N-Nitro-L-arginine protects against ischaemia-induced increases in nitric oxide and hippocampal neuro-degeneration in the gerbil

To assess the effects of the nitric oxide synthase inhibitor N^G-Nitro-L-arginine on behavioural, biochemical and histological changes following global ischaemia, the Mongolian gerbil was used. Ischaemia was induced by bilateral carotid occlusion for 5 min. N^G-Nitro-L-arginine was administered i.p. at either 1 or 10 mg/kg 30 min, 6, 24, and 48 h after surgery. 5 min bilateral carotid occluded animals were hyperactive 24, 48 and 72 h after surgery. N^G-Nitro-L-arginine caused some attenuation in this hyperactivity. The activity of nitric oxide synthase was increased in the cerebellum, brain stem, striatum, cerebral cortex and hippocampus of 5 min bilateral carotoid occluded animals. N^G-Nitro-L-arginine reversed the increase in nitric oxide synthase activity in all brain regions. Extensive neuronal death was observed in the CA₁ layer of the hippocampus in 5 min bilateral carotid occluded animals 96 h after surgery. N^G-Nitro-L-arginine significantly protected against the neuronal death of cells in the CA₁ layer.     

Diuretic effect of NG-nitro-l-arginine methyl ester in the rat

Abstract— Intravenous infusion of the nitric oxide synthase inhibitor N^G-nitro-l -arginine methyl ester, l -NAME (10 μg kg^?1 min^?1), to anaesthetized rats produced a diuresis and natriuresis. By contrast, infusion of the same dose of N^G-nitro-d -arginine methyl ester had no effect on either urine output or sodium excretion. The effects of l -NAME were first evident 120 min after the start of infusion and by 170 min a fivefold increase in urine volume and sodium excretion was recorded. l -NAME also produced a transient fall in inulin clearance and a persistent decline in renal blood flow. These renal effects of l -NAME were associated with a gradual elevation of mean arterial blood pressure, although this only attained statistical significance, in comparison with saline-infused animals, 170 min after the start of infusion. The findings indicate the diuresis and natriuresis evoked by l -NAME in the rat is a result of a direct tubular action together with a pressure diuresis.     

Role of nitric oxide in penile erection and yawning induced by 5-HT1c receptor agonists in male rats

The effect of the intracerebroventricular (i.c.v.) administration of N^G-nitro-l,-arginine methyl ester and N^G-monomethyl-l.-arginine, two inhibitors of nitric oxide (NO) synthase, on penile erection and yawning induced by 1-(3-chlorophenyl)-piperazine (m-CPP)- and N-(3-trifluoromethylphenyl)-piperazine (TFMPP), two selective 5HT_1c receptor agonists, was studied in male rats. Both NO synthase inhibitors (50–500 g i.c.v.) prevented dose-dependently the behavioural responses induced by m-CPP (0.5 mg/kg s.c.) or by TFMPP (I mg/kg s.c.), but N^G-nitro-l-arginine methyl ester was about 4–5 times more potent than N^G-monomethyl-l,-arginine. The D-isomer of N_G-monomethyl-l-arginine, which does not inhibit nitric oxide synthase, was ineffective. The inhibitory effect of N^G-nitro-l-arginine methyl ester on m-CPP- and TFMPP-induced responses was prevented by the administration of l-arginine (1 mg i.c.v.). In contrast, N^G-nitro-l-arginine methyl ester (20 g) was ineffective when injected in the paraventricular nucleus of the hypothalamus, a brain area that plays a key role in the expression of these behavioural responses. m-CPP- and TFMPP-induced penile erection and yawning was prevented also by the i.c.v. administration of LY 83583 (50–200 g) or methylene blue (50–400 g), two inhibitors of guanylate cyclase but not by reduced hemoglobin (50–400 g), a NO scavenger. The results suggest that central nitric oxide is involved in the expression of penile erection and yawning induced by 5-HT_1c receptor agonists.     

Involvement of nitric oxide in the response to 5-hydroxytryptamine in the rat in-vivo

Abstract— The involvement of nitric oxide (NO) in the effects of 5-HT on intestinal secretion and cardiovascular function in anaesthetized rats was investigated using N^G-nitro-l -arginine methyl ester (l -NAME), a specific NO-synthase antagonist, and its optical isomer d -NAME. l -NAME significantly reduced the prolonged hypotensive response to 5-HT. It also caused a small rightward shift in the colonic 5-HT dose-response curve. This suggests that NO plays a significant role in the prolonged hypotensive response to 5-HT, and may make a small contribution to the secretory response of the colon, but not that of the jejunum, in the rat in-vivo.     

Nitric Oxide Modulates the Acute Increase of Gastrointestinal Transit Induced by Endotoxin in Rats: a Possible Role for Tachykinins

Because of the evidence that endogenous nitric oxide (NO) plays an essential role in the physiological regulation of gastrointestinal motility we have investigated, by use of the NO synthase inhibitor, N^G-nitro-l -arginine methyl ester (l -NAME), the role of endogenous NO in the acute endotoxin-induced changes of gastrointestinal transit. Pre-treatment with E. coli endotoxin (100 μg kg^?, i.v.) induced a significant increase in the gastrointestinal transit of a charcoal suspension in anaesthetized rats. Previous administration of the NO synthase inhibitor, l -NAME (10 mg kg^?, i.v.) significantly prevented the effects of endotoxin. l -arginine (200 mg kg^?, i.v.) and the substance P antagonist [d -Pro², d -Trp^7,9]-substance P (SPA), significantly reversed the effects of l -NAME on gastrointestinal transit in rats treated with endotoxin. Pre-treatment with dexamethasone (5 mg kg^?, s.c., twice), an inhibitor of the expression of inducible NO synthase, did not affect the increase in the gastrointestinal transit through constitutive NO synthesis. The results suggest that constitutive nitric oxide is involved in the increase of gastrointestinal transit induced by endotoxin and that the reduction in transit induced by l -NAME in endotoxin-treated rats is mediated by endogenous tachykinins.     

The Role of Nitric Oxide and Sulphydryls in Gastric Mucosal Protection Induced by Sodium Cromoglycate in Rats

The role of endogenous nitric oxide and sulphydryls in gastric protection afforded by sodium cromoglycate against ethanol-induced gastric lesions was studied in rats. Drugs were administered either intraperitoneally (i.p.) or subcutaneously (s.c.) 30, 45 or 60 min before oral administration of ethanol. Administration of cromoglycate before ethanol dose-dependently inhibited ethanol-induced gastric lesions. Pretreatment with N^G-nitro-l -arginine methyl ester (L-NAME), an inhibitor of nitric oxide biosynthesis, dose-dependently aggravated gastric lesions and reduced cromoglycate-induced gastric protection. The attenuating effect of L-NAME on gastric protection elicited by cromoglycate was reversible by pretreatment with l -arginine but not by d -arginine. On the other hand, ethanol-induced gastric lesions were found to be associated with a reduction of nonprotein sulphydryl content of glandular stomachs. Pretreatment with cromoglycate prevented non protein sulphydryl depletion and afforded protection. Pretreatment with N-ethylmaleimide, a sulphydryl blocker, caused dose-dependent enhancement of ethanol-induced gastric lesions and further depletion of non protein-sulphydryl. Treatment with N-ethylmaleimide before cromoglycate reduced the gastric protection that was associated with depletion of nonprotein sulphydryls. Furthermore, combined N-ethylmaleimide and L-NAME pretreatment caused a greater aggravation of ethanol-induced gastric lesions and significantly produced a higher reduction of the protective effects of cromoglycate. However, pretreatment with l -arginine only partially restored the protective effects of cromoglycate. These results suggest that the protective effects of cromoglycate may be dependent on the maintenance of a critical level of both endogenous nitric oxide and nonprotein sulphydryls in the gastric mucosa.     

Neuroprotective effects of 7-nitroindazole in the gerbil model of global cerebral ischaemia

To evaluate the role played by nitric oxide in global cerebral ischaemia we examined the effects of 7-nitroindazole and a sodium salt of 7-nitroindazole (inhibitors of neuronal nitric oxide (NO) synthase) and N^G-nitro- -arginine methyl ester (a more general inhibitor of NO synthase) in the gerbil model of cerebral ischaemia. Four experiments were carried out. In the first experiment, animals were either sham-operated, subjected to 5 min bilateral carotid occlusion (BCAO) or administered 7-nitroindazole orN^G -nitro- -arginine methyl ester immediately after occlusion followed by three further doses at 3, 6 and 24 h post-occlusion. In the second experiment, we examined the effects of a sodium salt of 7-nitroindazole, which is more soluble than 7-nitroindazole, using the same protocol. In the third experiment, the effects of the sodium salt of 7-nitroindazole administered at 10 mg/kg at 0, 3, 6, 24, 27, 30, 33, 52, 55, 72, 75 and 78 h post-occlusion or at 0.05 mg/h for 72 h via mini-pumps were evaluated. In separate experiments, we examined the effects of three reference compounds dizocilpine (MK-801), 2,3-dihydroxy-6-nitro-7-sulphamoyl-benz(F)-quinoxaline (NBQX) and eliprodil using the same model. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5 min bilateral carotid occluded animals 5 days after surgery. Both 7-nitroindazole and N^G-nitro- -arginine methyl ester provided significant neuroprotection (P < 0.01) against this neuronal death. The sodium salt of 7-nitroindazole showed no protection when administered up to 12 times post-occlusion, but did provide significant (P < 0.01) neuroprotection when administered via mini-pump. The neuroprotection was similar to that provided by MK-801 and eliprodil, but not as good as that observed with NBQX. These results indicate that nitric oxide plays a role in ischaemic cell death and that selective neuronal nitric oxide synthase inhibitors can protect against ischaemic brain damage.     

Nitric oxide is involved in the memory facilitation induced by spermidine in rats

Rationale Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-d-aspartate receptor functions, which has been reported to facilitate memory formation.Objectives In the current study, we investigated the involvement of nitric oxide in the facilitatory effect of SPD on the memory of adult male Wistar rats in the inhibitory avoidance task.Results The coadministration of the nonspecific NOS inhibitor N ^G nitro-l-arginine methyl ester (l-NAME) (0.1 nmol, intrahippocampus) with spermidine (0.2 nmol), immediately after training, prevented the memory improvement caused by spermidine in the avoidance inhibitory task. Spermidine increased nitrite and nitrate levels (NO_X) in the hippocampus 30 min after its administration, and l-NAME coinjection prevented the stimulatory effect of spermidine on NO_X levels. The systemic injection of 7-nitroindazole (30 mg/kg, i.p.), 30 min before training, impaired memory and did not prevent spermidine-induced increase of NO_X levels in the hippocampus.Conclusions These results suggest that memory enhancement by spermidine is prevented by the nonspecific nitric oxide synthase inhibitor l-NAME.     

EFFECTS OF FR139317 ON RENAL RESPONSES TO ACUTE NITRIC OXIDE BLOCKADE IN ANAESTHETIZED RATS

1. Effects of FR139317, an endothelin ET_A receptor antagonist, on renal haemodynamic and excretory responses to acute nitric oxide (NO) blockade were examined using anaesthetized rats. 2. Intrarenal arterial infusion of N^G-nitro-l -arginine (NOARG), the NO synthase inhibitor, at a rate of 40 μg/kg per min, produced a significant decrease in renal blood flow, with no change in systemic blood pressure. There were significant decreases in urine flow and urinary excretion of sodium during infusion of NOARG. In animals pretreated with FR139317, similar renal responses to the NOARG infusion were observed. 3. These results suggest that an action of endothelin-1 via ET_A receptors does not greatly contribute to the renal haemodynamic and excretory responses to acute blockade of renal NO production.     

Possible Involvement of Nitric Oxide Synthase in Oxidative Stress-Induced Endothelial Cell Injury

Abstract: The purpose of this study was to characterize the protective effect of N^G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, on oxidative stress-induced endothelial cell injury. Intracellular oxidative stress was induced by 1-chloro-2,4-dinitrobenzene, a glutathione (GSH) depleting agent, and the leakage of intracellular lactate dehydrogenase was measured as a marker of cell injury. Addition of 1-chloro-2,4-dinitrobenzene (100-500 μM) induced leakage of lactate dehydrogenase from endothelial cells, and the leakage of lactate dehydrogenase was strongly attenuated by L-NAME, but not by N^G-methyl-L-arginine, also an inhibitor of nitric oxide synthase. However, cell injury induced by the Ca²⁺ ionophore ionomycin was not affected by L-NAME or N^G-methyl-L-arginine. Moreover, neither L-NAME nor N^G-methyl-L-arginine affected GSH depleting agent-induced or H₂O₂-induced cell injury in a rat foetal lung fibroblast cell line which lacks nitric oxide synthase. These results suggest that the protective effect of L-NAME is likely to be related to nitric oxide synthase, while the inhibition of nitric oxide production may not be involved in the protective effect of L-NAME, since N^G-methyl-L-arginine did not affect endothelial cell injury.     

Demonstration of the existence of nitric oxide-independent as well as nitric oxide-dependent vasodilator mechanisms in the in situ renal circulation in near term pregnant rats

1. We have investigated the role of endogenous nitric oxide on renal vascular reactivity in late pregnancy in in situ blood perfused kidneys of α-chloralose anaesthetized Wistar-Kyoto rats. Nitric oxide synthesis inhibition was achieved by intravenous administration of N^G-nitro-L-arginine or N^G-nitro-L-arginine methyl ester.
2. Intra-arterial mean blood pressure was lower in pregnancy compared with nonpregnant controls. Following nitric oxide synthesis inhibition mean blood pressure increased in both pregnant and nonpregnant groups, but remained lower in pregnant animals.
3. Basal renal perfusion pressure was similar in pregnant and nonpregnant groups. Intravenous administration of N^G-nitro-L-arginine resulted in dose-dependent increases in renal perfusion pressure but responses were substantially depressed in pregnancy.
4. Renal vasoconstrictor responses to regional angiotensin II (AII) were decreased in pregnancy, whereas those to noradrenaline (NA) did not differ from nonpregnant controls. N^G-nitro-L-arginine (5 mg kg⁻¹) potentiated renal responses to regional AII and NA in both groups, but AII responses remained lower in pregnancy. Blunted renal AII responses in pregnancy were still evident following large doses of N^G-nitro-L-arginine methyl ester (100 mg kg⁻¹).
5. The results demonstrate that nitric oxide synthesis inhibition increases renal perfusion pressure to a lesser extent in pregnant compared with nonpregnant rats, and that reduced renal pressor responses to AII are still evident in pregnancy after nitric oxide synthesis inhibition.
6. These results suggest that although endogenous nitric oxide synthesis modulates renal vasoconstrictor responses in both pregnant and nonpregnant animals, this mechanism does not fully account for the blunted renal vasoconstrictor responses to regional AII or nitric oxide inhibitors in near term pregnant rats. The nature of this important physiological vasodilator mechanism in pregnancy remains to be elucidated.

     

Vasodilator effects of adenosine on retinal arterioles in streptozotocin-induced diabetic rats

Adenosine is a potent vasodilator of retinal blood vessels and is implicated to be a major regulator of retinal blood flow during metabolic stress, but little is known about the impact of diabetes on the role of adenosine in regulation of retinal hemodynamics. Therefore, we examined how diabetes affects adenosine-induced vasodilation of retinal arterioles. Male Wistar rats were treated with streptozotocin (80 mg/kg, intraperitoneally), and experiments were performed 6–8 weeks later. Rats were treated with tetrodotoxin (50 μg/kg, intravenously [i.v.]) to eliminate any nerve activity and prevent movement of the eye and infused with methoxamine continuously to maintain adequate systemic circulation. Fundus images were captured with a digital camera that was equipped with a special objective lens, and diameters of retinal arterioles were measured. Adenosine increased diameters of retinal arterioles and decreased systemic blood pressure. These responses were significantly attenuated by the nitric oxide synthase inhibitor N^G-nitro-l-arginine methyl ester (30 mg/kg, i.v.) and the adenosine triphosphate-dependent K⁺ (K_ATP) channel blocker glibenclamide (20 mg/kg, i.v.). The depressor responses to adenosine were reduced in diabetic rats, whereas diabetes did not alter vasodilation of retinal arterioles to adenosine. In contrast, both depressor response and vasodilation of retinal arteriole to acetylcholine were reduced in diabetic rats. The retinal vasodilator responses to adenosine and acetylcholine observed in diabetic rats were diminished by N^G-nitro-l-arginine methyl ester. There were no differences in the responses to pinacidil, a K_ATP channel opener, between the diabetic and nondiabetic rats. These results suggest that both the activation of nitric oxide synthase and opening of K_ATP channels contribute to the vasodilator effects of adenosine in rats in vivo. However, diabetes has no significant impact on the vasodilation mediated by these mechanisms in the retinal circulation.     

NG-Nitro-l-arginine methyl ester inhibits the effect of an H3-histaminergic receptor agonist on NANC contraction in guinea-pig perfused bronchioles

Abstract— A role for nitric oxide in the H₃-histaminergic agonist-induced inhibition of the non-adrenergic, non-cholinergic (NANC) contraction has been studied in guinea-pig perfused bronchioles. (R)-α-Methylhistamine ((R)-α-MeHA), an agonist for H₃ receptors, inhibited the NANC contraction induced by electrical field stimulation. N^G-Nitro-l -arginine methyl ester (l -NAME) (50 μm ), an inhibitor of nitric oxide synthesis, blocked the effect of (R)-α-MeHA. The effect of l -NAME was reversed by l -arginine (50 μm ). l -NAME, l -arginine or (R)-α-MeHA were without effect on exogenous substance P- or neurokinin A-induced contractile responses of the perfused bronchioles. These results show that an H₃-agonist inhibited the release of neurotransmitters in NANC nerve endings of guinea-pig perfused bronchioles presumably by production of nitric oxide.     

OXYGEN RADICALS AND NITRIC OXIDE IN RAT MESENTERIC ISCHAEMIA-REPERFUSION: MODULATION BY L-ARGININE AND NG-NITRO-L-ARGININE METHYL ESTER

1. The aims of the present study were to detect changes in superoxide anion (O₂^?), nitric oxide (NO) and other reactive oxygen species (ROS) directly by measurement of chemilumin-escence (CL) and to investigate the role of L-arginine, a nitric oxide synthase (NOS) substrate, and N^G-nitro-L -arginine methyl ester (L-NAME), a NOS inhibitor, together with their molecular enantiomers D-arginine and D-NAME, in a rat mesenteric ischaemia-reperfusion (I/R) model. 2. Seventy-nine female Wistar albino rats were divided into eight groups. The first three groups underwent sham operation; group 1 was the control group, group 2 received L-arginine and group 3 received L-NAME. Ischaemia was produced in the remaining five groups by ligation of the superior mesenteric artery for 30 min followed by 60 min reperfusion. Group 4 rats were control I/R rats and groups 5-8 received either L-arginine, L-NAME, D-arginine or D-NAME, respectively. 3. Both luminol and lucigenin CL was significantly increased in I/R groups compared with sham-operated groups. L-Arginine significantly reduced CL measurements. D-Arginine was also protective, but not as much as L-arginine. Both L - and D-arginine had in vitro O₂^?-scavenging potential, as tested by the xanthine-xanthine oxidase system. N^G-Nitro-L-arginine methyl ester decreased lipid peroxidation values in addition to reducing CL measurements. Nitric oxide concentrations were significantly increased in I/R groups in comparison with sham-operated groups. Peroxynitrite formation was increased by I/R. Treatment with L-NAME was beneficial by reducing NO concentrations in the reperfused ileum. 4. In our I/R model, O₂^?, NO and other ROS were increased. Although NOS inhibitors were effective in reducing oxidative damage, increasing NO concentrations with L-arginine was also beneficial, presumably due to the ability of L-arginine to inhibit phagocyte adherence and its radical scavenging potential. In fact, NO may have different effects in terms of tissue injury or protection depending on the concentration of oxygen and the haemodynamic state of the tissue.     

Response of Rabbit Ear and Femoral Arteries to 5-Hydroxytryptamine During Cooling

The effects of cooling on the response of cutaneous and non-cutaneous arteries to 5-hydroxytryptamine (5-HT) were analysed. Segments 2-mm long from rabbit central ear (cutaneous) and femoral (non-cutaneous) arteries were prepared for isometric tension recording in an organ bath at 37 and 24°C (cooling). 5-HT (10^?9-3 times 10^?4 M) induced concentration-dependent contraction of the arteries. The sensitivity and maximal contraction of ear arteries and only the maximal contraction of femoral arteries to this amine were reduced at 24°C. Endothelium removal or pretreatment with the nitric oxide synthase inhibitor N^G-nitro-l -arginine methyl ester (l -NAME, 10^?5 m ) did not affect the response at 37°C but reversed the decreased sensitivity at 24°C in ear arteries, and neither procedure modified the reactivity at 24 or 37°C in femoral arteries to 5-HT. At both temperatures, the response of ear arteries to 5-HT was shifted to the right by phentolamine (10^?6M) more than by the 5-HT antagonist, ketanserin (3 times 10^?7M), and that of femoral arteries was shifted to the right by ketanserin or the 5-HT₁/5-HT₂ antagonist methysergide (3 times 10^?7 M) more than by phentolamine, in arteries with and without endothelium. These data concur with the proposition that the contraction to 5-HT is mediated mainly by α-adrenergic receptors in ear arteries and mainly by 5-HT-ergic receptors in femoral arteries, and suggest that cooling reduces the sensitivity of cutaneous, but not of deep arteries to 5-HT, probably by endothelium-nitric oxide-dependent mechanisms.     

Effects of Nω-nitro-l-arginine and capsaicin on neurogenic vasomotor responses in isolated mesenteric arteries of the monkey

Abstract— Monkey isolated mesenteric arterial rings denuded of endothelium constricted upon transmural nerve stimulation (TNS) in the absence of active muscle tone. The constriction was potentiated by Nω-nitro-l -arginine (3 × 10^?5 m ), but not by the d -enantiomer (3 × 10^?5 m ). The potentiation was reversed by l -arginine (3 × 10^?4 m ). The neurogenic vasoconstriction of mesenteric arteries was also augmented by capsaicin, but to a lesser extent than that induced by Nω-nitro-l -arginine. Indomethacin (10^?5 m ) did not affect TNS-induced vasoconstriction. These findings suggest that nerve-derived nitric oxide or a related substance may play a greater role than do capsaicin-sensitive vasodilator transmitters in neurogenic regulation of mesenteric arterial tone in the monkey. The transmitter mechanisms for vasodilation in mesenteric circulation vary among species.     

Nitric oxide synthase inhibition blocks phencyclidine-induced behavioural effects on prepulse inhibition and locomotor activity in the rat

The ability of the nitric oxide synthase inhibitor, N ^G-nitro-L-arginine methyl ester (L-NAME), to block the behavioural effects of the potent psychotomimetic, phencyclidine, was tested in rats using two different behavioural models. L-NAME was found to block both phencyclidine-induced disruption of prepulse inhibition of acoustic startle and phencyclidine-induced stimulation of locomotor activity. A selective action of L-NAME on the effects of phencyclidine was indicated, since L-NAME did not alter the effects of amphetamine, another potent psychotomimetic, in these behavioural models. These observations suggest that a nitric oxide-dependent mechanism may be involved in the effects of phencyclidine in the central nervous system. Received: 2 September 1996/Final version: 21 December 1996     

EFFECTS OF CHRONIC NICOTINE INGESTION ON PRESSOR RESPONSE TON-NE2RO- -ARGININE METHYL ESTER ANDEX VIVOCONTRACTION AND RELAXATION RESPONSE OF AORTA TO -ARGININE

Effects of nitric oxide synthase inhibition on blood vessels were studied in nicotine-treated rats. Male Sprague–Dawley rats drank a nicotine solution with a concentration of 25 or 50 μg/ml for 15 days. The blood pressure and heart rate of chloralose-anaesthetized rats and isolated aortic strip contractions were measured.N^ωNitro- -arginine methyl ester ( -NAME)-induced hypertension was significantly reduced after chronic nicotine treatment. TheE_maxof contractions of isolated aortic strips to noradrenaline were dose-dependently enhanced by nicotine and the potentiation was abolished by -arginine. The relaxation of aortic strips to acetylcholine was significantly decreased in nicotine-treated rats, whereas -arginine, but not -arginine, reversed this action. Neither nicotine nor -NAME affected the heart rate. The results show that chronic nicotine treatment reduced the pressor response of -NAME.     

Possible role of nitric oxide in 5-hydroxytryptamine-induced increase in vascular permeability in mouse skin

In order to test the hypothesis that a 5-hydroxytryptamine (5-HT)-induced increase in vascular permeability results from a cascade triggered by activation of the synthesis of nitric oxide (NO), the vascular permeability was investigated using the Pontamine sky blue leakage method in male mice. Subcutaneous injection of 5-HT induced a dose-related increase of vascular permeability at the injection site. The vascular permeability induced by 5-HT was inhibited by pretreatment with intraperitoneal injection of ketanserin (5-HT_2A antagonist) and methysergide (5-HT_1/2A antagonist), less efficiently by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine (NAN-190) (5-HT_1A antagonist), but not by granisetron (5-HT₃ antagonist). Increase in vascular permeability induced by 5-HT was inhibited by concurrent intravenous administration of NO synthase inhibitors N^G-nitro-Lrarginine methyl ester (L-NAME) and methylene blue but not by the inactive enantiomer N^G-nitro-D-arginine methyl ester (D-NAME). These results suggest that 5-HT increases vascular permeability by activating the 5-HT receptors and that endogenous NO is involved in this effect of 5-HT. Correspondence to: E. Fujii at the above address     

Further studies on anti- and proconvulsant effects of inhibitors of nitric oxide synthase in rodents

We confirmed that the effects of inhibitors of nitric oxide (NO) synthase, such as N^ω-nitro-l-arginine methyl ester and N^G-nitro-l-arginine, differ depending on several experimental factors. Both compounds but not their less active enantiomers delayed picrotoxin-induced clonus in mice yet increased the incidence of clonus following low-dose picrotoxin. N^ω-nitro-l-arginine methyl ester significantly reduced the latencies of both myoclonus and clonus in older but not younger Sprague–Dawley rats receiving pentylenetetrazol s.c. By contrast, there was no significant change in the latencies for myoclonus and clonus in Wistar rats (older and younger). However, when pentylenetetrazol was administered i.p. rather than s.c., N^ω-nitro-l-arginine methyl ester dramatically increased latencies of convulsive indicators, including tonus, in both Sprague–Dawley and Wistar rats. N^ω-nitro-l-arginine methyl ester also delayed tonus but not myoclonus or clonus in mice, regardless of the systemic route of administration of pentylenetetrazol. Both N^ω-nitro-l-arginine methyl ester and N^G-nitro-l-arginine increased the tonic CD₅₀ of pentylenetetrazol in mice and N^ω-nitro-l-arginine methyl ester delayed 4-aminopyridine-induced tonus. However, N^ω-nitro-l-arginine methyl ester reduced the tonic CD₅₀ of both picrotoxin and 4-aminopyridine in mice and failed to suppress tonus following maximal electroshock. Evidently, inhibitors of NO synthase are not universally effective antitonic drugs.