Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo.

1. Three analogues of L-arginine were characterized as inhibitors of endothelial nitric oxide (NO) synthase by measuring their effect on the endothelial NO synthase from porcine aortae, on the vascular tone of rings of rat aorta and on the blood pressure of the anaesthetized rat. 2. NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO) and NG-nitro-L-arginine methyl ester (L-NAME; all at 0.1-100 microM) caused concentration-dependent inhibition of the Ca2(+)-dependent endothelial NO synthase from porcine aortae. 3. L-NMMA, L-NIO and L-NAME caused an endothelium-dependent contraction and an inhibition of the endothelium-dependent relaxation induced by acetylcholine (ACh) in aortic rings. 4. L-NMMA, L-NIO and L-NAME (0.03-300 mg kg-1, i.v.) induced a dose-dependent increase in mean systemic arterial blood pressure accompanied by bradycardia. 5. L-NMMA, L-NIO and L-NAME (100 mg kg-1, i.v.) inhibited significantly the hypotensive responses to ACh and bradykinin. 6. The increase in blood pressure and bradycardia produced by these compounds were reversed by L-arginine (30-100 mg kg-1, i.v.) in a dose-dependent manner. 7. All of these effects were enantiomer specific. 8. These results indicate that L-NMMA, L-NIO and L-NAME are inhibitors of NO synthase in the vascular endothelium and confirm the important role of NO synthesis in the maintenance of vascular tone and blood pressure.     

Regional and cardiac haemodynamic effects of NG-nitro-L-arginine methyl ester in conscious, Long Evans rats.

1. Regional haemodynamic responses to i.v. bolus doses (0.1-10.0 mg kg-1) of NG-nitro-L-arginine methyl ester (L-NAME) were measured in conscious, Long Evans rats (n = 8) chronically instrumented with renal, mesenteric and hindquarters pulsed Doppler flow probes and intravascular catheters. 2. L-NAME caused dose-dependent pressor effects associated with renal, mesenteric and hindquarters vasoconstrictions. The mesenteric vascular bed showed earlier onset with more rapid, and greater, maximum vasoconstrictions than the renal or hindquarters vascular beds; however, the hindquarters vasoconstriction was more persistent. D-NAME was without significant effects (n = 2). 3. Primed infusion of L-arginine (100 mg kg-1 bolus followed by 100 mg kg-1 h-1 infusion), starting 10 min after an i.v. bolus injection of L-NAME (10 mg kg-1), caused significant reversal of the pressor responses, and renal and mesenteric vasoconstrictions, but not of the hindquarters vasoconstriction. Primed infusions of L-arginine (100 mg kg-1, 100 mg kg-1 h-1) starting 5 min after L-NAME (1 mg kg-1) additionally caused some reversal of the hindquarters vasoconstriction, but this effect was transient. 4. Primed infusion of L-arginine (100 mg kg-1, 100 mg kg-1 h-1) starting 30 min before i.v. bolus injection of L-NAME (10 mg kg-1) caused significant attenuation of the pressor effects and the renal and mesenteric vasoconstrictions but not of the hindquarters vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide involvement in consolidation, but not retrieval phase of cognitive performance enhanced by atorvastatin in mice

Atorvastatin, a widely-used medication in treatment of hypercholesterolemia, has shown some benefits in treating cognition impairment in Alzheimer's disease. In this study, effects of atorvastatin on spatial recognition memory and the involvement of nitric oxide (NO) has been determined on consolidation and retrieval of memory in a two-trial recognition Y-maze test. Memory was impaired using scopolamine (1mg/kg, i.p.); atorvastatin (1, 5mg/kg, p.o.) was administered, either in presence or in absence of a non-specific NO synthase inhibitor, L-NAME (3, 10mg/kg, i.p.); a specific inducible NO synthase inhibitor, aminoguanidine (100mg/kg, i.p.); and a NO precursor, L-arginine (750 mg/kg, i.p.). Results: 1) atorvastatin (5mg/kg) significantly improved memory performance in a dose-dependent manner on consolidation and retrieval stage of memory in scopolamine-treated mice; 2) the beneficial effects of atorvastatin on memory consolidation was significantly reversed by L-NAME (10mg/kg) and aminoguanidine; 3) L-arginine slightly potentiated the effects of sub-effective dose of atorvastatin (1mg/kg) on memory consolidation; 4) either L-NAME (up to 10mg/kg), or aminoguanidine did not affect the memory improvement by atorvastatin on retrieval stage; 5) the effects of sub-effective dose of atorvastatin (1mg/kg) on retrieval of memory were not potentiated by L-arginine. The present study demonstrates that atorvastatin improves both consolidation and retrieval phases of memory. This effect is affected by NO synthase inhibitors and NO precursor, L-arginine, only in memory consolidation phase, but not in retrieval phase. It is concluded that NO might be involved in consolidation of spatial memory improvement by atorvastatin.     

Nitric oxide mediates the inhibition by interleukin-1 beta of pentagastrin-stimulated rat gastric acid secretion.

Bolus injection of interleukin-1 beta (2 micrograms kg-1, i.v.) inhibited acid secretion induced by intravenous infusion of pentagastrin (8 micrograms kg-1 h-1) in the continuously perfused stomach of the anaesthetized rat. Administration of interleukin-1 beta did not modify mean systemic arterial blood pressure. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 2-10 mg kg-1, i.v.), but not dexamethasone (5 mg kg-1, s.c. twice over 16 h), restored the acid secretory responses to pentagastrin. The actions of L-NAME were reversed by the prior administration of L-arginine (100 mg kg-1, i.v.), but not by its enantiomer D-arginine (100 mg kg-1, i.v.). L-NAME (5 mg kg-1, i.v.) increased blood pressure but this was not the mechanism by which interleukin-induced acid inhibition was prevented, since similar systemic pressor responses induced by phenylephrine (10 micrograms kg-1 min-1, i.v.), had no such effect. These findings suggest that interleukin-induced inhibition of acid responses to pentagastrin involves synthesis of NO from L-arginine.     

Canine renovascular responses to sumatriptan and 5-carboxamidotryptamine: modulation through endothelial 5-HT1-like receptors by endogenous nitric oxide.

1. In anaesthetized dogs, intra-left atrial (i.l.a.) administration of the 5-HT1-like receptor agonists, sumatriptan (1-10 micrograms kg-1) and 5-carboxamidotryptamine (0.03-0.3 micrograms kg-1) produced dose-related reductions in renal blood flow and vascular conductance, which were characterized by their rapid onset and recovery. 2. In these animals, i.v. administration of the inhibitor of nitric oxide (NO) synthase, NG-nitro-L-arginine methyl ester (L-NAME; 10 mg kg-1) significantly augmented the renal vasoconstrictor responses to i.l.a. sumatriptan and 5-carboxamidotryptamine. 3. The effects of L-NAME upon these responses to sumatriptan and 5-carboxamidotryptamine were significantly reversed by subsequent i.v. administration of L-arginine (1000 mg kg-1). 4. L-NAME significantly attenuated the systemic hypotensive responses to i.v. acetylcholine (0.3-3 micrograms kg-1) and this effect was also reversed by L-arginine. 5. L-NAME had no effect upon the renal vasoconstrictor response to i.l.a. administration of angiotensin II, nor did it affect the renal vascular conductance recovery response to brief mechanical occlusion of the renal artery. 6. These data suggest that sumatriptan and 5-carboxamidotryptamine stimulate the release of NO through the activation of a 5-HT1-like receptor located on the endothelial cells. 7. It is concluded that in canine renal vasculature, 5-HT1-like agonists (and presumably endogenous 5-hydroxytryptamine) can cause simultaneous activation of a 5-HT1-like receptor on both vascular smooth muscle and endothelial cells. The net renal vascular response to these agonists is therefore a function of both the vascular smooth muscle vasoconstriction and the concurrent vasodilator influence of NO released from the endothelium.     

Modulation of morphine antinociception in the mouse by endogenous nitric oxide.

1. L-Arginine (100-1000 mg kg-1) administered orally (p.o.) or intraperitoneally (i.p.), but not intracerebroventricularly (i.c.v., 0.08 mg per mouse), reduced the antinociceptive effect of morphine (0.5-10 mg kg-1 s.c.) assessed in mice using three different tests: hot plate, tail-flick and acetic acid-induced writhing. D-Arginine (up to 1000 mg kg-1 p.o. or i.p.) was ineffective. 2. NG-Monomethyl-L-arginine (L-NMMA, 5-50 mg kg-1 i.p.) and NG-nitro-L-arginine methyl ester (L-NAME, 5- 30 mg kg-1 i.p.), but not NG-nitro-D-arginine methyl ester (D-NAME, 30 mg kg-1 i.p.), reversed in all assays the effect of L-arginine on morphine-induced antinociception. 3. Morphine (10 mg kg-1 s.c.), L-arginine (1000 mg kg-1 p.o.) or L-NAME (30 mg kg-1 i.p.), either alone or in combination, did not produce changes in locomotor activity or sensorimotor performance of animals. 4. These results suggest that the L-arginine-nitric oxide pathway plays a modulating role in the morphine-sensitive nociceptive processes.     

Inhibition of nitric oxide biosynthesis and carotid arteriovenous anastomotic shunting in the pig.

1. The role of nitric oxide (NO) biosynthesis in the regulation of blood flow through arteriovenous anastomoses was evaluated in the carotid circulation of the anaesthetized pig. For this purpose, the effect of intracarotid (i.c.) administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME: 0.1, 0.3 and 1.0 mg kg-1; n = 6) or saline (n = 6) was studied on the distribution of common carotid blood flow, using the radioactive microsphere method. 2. Apart from the highest dose, L-NAME caused no major changes in the systemic haemodynamic variables. Both cardiac output and systemic vascular conductance were reduced by L-NAME (1 mg kg-1), being reversed partly by L-arginine (100 mg kg-1, i.c.). In both groups, L-arginine slightly reduced mean arterial blood pressure. 3. Total common carotid artery blood flow as well as its distribution over the capillary and arteriovenous anastomotic fraction remained stable after saline injection. In contrast, L-NAME caused a dose-dependent decline in common carotid artery blood flow and conductance and this decline was confined entirely to its arteriovenous anastomotic part. 4. Subsequent intracarotid injection of L-arginine (100 mg kg-1) reversed the reduction in total carotid conductance almost completely and that in the arteriovenous anastomotic region partially. Additionally, L-arginine increased capillary conductance significantly in the L-NAME--as well as the saline-treated animals. 5. These results indicate that the L-arginine-NO pathway contributes little to the regulation of tissue perfusion in the porcine carotid circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous nitric oxide and sensory neuropeptides interact in the modulation of the rat gastric microcirculation.

1. The effects of depletion of sensory neuropeptides from primary afferent neurones by capsaicin pretreatment, on the changes in resting gastric mucosal blood flow following administration of inhibitors of nitric oxide biosynthesis have been investigated in the pentobarbitone-anaesthetized rat. 2. Bolus administration of the NO-synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.8-12.5 mg kg-1 i.v.), induced a dose-dependent increase in systemic arterial blood pressure (BP) and a reduction in resting mucosal blood flow, as determined by laser Doppler flowmetry. 3. Concurrent administration of L-arginine (300 mg kg-1 i.v.) attenuated the effects of L-NAME (6.25 mg kg-1) on resting mucosal blood flow and BP. The enantiomer, D-NAME (50 mg kg-1 i.v.), which does not inhibit NO biosynthesis, had no effect on either parameter. 4. The fall in mucosal blood flow induced by submaximal doses of L-NAME (0.8-3.2 mg kg-1) was substantially augmented in rats pretreated 2 weeks earlier with capsaicin. 5. The fall in resting mucosal blood flow induced by the less potent NO-synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 1.6-25 mg kg-1 i.v.) was likewise significantly augmented in capsaicin-pretreated rats. 6. Pretreatment (15 min) with indomethacin (5 mg kg-1 i.v.) did not augment further the microvascular actions of L-NAME or L-NMMA in capsaicin-pretreated rats, suggesting the lack of interaction of endogenous prostanoids with these other mediators in regulating local blood flow. The effects of L-NAME on BP were not altered by capsaicin and indomethacin administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide modulates state dependency induced by lithium in an inhibitory avoidance task in mice

The effect of intracerebroventricular (i.c.v.) injections of L-arginine, a nitric oxide (NO) precursor and L-NAME, an inhibitor of NO synthase, on retrieval of state-dependent memory induced by LiCl (lithium) was investigated. A one-trial step-down inhibitory avoidance task was used for memory assessment in adult male NMRI mice. Intraperitoneal administration of lithium (10 mg/kg), immediately after training, impaired memory on the test day. Pretest administration of different doses of lithium (5, 10 and 20 mg/kg) reversed the impairment of memory caused by posttraining lithium (10 mg/kg). In addition, pretest administration of L-arginine (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) or L-NAME (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) also reversed amnesia induced by posttraining lithium. Furthermore, pretest coadministration with lithium of a dose of L-arginine (0.0001 microg/mouse, i.c.v.) or L-NAME (0.0001 microg/mouse, i.c.v.) that had no effects when administered alone, increased the effect of lithium on retrieval of inhibitory avoidance memory. The results suggest that NO may have a modulatory role on state-dependent retrieval of inhibitory avoidance memory induced by lithium.     

Influence of NG-nitro-L-arginine methyl ester on vagally induced gastric relaxation in the anaesthetized rat.

1. The influence of the nitric oxide (NO) biosynthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the gastric relaxation induced by peripheral vagal stimulation was investigated in the anaesthetized rat. 2. Peripheral vagal stimulation (10 Hz, 10 V, 1 ms for 20 s) induced a reproducible biphasic response: a short-lasting increase followed by a more pronounced decrease in intragastric pressure. This response also occurred in reserpinized animals (5 mg kg-1, i.p., 24 h before the experiment) while atropine (1 mg kg-1, i.v.) abolished the initial increase in intragastric pressure. 3. L-NAME (1-30 mg kg-1, i.v.) induced an increase in arterial blood pressure. L-NAME (1 mg kg-1, i.v.) had no influence on the vagally induced gastric response while L-NAME (10 and 30 mg kg-1 i.v.) significantly changed it: the initial increase in intragastric pressure was enhanced while the decrease in intragastric pressure was reduced or abolished. NG-nitro-L-arginine (L-NNA, 10 mg kg-1, i.v.) had the same effect. 4. An i.v. infusion of phenylephrine (10 micrograms kg-1 min-1) inducing a pressor response similar to that produced by L-NAME (30 mg kg-1, i.v.) did not influence the vagal gastric response. Infusion of L-arginine (300 mg kg-1 bolus, then 100 mg kg-1 h-1) starting 30 min beforehand, reduced the pressor effect and prevented the influence of L-NAME (10 mg kg-1, i.v.) on the vagal gastric response.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of nitric oxide as an endogenous regulator of platelet and neutrophil activation within the pulmonary circulation of the rabbit.

1. Intravenous (i.v.) administration of adenosine diphosphate (ADP), platelet activating factor (PAF) and thrombin induced a dose-related accumulation of 111indium-labelled platelets within the thoracic region of anaesthetized rabbits. 2. I.v. administration of the inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 10 mg kg-1) significantly potentiated the peak platelet accumulation induced by ADP, PAF and thrombin. Additionally L-NAME prolonged the disaggregation of platelets in comparison to D-NAME (10 mg kg-1). Such changes were reversible by the administration of L-arginine (900 mg kg-1). 3. I.v. administration of PAF induced a small accumulation of 111indium-labelled neutrophils within the pulmonary circulation which could be greatly potentiated by pretreatment of the animals with L-NAME. In contrast, thrombin administration did not cause significant accumulation of 11indium-labelled erythrocytes in the pulmonary circulation of anaesthetized rabbits. 4. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of radiolabelled platelets within the cranial vasculature which was not potentiated by the prior administration of L-NAME (at either 10 mg kg-1 or 100 mg kg-1). 5. These results suggest that endogenous NO may regulate platelet and polymorphonuclear leukocyte activation within the pulmonary but not the cerebral circulation of rabbits.     

Evidence that endogenous nitric oxide modulates plasma fibrinogen levels in the rat.

This study investigated the effect of prolonged inhibition of nitric oxide (NO) synthase on plasma fibrinogen levels and platelet count in the rats. NG-nitro-L-arginine methyl ester (L-NAME), when administered orally twice a day, at 10-100 mg kg-1, for 7 consecutive days, 14 times in all, significantly elevated fibrinogen levels and systolic blood pressure in a dose-dependent manner. The same dose range of L-NAME failed to alter platelet count and plasma protein concentrations. The increase in fibrinogen levels produced by chronic treatment with L-NAME at 30 mg kg-1 was reversed by L-arginine at 500-1500 mg kg-1 in a dose-dependent manner. These findings suggest that endogenous NO tonically acts to reduce plasma fibrinogen levels in rats under physiological conditions.     

Endotoxin inhibition of distension-stimulated gastric acid secretion in rat: mediation by NO in the central nervous system.

1. The involvement of nitric oxide in the acute inhibitory effects of low doses of endotoxin, following intracerebroventricular (i.c.v.) or intravenous (i.v.) administration, on gastric acid secretion stimulated by distension or i.v. infusion of pentagastrin has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. The i.c.v. administration of E. coli endotoxin (800 ng kg-1) abolished the acid secretory response induced by gastric distension (20 cm water intragastric pressure) within 30 min of administration. 3. By contrast, submaximal rates of acid secretion induced by i.v. infusion of pentagastrin (8 micrograms kg-1 h-1) were not inhibited by i.c.v. administration of endotoxin (800 ng kg-1). 4. Prior i.c.v. administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 800 micrograms kg-1) restored the acid secretory responses to distension in rats treated with endotoxin (i.c.v.). 5. Likewise, i.v. administration of endotoxin (5 micrograms kg-1) abolished the acid secretory response induced by gastric distension within 30 min of administration. Prior i.c.v. injection of L-NAME (800 micrograms kg-1) or its i.v. administration (10 mg kg-1) restored acid secretory responses in rats receiving i.v. endotoxin. 6. The reversal by L-NAME (i.v.) of the acid inhibitory effects of endotoxin (i.v.) was prevented by L-arginine (12 mg kg-1, i.c.v. or 100 mg kg-1, i.v.), but not by its enantiomer D-arginine. 7. The present results imply the existence of an acute response to endotoxin involving NO synthesis in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anticonvulsant effects of 7-nitroindazole in rodents with reflex epilepsy may result from L-arginine accumulation or a reduction in nitric oxide or L-citrulline formation.

1. To investigate the role of nitric oxide in epilepsy we have studied the effects of agents which affect nitric oxide synthesis in sound-induced seizures in DBA/2 mice and in genetically epilepsy-prone (GEP) rats. 2. The neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole (7-NI) is anticonvulsant in these models with ED50 values against clonic seizures in mg kg-1 i.p. (times following injection) of: 74 (+0.25 h), 120 (+1 h) in DAB/2 mice, and 56 (+0.25 h), 42 (+0.5 h), 36 (+1 h), 28 (+2 h), 38 (+4 h), 93 (+8 h) in GEP rats. 3. Therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) for 7-NI are low, ranging from 0.6 to 1.1 at +0.25 h to +1 h after administration in GEP rats, but are more favourable at later times (1.6 at +2 h and 2.9 at +4 h). 4. The substrate for nitric oxide synthase, L-arginine (500-5000 mg kg-1, i.p. or 100-300 micrograms, i.c.v.) but not D-arginine (300 micrograms i.c.v.) is anticonvulsant in DBA/2 mice. L-Arginine (500-5000 mg kg-1, i.p. or 1800-6000 micrograms, i.c.v.) is a more potent anticonvulsant than D-arginine (1500-2500 mg kg-1, i.p. or 6000 micrograms, i.c.v.) in GEP rats. 5. In DBA/2 mice, L-arginine (30 micrograms i.c.v.) reverses the anticonvulsant effect of 7-NI (50 mg kg-1, i.p.). 6. In GEP rats, low dose L-arginine (25-50 mg kg-1, i.p.) but not D-arginine (50 mg kg-1, i.p.) reverses the anticonvulsant effect of low dose 7-NI (25 mg kg-1, i.p.). A higher dose of L-arginine (500 mg kg-1, i.p.) or 7-NI (50 mg kg-1, i.p.) produces summation of anticonvulsant effect. 7. The product for nitric oxide synthase, L-citrulline (250-831 micrograms i.c.v.), is convulsant in DBA/2 mice. 8. The anticonvulsant effect of the neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole, may therefore be mediated by L-arginine accumulation, as well as by a reduction in nitric oxide and L-citrulline formation in rodent models of reflex epilepsy.     

Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin.

1. The role of nitric oxide (NO) formed by the inducible isoform of NO synthase (NOS) in the generation of indomethacin-induced intestinal microvascular leakage was investigated in the rat. 2. Indomethacin (10 mg kg-1, s.c.) provoked an elevation of vascular leakage of radiolabelled human serum albumin in the jejunum over 48 h, commencing 18 h after its administration. This was associated with the induction of a calcium-independent NOS, as assessed by the conversion of radiolabelled L-arginine to citrulline. 3. Pretreatment with the glucocorticoid, dexamethasone (1 mg kg-1 day-1, s.c.) inhibited the induction of NOS and reduced jejunal microvascular leakage, determined 24 and 48 h after indomethacin. 4. Administration of the broad-spectrum antibiotic, ampicillin (800 mg kg-1 day-1, p.o.) likewise inhibited both the induction of NOS and the plasma leakage observed 24 and 48 h after indomethacin. 5. Ampicillin pretreatment did not, however, inhibit the induction of NOS, determined 5 h following endotoxin (3 mg kg-1 i.v.) challenge. Furthermore, incubation with ampicillin (1 mM, 10 min) did not inhibit the activity of the calcium-independent isoform in vitro. 6. Administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 2-10 mg kg-1, s.c.), at the time of the detectable expression of the inducible NOS (18 h after indomethacin), dose-dependently attenuated the plasma leakage, determined 6 later. This effect was reversed by pretreatment with L-arginine (300 mg kg-1, s.c.) 15 min before L-NAME. 7. These findings suggest that induction of a calcium-independent NOS following indomethacin administration involves gut bacteria and leads to microvascular injury in the rat jejunum.     

Regulation of NANC neural bronchoconstriction in vivo in the guinea-pig: involvement of nitric oxide, vasoactive intestinal peptide and soluble guanylyl cyclase.

1. We investigated the effect of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the peptidase alpha-chymotrypsin on non-adrenergic, non-cholinergic (NANC neural) bronchoconstriction induced by electrical stimulation of the vagus nerves and by capsaicin in anaesthetized guinea-pigs in vivo using pulmonary insufflation pressure (PIP) as an index of bronchial tone. We also investigated the contribution of soluble guanylyl cyclase (SGC) to NANC neural relaxant mechanisms. 2. In the presence of atropine and propranolol, electrical stimulation of the vagus nerves induced a frequency-dependent increase in PIP above baseline of 67% at 2.5 Hz, of 128% at 5 Hz and of 230% at 10 Hz. L-NAME (1-50 mg kg-1, i.v.), at doses inducing increases in systemic blood pressure, dose-relatedly potentiated NANC bronchoconstriction. At 10 mg kg-1 i.v., L-NAME significantly (P < 0.05) potentiated NANC bronchoconstriction by a further 106% at 2.5 Hz and a further 147% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. L-NAME did not induce bronchoconstriction in sham-stimulated control animals. D-NAME did not potentiate NANC bronchoconstriction. Raising systemic blood pressure with phenylephrine did not potentiate vagally-induced bronchoconstriction (2.5 Hz). 3. The NO precursor L-arginine, but not D-arginine, (100 mg kg-1, i.v.) significantly reversed the potentiation by L-NAME of NANC bronchoconstriction. L-Arginine alone significantly inhibited neurogenic bronchoconstriction at 10 Hz (by 74%); the inhibition of 25% at 2.5 Hz was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide mediates rat mucosal vasodilatation induced by intragastric capsaicin.

The role of endogenous nitric oxide (NO) in the gastric mucosal vasodilatation induced by acute intragastric perfusion with capsaicin or close-arterial infusion of rat alpha-calcitonin gene-related peptide (CGRP) was evaluated in the pentobarbitone-anaesthetised rat using laser Doppler flowmetry (LDF). The mucosal vasodilatation induced by intraluminal capsaicin (160 microM) was dose dependently reduced by the inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME; 1-5 mg kg-1 i.v.), effects reversed by concurrent administration of L-arginine (100 mg kg-1 i.v.). L-NAME (2 mg kg-1) induced a small reduction in the mucosal vasodilatation induced by close-arterial infusion of rat alpha-CGRP (50 pmol kg-1 min-1). These findings indicate a role of NO in the gastric vasodilatation induced by stimulation of sensory neurones with intragastric capsaicin.     

Interactions of constitutive nitric oxide with PAF and thromboxane on rat intestinal vascular integrity in acute endotoxaemia.

1. The involvement of endogenous platelet activating factor (PAF) and thromboxane A2 in the acute microvascular damage in the ileum and colon induced by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) following endotoxin administration was investigated in the rat over a 1 h period. 2. Administration of L-NAME (1-10 mg kg-1, s.c.) concurrently with E. coli lipopolysaccharide (LPS; 3 mg kg-1, i.v.) dose-dependently increased vascular permeability in the ileum and colon, as determined by the leakage of radiolabelled albumin, and caused macroscopic mucosal damage in the ileum determined 1 h later. Neither LPS administration nor L-NAME (5 mg kg-1) alone affected resting vascular permeability. 3. Infusion of phenylephrine (10 micrograms kg-1 min-1, i.v. for 1 h) caused an elevation in blood pressure similar to that found following L-NAME administration (5 mg kg-1, i.v. or s.c.), but did not increase intestinal vascular permeability, when administered with LPS (3 mg kg-1, i.v.). 4. The increased vascular permeability in the ileum and colon and macroscopic damage in the ileum, induced by L-NAME (5 mg kg-1, s.c.) and LPS (3 mg kg-1, i.v.) was dose-dependently inhibited following s.c. pretreatment (15 min before challenge) with the thromboxane synthase inhibitors, OKY 1581 (5-25 mg kg-1) or 1-benzyl-imidazole (1-50 mg kg-1), or with the thromboxane receptor antagonist, BM 13177 (0.2-2 mg kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of nerve stimulation-induced vasodilatation in corpora cavernosa of the pithed rat by blockade of nitric oxide synthase.

1. The effect of inhibition of nitric oxide synthase by NG-nitro-L-arginine methyl ester (L-NAME) on nerve stimulation-induced vasodilation in corpora cavernosa was studied in the pithed rat. Corporal vasodilation was estimated by the increase in ratio (corpora cavernosal pressure/systemic blood pressure; CP/BP) following electrical stimulation of the sacral part of the spinal cord. 2. L-NAME (2, 5, 10 and 25 mg kg-1) caused an increase in BP and a dose-dependent inhibition of the rise in the CP/BP ratio following stimulation. 3. The inhibitory effect of L-NAME (25 mg kg-1) on the corporal response to spinal cord stimulation, as well as the pressor response, was partially prevented by prior administration of L- but not D-arginine (400 mg kg-1, i.v.). 4. L-NAME (20 mg kg-1, i.v.) did not inhibit the rise in corporal pressure resulting from direct intracavernosal administration of papaverine (400 micrograms over 2 min). However, this response was inhibited by 5-hydroxytryptamine (20 micrograms kg-1, i.v.). 5. The results are indicative of a role of nitric oxide (NO) in the corporal vasodilator response to erectile stimulation.     

Effects of nitric oxide synthesis inhibition on the goat coronary circulation under basal conditions and after vasodilator stimulation.

1. The role of nitric oxide in the coronary circulation under basal conditions and when exposed to various vasodilator stimuli was studied in instrumented, anaesthetized goats, by examining the action of inhibiting endogenous nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME). 2. In 12 goats, left circumflex coronary blood flow (electromagnetically measured), systemic arterial blood pressure and heart rate were continuously recorded. L-NAME (3-4, or 8-10 mg kg-1 injected i.v.) decreased resting coronary blood flow by 20 and 28%, increased mean arterial pressure by 23 and 30% and increased coronary vascular resistance by 47 and 65%, respectively, without affecting heart rate, or blood gases or pH. These haemodynamic effects were reversed by L-arginine (200-300 mg kg-1 by i.v. injection, 5 goats). 3. Acetylcholine (0.001-0.1 micrograms), sodium nitroprusside (0.01-0.3 mg), and diazoxide (0.1-3 mg), injected intracoronarily in 6 goats, produced dose-dependent increases in coronary blood flow; sodium nitroprusside (0.1-0.3 mg) also caused hypotension and tachycardia. 4. During the effects of L-NAME, the coronary vasodilatation to acetylcholine was attenuated, to sodium nitroprusside was increased, and to diazoxide was unaffected, in comparison with control conditions. The hypotensive effects of sodium nitroprusside were also increased during treatment with L-NAME. 5. Graded coronary hyperaemic responses occurred after 5, 10 or 20 s of coronary occlusion. The magnitude of hyerpaemia for each occlusion duration was increased during treatment with L-NAME, in comparison to control.(ABSTRACT TRUNCATED AT 250 WORDS)