results suggest that nitric oxide derived from endothelial cells attenuates vasoconstrictor responses to both nerve stimulation and noradrenaline.
Journal of Autonomic Pharmacology, 1995
In rat duodenum, electrical field stimulation (EFS) induced a relaxation due to activation of non-adrenergic, non-cholinergic (NANC) inhibitory intramural neurones. 2 Nitric oxide synthase (NOS) inhibitors, Nu-nitro-L-arginine (L-NNA) and W-nitro-L-arginine methyl ester (L-NAME), caused a dose-dependent reduction in amplitude of the NANC relaxation. Responses to low frequencies of stimulation were more sensitive to NOS inhibitors than those to high frequencies. 3 Effects induced by NOS inhibitors were stereospecific since D-NNA and D-NAME did not affect NANC relaxation. L-arginine, but not D-arginine, partially prevented the effects induced by NOS inhibitors on NANC relaxation. 4 The nitrovasodilator drug, sodium nitroprusside, caused muscle relaxation which was not affected by preincubation with either tetrodotoxin (TTX), L-NNA or L-NAME. 5 a-Chymotrypsin reduced relaxations elicited by stimulation of NANC nerves, especially when high frequencies of stimulation were used. The residual NANC relaxation was further reduced by NOS inhibitors. In the same way, a-chymotrypsin was able to further reduce the relaxation observed after NOS inhibitors. 6 These results suggest that nitric oxide (NO) and a peptide are involved in NANC relaxation of rat duodenal smooth muscle. NO and peptidergic pathways act in parallel to produce muscle relaxation and they are preferentially activated by stimuli at low and high frequencies, respectively.
Neuroscience Letters, 2004
In the last few decades, cholinergic connections located into posterior hypothalamus (PH) have been implicated in the central regulation of blood pressure (BP). Here we investigated the role of nitric oxide (NO) in the blood pressure response elicited by infusion of physostigmine into PH of normotensive rats. In freely moving rats, physostigmine (60-200 nM) produced a dose-and time-dependent elevation of BP which was antagonized by the antimuscarinic drug scopolamine (60 nM) and by l-NAME (100 M), an inhibitor of NO synthase, both infused into the same site. In contrast, l-arginine (l-Arg; 100 M), the precursor of NO, and glyceryltrinitrate (GTN; 140 nM), an NO donor, infused into the PH did not affect physostigmine-related pressor response. In rats pre-treated with Escherichia coli lipopolisaccharide (LPS; 0.5 g i.p. 24 h beforehand), however, scopolamine, l-Arg and GTN produced a decrease of BP, an effect antagonized by l-NAME. This suggests that NO only slightly modulates physostigmine-related pressor response elicited into PH of LPS-untreated rats. In contrast, the release of large amounts of NO generated by pre-treating rats with LPS, down-regulates cholinergic connections located at the PH, thus contributing in the central dysregulation of BP which can be found when high circulating endotoxin levels may occur.
European Journal of Pharmacology, 1996
The possible modulation by the endothelium of the contractile responses to sympathetic nerve stimulation was examined in isolated superfused human saphenous vein. Contractile response curves for transmural nerve stimulation and noradrenaline were higher in endothelium-denuded than in intact human saphenous vein rings. In vessels with endothelium, transmural nerve stimulation-and noradrenaline-induced contractions were unaffected by the cyclooxygenase inhibitor, indomethacin (10 txM), but were potentiated by the nitric oxide (NO) synthase inhibitor, L-N°'-nitro-L-arginine (L-NNA, 3 ~M) even when combined with o-arginine (0.3 mM), but not with L-arginine (0.3 mM). As in the case of noradrenaline, contractile responses to 5-HT, but not to KC1, were enhanced by endothelium removal, L-NNA or L-NNA Flus D-arginine, but were unaffected by L-NNA plus L-arginine. The guanylyl cyclase inhibitor, methylene blue (10 ~M), potentiated both transmural nerve stimulation-and noradrenaline-induced contractions in endothelium intact rings, whereas it enhanced, although to a lesser degree, only the neurally evoked contractions in endothelium-denuded human saphenous vein. In the vessels without endothelium L-NNA failed to affect the vasoconstriction induced by both transmural nerve stimulation and noradrenaline. Our results suggest that at least two inhibitory factors are involved in modulating the sympathetic vasoconstriction in the human saphenous vein: (1) at a postjunctional level, NO, the release of which from endothelial cells is probably stimulated by the activation of specific receptors, and (2) at a prejunctional level, an unidentified vasodilator agent, which is unmasked by the removal of the endothelium layer and which is probably co-released along with noradrenaline, and which acts through the guanylyl cyclase pathway.