Nitric Oxide Donor Molsidomine Research Articles

Molsidomine antagonizes L-NAME-induced acquisition deficits in a recognition memory task in the rat

The present study was designed to investigate the role of nitric oxide (NO) on the acquisition of a recognition memory task in the rat. For this purpose, the effects on memory exerted by pre-training administration of the NO synthase inhibitor L-NAME ( N ω -nitro- l-arginine methyl ester) and the NO donor molsidomine ( N-[ethoxycarbonyl]-3-[4-morpholinosydnomine]) were assessed by using the object recognition task, a working memory paradigm based on the differential exploration of a new and familiar object. In a first dose–response study, it was found that L-NAME (10, 30, and 60 mg kg −1, i.p.) at 30 but not at 10 mg kg −1 disrupted animals performance, whereas the dose of 60 mg kg −1 induced side effects. Molsidomine (2 and 4 mg kg −1, i.p.) at 4 but not at 2 mg kg −1, antagonized the L-NAME-induced performance deficits. These results indicate that NO is involved in the acquisition of a recognition memory task.

Heme oxygenase in the retina in diabetes

Introduction. Heme oxygenase (HO) isoforms, HO-1, and HO-2, are responsible for heme breakdown to iron and carbon monoxide (CO). HO may respond to oxidative stress and may modulate the expression of vasoactive factors like nitric oxide (NO). Since diabetes induced oxidative stress may change HO, the present study examined whether diabetes is associated with HO alterations, its relationship with NO, endothelin-1(ET-1) and the functional significance. Materials & Methods. Male SD rats with Streptozotocin induced diabetes were investigated after six-weeks. Poorly controlled diabetic animals were randomized to one of three treatment groups (n = 6 each group); a) untreated, b) HO-1 inhibitor SnPP-IX (50µmol/kgIP/day), c) NO donor molsidomine (120mg/L PO/day) and were compared with age and sex matched non diabetic control animals with or without SnPP-IX treatment. Color Doppler ultrasound analysis was used to determine retinal resistivity index (RI). mRNA for HO-1, HO-2, ET-1, eNOS and iNOS were analyzed with competitive RT-PCR. HO distribution in the retina was investigated by immunocytochemistry. Results. Diabetic animals expressed lower body weight, higher blood glucose and increased glycated hemoglobin levels. HO-1 and HO-2 immuno-reactivity were identified in the retina. Diabetes induced increased RI was associated with up-regulation of both ET-1 and HO-1 mRNA expression but not eNOS or iNOS mRNA. Both SnPP-IX and molsidomine treatments prevented a diabetes increase of RI, in spite of increased ET-1 expression and were associated with increased iNOS mRNA. Conclusions. The present data suggests that the HO system is up-regulated in short term diabetes leading to HO and NO interactions which may modulate vascular function in the retina.

Nitric oxide enhances experimental wound healing in diabetes.

Diabetes is characterized by a nitric oxide deficiency at the wound site. This study investigated whether exogenous nitric oxide supplementation with the nitric oxide donor molsidomine (N-ethoxycarbomyl-3-morpholinyl-sidnonimine) could reverse the impaired healing in diabetes. Wound healing was studied by creating a dorsal skin incision with subcutaneous polyvinyl alcohol sponge implantation in diabetic and non-diabetic rats. Half of each group was treated with molsidomine. Collagen metabolism was assessed by wound breaking strength, hydroxyproline (OHP) content, RNA expression for collagen type I and III, and matrix metalloproteinase (MMP) 2 activity in wound sponges. Wound fluid, plasma and urinary nitric oxide metabolite levels, and the number of inflammatory cells were assessed. OHP content and wound breaking strength were significantly increased by molsidomine. MMP-2 activity in wound fluid was decreased in diabetes and upregulated by nitric oxide donors. The impaired inflammatory reaction in diabetes was unaffected by nitric oxide donor treatment and ex vivo nitric oxide synthesis was no different between wound macrophages from control and diabetic animals, suggesting that the nitric oxide deficiency in the wound is due to a smaller inflammatory reaction in diabetes. The nitric oxide donor molsidomine can at least partially reverse impaired healing associated with diabetes.

Molsidomine attenuates Nω-nitro- l-argininemethylester-induced deficits in a memory task in the rat

The present study was designed to investigate the role of nitric oxide (NO) on recognition memory in the rat. For this purpose, the effects on memory exerted by post-training administration of the NO synthase (NOS) inhibitor N ω-nitro- l-argininemethylester ( l-NAME) and the NO donor molsidomine were assessed by using the object recognition task. In a first dose–response study, l-NAME, at 30 but not at 10 mg/kg impaired the animals' performance, whereas at 60 mg/kg, it induced side-effects. Molsidomine, 4 mg/kg, antagonized the l-NAME-induced performance deficits. These results indicate that NO is involved in post-training memory processes.

Effects of the Nitric Oxide Donor Molsidomine on the Early Stages of Liver Damage in Rats with Bile Duct Ligation: A Biochemical and Immunohistochemical Approach

This study aimed to evaluate the effects of the nitric oxide donor molsidomine on the early stages of liver damage and biochemical changes in rats with bile duct ligation (BDL). Forty prepubertal male Sprague-Dawley rats weighing 125–140 g were studied. Group 1 rats (sham-control, n = 10) were not subjected to any surgical manipulation. Group 2 rats (BDL/untreated, n = 10) were subjected to BDL but no drug was administered. Group 3 rats (BDL/L-NAME, n = 10) received a daily dose of N^G-nitro-L-arginine methyl ester (L-NAME) intraperitoneally for 7 days after BDL. Group 4 rats (BDL/molsidomine, n = 10) received a daily dose of molsidomine by gastric tube for 7 days after BDL. After 1 week, biochemical and histological evaluations were performed and the liver hydroxyproline content was measured. Serum bilirubin and liver enzymes were significantly increased in the BDL/untreated, BDL/L-NAME and BDL/molsidomine groups in comparison with the sham-control group 1 week after BDL. However, the liver enzymes were significantly decreased in the BDL/molsidomine group in comparison with the BDL/untreated and BDL/L-NAME groups. In the BDL/L-NAME group, proliferation of portal and periportal biliary ductules with disorganization of the hepatocyte plates, dilated portal spaces and areas of polymorphonuclear leukocyte infiltration, fibrosis and hepatocyte necrosis were observed. In the BDL/molsidomine group, polymorphonuclear leukocyte infiltration, hepatocyte necrosis and fibrosis were rarely seen. The hydroxyproline content in the liver was increased 1 week after obstruction in the BDL/untreated and BDL/L-NAME groups when compared to BDL/molsidomine group. Collagen type-IV expression was not observed in the BDL/molsidomine group in contrast to the BDL/untreated and BDL/L-NAME groups. In conclusion, during 1 week of treatment, the nitric oxide donor molsidomine improved hepatic fibrosis in the hepatic parenchyma and did not affect serum bilirubin values, but positively affected the serum aspartate aminotransferase and alanine aminotransferase values.

Effects of the nitric oxide donor molsidomine on different memory components as assessed in the object-recognition task in the rat.

Nitric oxide (NO) is sought to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit NO synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The present study was designed to further investigate in the rat the effects on distinct memory processes exerted by the NO donor molsidomine. For this aim, the object-recognition task was chosen. This test is based on the differential exploration of a new and familiar object.METHODS. Object recognition was evaluated in a two-trial nonrewarded paradigm. In a first study, the influence of the retention time (the delay between the two trials) on the performance of 3-month-old male rats was assessed. Subsequently, the effects of molsidomine (2 mg/kg and 4 mg/kg), injected i.p., on acquisition, storage, and retrieval of information were evaluated. For the latter experiments, the delay condition at which recognition memory was extinguished in the normal rat was used (24 h). Under our experimental conditions, object recognition was extinguished in the rat when an intertrial interval (ITI) of 24 h was utilized. Using this ITI, molsidomine at 4 mg/kg but not at 2 mg/kg improved the animal's performance in the object-recognition task, suggesting that molsidomine affected acquisition, storage, and retrieval of information. These results indicate that the NO donor molsidomine may modulate different aspects of memory.

Effects of molsidomine on scopolamine-induced amnesia and hypermotility in the rat

Nitric oxide (NO) is hypothesized to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit nitric oxide synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The aim of this study was to assess in the rat the effects of the NO donor molsidomine (2 and 4 mg/kg, i.p.) on memory deficits caused by scopolamine. For this purpose, the object recognition task and the step-through passive avoidance procedure were chosen. In addition, the effects of molsidomine in antagonizing the scopolamine-induced hypermotility were also examined. Scopolamine at 0.2 mg/kg (object recognition) and 0.75 mg/kg (passive avoidance) disrupted acquisition in both the tasks and induced locomotor hyperactivity at the dose of 0.2 mg/kg. Molsidomine at either dose reversed the scopolamine-induced deficits in the object recognition paradigm but did not counteract the hypermotility and the deficits occurred in the passive avoidance test. These results suggest that to some extent, the NO donor molsidomine is involved in memory processing.

The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs.

We investigated the effects of the nitric oxide (NO) donor molsidomine and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on pulmonary endothelin (ET)-1 gene expression and ET-1 plasma levels in chronic hypoxic rats. Two and four weeks of hypoxia (10% O2) significantly increased right ventricular systolic pressure, the medial cross-sectional vascular wall area of the pulmonary arteries, and pulmonary ET-1 mRNA expression (2-fold and 3.2-fold, respectively). ET-1 plasma levels were elevated after 4 wk of hypoxia. In rats exposed to 4 wk of hypoxia, molsidomine (15 mg x kg(-1) x day(-1)) given either from the beginning or after 2 wk of hypoxia significantly reduced pulmonary hypertension, pulmonary vascular remodeling, pulmonary ET-1 gene expression, and ET-1 plasma levels. L-NAME administration (45 mg x kg(-1) x day(-1)) in rats subjected to 2 wk of hypoxia did not modify these parameters. Our findings suggest that in chronic hypoxic rats, exogenously administered NO acts in part by suppressing the formation of ET-1. In contrast, inhibition of endogenous NO production exerts only minor effects on the pulmonary circulation and pulmonary ET-1 synthesis in these animals.

Nitric Oxide and Molsidomine in the Management of Pulmonary Hypertension in Takayasu's Arteritis

We present three patients with pulmonary hypertension in Takayasu's arteritis who showed long-term favorable response, clinically and hemodynamically, to nitric oxide donor molsidomine. In these patients, nitric oxide inhalation was effective in reducing pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Molsidomine (single dose of 4 mg p.o.) was also effective in reducing PAP and PVR, but nifedipine was not. With molsidomine, 4 mg tid, dyspnea, exercise capacity, and hemodynamic parameters were improved. These favorable responses have lasted during the 3-month follow-up period in all patients.

Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide.

Inducible heme oxygenase (HO-1) has recently been recognized as an antioxidant and cytoprotective gene. By use of Western blotting, cell viability analysis, and antisense technique, the present study investigates the involvement of HO-1 in endothelial protection induced by the clinically used nitric oxide (NO) donor molsidomine (specifically, its active metabolite 3-morpholinosydnonimine [SIN-1]) and the second messenger cGMP. In bovine pulmonary artery endothelial cells, SIN-1 and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) at 1 to 100 micromol/L induced the synthesis of HO-1 protein in a concentration-dependent fashion up to 3-fold over basal levels. HO-1 induction by SIN-1 was inhibited in the presence of the NO scavenger phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4, 3-a]quinoxalin-1-one. 8-Bromo-cGMP (1 to 100 micromol/L) and dibutyryl cGMP (1 to 100 micromol/L) as well as the activator of particulate guanylyl cyclase atrial natriuretic peptide (1 to 100 nmol/L) produced increases in HO-1 protein similar to those produced by SIN-1. SIN-1 and 8-bromo-cGMP increased heme oxygenase activity (bilirubin formation). Cytoprotection by NO donors was abrogated in the presence of the heme oxygenase inhibitor tin protoporphyrin IX. Pretreatment of cells with a phosphorothioate-linked HO-1 antisense oligonucleotide prevented protection by SIN-1 or 8-bromo-cGMP against tumor necrosis factor-alpha cytotoxicity, whereas sense and scrambled HO-1 were without effect under these conditions. Our results show for the first time that HO-1 is a cGMP-sensitive endothelial gene and establish conclusively a causal relationship between HO-1 induction and endothelial protection by the NO/cGMP system. By targeting cytoprotective HO-1, NO donors may therefore be expected to induce antioxidant, antiatherogenic, and anti-inflammatory effects.

Protective effect of the nitric oxide donor molsidomine on indomethacin and aspirin-induced gastric injury in rats.

To study the effect of the nitric oxide donor, molsidomine, on gastric and duodenal injury induced by indomethacin and aspirin. Sprague-Dawley rats weighing 180-200 g were used after 24 h fasting. Indomethacin (5 mg/kg) was given subcutaneously as a single dose and followed by multiple injections of histamine. Molsidomine (0.05 mg/kg) or distilled water was given by gavage 30 min before indomethacin and repeated at 3 h intervals for two doses. Rats were killed 2 h after the last dose of molsidomine. Aspirin (500 mg/kg) was given by gavage and repeated 2.5 h later. Molsidomine or distilled water was given 30 min before the initial aspirin dose and repeated after 2 h. Animals were killed 2.5 h after the second dose of aspirin. The severity of the gastric mucosal damage was graded from 0 to 3, and the duodenal bulb ulcer surface area calculated by two independent observers using a dissecting microscope. Indomethacin and aspirin resulted in significant gastric mucosal damage with median scores of 2 (interquartile ranges 1.4-3, n = 16 and 2-3, n = 10, respectively). Molsidomine significantly ameliorated indomethacin- and aspirin-induced damage with median scores of 1 (interquartile ranges 0.5-1.5, n = 19 and 0.6-1.9, n = 10, respectively; P<0.008 and P<0.02, respectively (Mann-Whitney Utest)). Molsidomine had no effect on duodenal bulb ulcerations caused by indomethacin. Oral molsidomine has a protective effect on gastric mucosa against damage induced by ulcerogenic agents. This could have an important clinical benefit, especially in cardiac patients taking aspirin in addition to a nitric oxide donor such as molsidomine.

Nitric oxide donors can increase heart rate independent of autonomic activation.

Administration of nitric oxide (NO) donors in vivo is accompanied by a baroreflex-mediated increase in heart rate (HR). In vitro, however, NO donors can increase HR directly by stimulating a pathway that involves NO, cGMP, and the hyperpolarization-activated current (I(f)). The aim of this study was to assess the functional significance of this pathway in vivo by testing whether NO donors can increase HR in the anesthetized rabbit independent of the autonomic nervous system. New Zealand White rabbits were vagotomized, cardiac sympathectomized, and treated with propranolol (0.3 mg/kg iv). The NO donor molsidomine (0.2 mg/kg iv) caused a progressive increase (Delta) in HR (DeltaHR, 14 +/- 3 beats/min; P < 0.01). This effect was significantly reduced by the I(f) blocker ZD-7288 (0.2 mg/kg iv; DeltaHR, 2 +/- 3 beats/min; P = not significant). Similar results were seen with sodium nitroprusside. The positive chronotropic effect of sodium nitroprusside (50 microM) was confirmed in the isolated working rabbit heart preparation (DeltaHR, 17 +/- 3 beats/min; P < 0.01). In conclusion, NO donors exert a small, but significant, positive chronotropic effect in vivo that is independent of the autonomic nervous system. These results are also consistent with data in sinoatrial node cells that show that NO donors increase HR by stimulating I(f).

NO-cGMP pathway accentuates the decrease in heart rate caused by cardiac vagal nerve stimulation.

The role of the cardiac muscarinic-receptor-coupled nitric oxide (NO) pathway in the cholinergic control of heart rate (HR) is controversial. We investigated whether adding excessive NO or its intracellular messenger cGMP could significantly modulate the HR response to vagal nerve stimulation (VNS) in the anesthetized rabbit and isolated guinea pig atria. The NO donor molsidomine (0.2 mg/kg iv) significantly enhanced the decrease in HR seen with right VNS (5 Hz, 5 V, 30 s) in vivo. A qualitatively similar effect was seen with the NO donor sodium nitroprusside (SNP; 10 and 100 microM) during VNS in vitro. This effect was still present when the baseline shift in HR caused by SNP was eliminated by using the specific hyperpolarization-activated current antagonist 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride (ZD-7288, 1 microM). The accentuated decrease in HR with SNP during VNS was mimicked by the stable analog of cyclic GMP, 8-bromoguanosine 3',5'-cyclic monophosphate (0.5 mM). This, however, was not seen with bath application of the stable analog of acetylcholine, carbamylcholine chloride (100 nM). We conclude that excessive NO enhances the magnitude of the decrease in HR caused by VNS. This effect appears to involve a presynaptic action via a cGMP-dependent pathway because it was not mimicked by bath-applied carbamylcholine chloride.

Optimal levels of nitric oxide are crucial for implantation in mice.

This study was performed to clarify the critical role of optimal levels of nitric oxide on fecundity in mice during the implantation period. Mature female pregnant mice were treated with either nitric oxide donor molsidomine (3, 15, 60 mg kg(-1)) or nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-name; 0.3, 1.5, 6 mg kg(-1)) every 12 h, seven times from the night of Day 2 to Day 5 of gestation. They were killed on Day 14 of gestation. Pregnancy rates in each group (n = 22) and the number of live or absorbed fetuses in each mouse was calculated. The pregnancy rates in the experimental group were reduced in a dose-dependent manner. The rate in the control group was 100%, whereas those in the 60-mg molsidomine and 6-mg L-name groups were 40.9 and 31.8%, respectively. Histological analysis of uteri on Day 5 of gestation after treatment with 60 mg molsidomine or 6 mg L-name suggested retarded decidualization of stromal cells or defective function of predecidualized cells. In conclusion, optimal levels of nitric oxide are crucial for endometrial function and embryo implantation.

Effect of nitric oxide donor molsidomine on gastric emptying in humans

Effect of nitric oxide donor molsidomine on gastric emptying in humans

The Role of the Nitric Oxide (NO) Pathway in the Discriminative Stimuli of Amphetamine and Cocaine

SKI. The role of the nitric oxide (NO) pathway in the discriminative stimuli of amphetamine and cocaine. PHARMACOL BIOCHEM BEHAV 59(3) 703–708, 1998.—To examine the role of the nitric oxide (NO) pathway in the stimulus effects induced by some psychostimulants, separate groups of rats were trained to discriminate between amphetamine (AMPH; 0.5 mg/kg) and saline, or cocaine (COC; 5 mg/kg) and saline using a standard two-lever operant procedure. Substitution studies showed that AMPH and COC generalized for the training drugs in a dose-dependent manner, their ED 50 values being 0.1 mg/kg and 1.2 mg/kg, respectively. The dose–response function of both those psychostimulants did not change in the course of the experiment. Moreover, AMPH and COC induced crosssubstitution effects towards each other. Successive combination tests demonstrated that injection of a fixed dose of the NO synthase (NOS) inhibitor 7-nitro indazole (7-NI; 25 mg/kg) plus different doses of AMPH or COC resulted in a leftward shift in the dose–response curves of those psychostimulants and a decrease in their ED 50 values. On the other hand, pretreatment with the NO donor molsidomine (MOL), injected in a fixed dose of 100 mg/kg before AMPH and COC, shifted the dose–response curves of the psychostimulants to the right and increased their ED 50 values. Our results indicate that NO plays an inhibitory role in the dopamine (DA)-evoked discrimination effects of AMPH and COC in rats.

Atrial natriuretic peptide, cyclic GMP analogues and modulation of guanylyl cyclase do not alter stimulated POMC peptide release from perifused rat or sheep corticotrophs.

Corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) are two potent stimulators for secretion of proopiomelanocortin (POMC)-derived hormones, from corticotrophs. CRH also stimulates POMC synthesis. Atrial natriuretic peptide (ANP) has been reported to inhibit POMC peptide release and is thought to act through cGMP signalling pathways. A multicolumn cell perifusion system was used to investigate the role of cGMP signalling pathways in CRH- and AVP-stimulated POMC peptide release from primary cultures of ovine or rat anterior pituitary cells. The CRH and/or AVP stimulations were applied at 30 min intervals as 5 min pulses, and the various treatments were infused over a period of 50 min, overlapping with 2 of the stimulations. ANP (10 nM) had no effect on beta-endorphin (betaEP) release from ovine cells, stimulated by 0.5 nM CRH and 5 nM AVP together, or 5 nM CRH and 50 nM AVP separately. Rat anterior pituitary cells were stimulated with 0.05 nM CRH/0.5 nM AVP or 0.5 nM CRH/5 nM AVP and treated with 1 nM or 10 nM ANP, respectively. No inhibition of ACTH or betaEP was observed. Similarly, the nitric oxide donors molsidomine (100 microM), SIN-1 (100 microM) and NaNO2 (100 microM) did not inhibit betaEP release stimulated by 0.5 nM CRH/5 nM AVP in ovine cells. The cGMP analogues 8-bromo-cGMP (10 microM and 100 microM) and dibutyryl cGMP (100 microM) also had no effect on betaEP and ACTH release from ovine or rat anterior pituitary cells. Dexamethasone (8 microM), a synthetic glucocorticoid known to block POMC synthesis and secretion of betaEP and ACTH by a distinct mechanism, was used as a control and suppressed CRH/AVP-stimulated betaEP secretion from ovine anterior pituitary cells. These results contrast with some previous studies and demonstrate that the cGMP signalling pathway in sheep or rat anterior pituitary cells does not directly inhibit secretion of POMC-derived hormones from corticotrophs.

Molsidomine increases endotoxic survival and decreases cytokine production.

We hypothesized that nitric oxide (NO) may exert feedback regulatory control over cytokine production and improve survival in endotoxin (ETX) shock. To test this hypothesis, we evaluated the pre-endotoxin effect of the NO donor molsidomine (MOL) on circulating tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6 levels, the production of these cytokines in the perfused liver, and endotoxic lethality in mice. Male BDF mice weighing 28-32 g were administered either 100 mg/kg MOL or saline (SAL) i.p. Thirty minutes later, the mice received either 50 mg/kg Salmonella enteriditis ETX or SAL i.p. Mice were killed at 90 min after ETX or SAL, for either the determination of plasma cytokine levels by enzyme-linked immunosorbent assays or for use in the perfused liver assessment of cytokine production. MOL treatment significantly reduced the post-ETX circulating levels of TNF to 84%, IL-1 to 65%, and IL-6 to 56%, as compared with SAL-treated ETX controls. Endotoxic livers from MOL-pretreated mice produced 82% less TNF, 88% less IL-1, and 54% less IL-6 over a 2 h perfusion, as compared with SAL-treated ETX controls. MOL pretreatment also decreased lethality in ETX shock from 90 to 50% (p < .05). Therefore, NO may provide a beneficial effect during sepsis by inhibiting hepatic cytokine production, and thus providing survival benefits.

L-arginine is unlikely to exert neuroendocrine effects in humans via the generation of nitric oxide.

There is now considerable evidence that nitric oxide is an important neuroregulatory agent, but there has been very little investigation of its possible role in neuroendocrine mechanisms in humans. We have investigated the effects of two nitric oxide precursors, L-arginine and molsidomine, under basal conditions on the pituitary hormones growth hormone (GH), prolactin, luteinizing hormone, follicle-stimulating hormone, thyrotrophin, adrenocorticotrophin (ACTH) and vasopressin, and also on serum cortisol; we have also studied the effect of L-arginine on circulating prolactin, ACTH and cortisol in normal human subjects under hypoglycaemic stress. L-Arginine stimulated both GH and prolactin release under basal conditions but had no effect on the other hormones studied, while the nitric oxide donor molsidomine showed no effect on any hormone studied. L-Arginine potentiated the hypoglycaemia-stimulated release of ACTH but did not influence the rise in GH. The current studies suggest that the effects of L-arginine on the stimulation of GH and prolactin release are unlikely to be mediated via the generation of nitric oxide.

Pharmacological evidence that nitric oxide can act as an endogenous antipyretic factor in endotoxin-induced fever in rabbits

1. 1. This study investigates the effects of the nitric oxide donors on lipopolysaccharide-induced fever in rabbits, and the effect of brain nitric oxide synthase inhibition on the febrile response in pyrogen tolerant animals. 2. 2. The febrile response was reduced by intravenous injections of the nitric oxide donors molsidomine (1.0 mg/kg) and isosorbide dinitrate (0.5 mg/kg) 60min after intravenous treatment with lipopolysaccharide. 3. 3. The magnitude of fever was also attenuated by intracerebroventricular administration of molsidomine (75 μg). 4. 4. Intracerebroventricular pretreatment with the nitric oxide synthase inhibitor, N G-nitro- l-arginine (100μg) 10 min before the injection of lipopolysaccharide significantly enhanced the febrile response in pyrogen tolerant animals. 5. 5. The results suggest that nitric oxide is involved in the central mechanisms of thermoregulation during fever as one of the effective endogenous antipyretics.