Administration Of Molsidomine Research Articles

Protectoral action of molsidomin ATP combination in chronic stress in young and old rats

Adaptive reactions to chronic stress, reaching a certain intensity, can become harmful and be involved in any pathological process. Therefore, the search for new ways to increase the adaptive capacity reduced with age and the body's resistance to the negative effects of chronic stress remains relevant. The aim of the study was to experimentally study the age-related protective properties of the combination of molsidomine and ATP in chronic mild stress. The experiments were performed on young (6 months) and old (26 months) Wistar rats exposed to stressors that changed periodically at random for 8 weeks. During the 6-8th week of the experiment, against the background of stress, the animals were sublingually administered a pharmacological combination based on molsidomine - 2 mg / kg, ATP - 10 mg / kg. It was found that the adaptive reactions of young and old animals to chronic stress have qualitative and quantitative differences. Chronic stress in old rats caused changes in behavior and psycho-emotional state, deterioration of cognitive function, changes in lipoperoxidation. On the part of the immune system in old rats, against the background of a pronounced age involution of lymphoid organs, no significant changes in thymus mass and cellularity were observed during chronic stress, while the mass and cellularity of the spleen increased. The combination of molsidomine and ATP prevented post-stress changes in animal behavior, reduced anxiety, normalized social activity, restored the lost ability to recognize, improved cognitive function. The drug contributed to the preservation of the function of immunocompetent organs in young animals and to a lesser extent showed a protective effect in older animals against the background of involutional changes caused by both aging and chronic stress. The combination of molsidomine and ATP had an antioxidant effect. Thus, in chronic mild stress, older animals showed a different response from young animals to both stress and the administration of molsidomine with ATP. The applied pharmacological combination can be considered as a promising stress-protective agent that has a complex effect on various pathogenetic links of chronic stress due to its neuro- and immunomodulatory, energy-saving, antioxidant properties. Keywords: aging, chronic stress, anxiety, social activity, cellularity of the thymus and spleen, lipid peroxidation, combination of molsidomine and ATP, pharmacological action.

Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage

BackgroundPatients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological–clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD).MethodsIn this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule.ResultsVery likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8–6, modified Rankin Scale (mRS) 0–1 or National Institutes of Health Stroke Scale (NIHSS) 0–2.ConclusionsEven in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.

Contribution of the nitric oxide donor molsidomine and the antiparkinsonian drug l-DOPA to the modulation of the blood pressure in unilaterally 6-OHDA-lesioned rats.

Interaction between dopaminergic and nitrergic neurotransmission in the brain plays a crucial role in the control of motor function and in the regulation of blood pressure (BP). In Parkinson's disease (PD), dopaminergic denervation of the striatum leads to disturbances in the nitrergic system in the basal ganglia. Recently, it has been demonstrated that addition of a low dose of the nitric oxide donor molsidomine to l-DOPA therapy improves dopaminergic neurotransmission in the denervated nigrostriatal system and weakens dyskinesias in rodent models of the disease. The aim of the present study was to examine the impact of chronic administration of molsidomine (2mg/kg) and l-DOPA (25mg/kg), alone and in combination, on systolic (SBP) and diastolic (DBP) blood pressure in the anesthetized, unilaterally 6-OHDA-lesioned rats. The measurement of SBP and DBP was performed 24h after the penultimate and immediately after the last drug doses. In 6-OHDA-lesioned rats receiving saline, spontaneous, small decreases in SBP and DBP were observed during the measurements lasting 60min. Administration of molsidomine alone or in combination with l-DOPA distinctly decreased the BP in 6-OHDA-lesioned rats already after 10min compared to those treated with saline or l-DOPA alone, respectively. In both groups, the molsidomine-mediated declines in BP persisted till the end of measurement but they disappeared after 24h. Our results indicate that in this PD model molsidomine evokes a short-lasting decrease in BP in contrast to conventional antihypertensive drugs that maintain long-term effect and worsen orthostatic hypotension in parkinsonian patients.

The nitric oxide donor molsidomine induces anxiolytic-like behaviour in two different rat models of anxiety

Experimental evidence indicates the implication of the nitric oxide (NO) in anxiety. Contradictory results were reported however, concerning the effects of NO donors in animal models of anxiety disorders. The present study investigated the effects of the NO donor molsidomine on anxiety-like behaviour and compared them with the anxiolytic diazepam in rats. For this purpose, the light/dark and the open field tests were used. The effects of molsidomine on motility were also assessed. Intraperitoneal (i.p.) administration of molsidomine (1 and 4mg/kg) did not influence rats' performance either in the light/dark or in the open field test. Administration of 2mg/kg molsidomine significantly prolonged the time spent in the light chamber in the rats compared with the vehicle-treated animals, did not affect the first latency to enter the dark chamber and did not influence the number of transitions between the light and dark compartments of the apparatus. In the open field test, rats that received 2mg/kg molsidomine spent more time in the central zone of the apparatus and exhibited an increment of rearing episodes compared with control and to molsidomine 1 and 4mg/kg-treated rats. Nevertheless, molsidomine, at any dose tested, did not alter locomotor activity compared with vehicle-treated rats in a motility test. The present results indicate that the 2mg/kg molsidomine induced anxiolytic-like effects in the light/dark and open field tests in the rat cannot be attributed to changes in locomotor activity. The magnitude of the molsidomine (2mg/kg)-induced anxiolytic-like effects was not different to that produced by the benzodiazepine anxiolytic diazepam (1mg/kg).

Molsidomine, a nitric oxide donor, modulates rotational behavior and monoamine metabolism in 6-OHDA lesioned rats treated chronically with L-DOPA

Some biochemical and histological studies of Parkinson’s disease patients’ brains and 6-OHDA-lesioned rats suggest that dopaminergic dennervation of the striatum leads to the nitrergic system hypofunction in this structure. Hence, recently the modulation of nitric oxide (NO)– soluble guanylyl cyclase–cyclic GMP signaling is considered to be a new target for the treatment of Parkinson’s disease. The aim of our study was to examine the impact of chronic combined treatment with low doses of the NO donor molsidomine (2 and 4mg/kg) and L-DOPA (12.5 and 25mg/kg) on rotational behavior and monoamine metabolism in the striatum (STR) and substantia nigra (SN) of unilaterally 6-OHDA-lesioned rats.Chronic administration of molsidomine at a dose of 2mg/kg jointly with 25mg/kg of L-DOPA significantly decreased the number of contralateral rotations when compared to L-DOPA alone. Other combinations of the examined drug doses were less effective. The tissue DA levels in the ipsilateral STR and SN after the last chronic doses of molsidomine (2mg/kg) and L-DOPA (12.5 or 25mg/kg), were significantly higher than after L-DOPA alone. Chronic L-DOPA treatment alone or jointly with a lower dose of molsidomine decreased 5-HT levels and accelerated its catabolism in the examined structures. However, combination of a higher dose of molsidomine with L-DOPA (25mg/kg) did not reduce 5-HT content while its catabolism was less intensive. The obtained results show that low doses of molsidomine can modulate rotational behavior and tissue DA and 5-HT concentrations in the STR and SN of 6-OHDA-lesioned rats treated chronically with L-DOPA.

The nitric oxide (NO) donor molsidomine antagonizes scopolamine and l-NAME-induced performance deficits in a spatial memory task in the rat

Nitric oxide (NO) is considered as an intracellular messenger in the brain. Its involvement in learning and memory processes has been proposed. Compounds that inhibit NO synthase (NOS), the key synthesizing enzyme, may inhibit cognition, while NO donors may facilitate it. The present study was designed to investigate the effects of the NO donor molsidomine on rats’ spatial memory. Thus, the ability of molsidomine (2 and 4 mg/kg, i.p.) in attenuating spatial memory deficits produced either by the muscarinic receptor antagonist scopolamine (0.2 mg/kg, s.c.) or by the NOS inhibitor l-NAME (30 mg/kg, i.p.) was assessed. For this aim, the object location test was selected. In the first study, molsidomine (4 mg/kg) counteracted the scopolamine-induced performance deficits in this spatial memory task. Subsequently, pre-training administration of molsidomine (4 mg/kg but not 2 mg/kg) antagonized also the impairing effects produced by l-NAME in the object location paradigm. These results indicate that NO is involved in spatial recognition memory and that an NO component modulates the effects of the cholinergic system on spatial memory.

Comparative effects of once-daily molsidomine in coronary patients from two distinct European ethnicities

Molsidomine, a direct nitric oxide donor, is frequently used in several European countries for the treatment of stable angina. The aim of this study was to compare the effects of a new once-daily 16-mg dose formulation, Coruno (Therabel Pharmaceuticals, Loughrea, Ireland), in patients with stable angina belonging to two distinct European ethnicities. A total of 261 Hungarian and 267 Polish patients took part in this multicenter, randomized, double-blind, placebo-controlled clinical trial. Exercise testing was performed after the first administration of molsidomine and repeated after a 2-week treatment. Frequency of anginal attacks, short-acting nitroderivative tablet consumption, and incidence of adverse events were also evaluated. Demographic and clinical characteristics were significantly different in Hungarian compared with Polish patients. Hungarian patients had a lower proportion of males, were shorter in stature, had less previous smoking experience, consumed more alcohol, had less severe coronary disease (electrocardiographic evidence, rate of anginal crises, and nitroderivative consumption), and higher exercise capacity. However, molsidomine-related improvement in exercise capacity at start of the study was similar in both cohorts. After a 2-week treatment, improvement was fully maintained in Polish and only minimally reduced in Hungarian patients. Furthermore, molsidomine reduced significantly more anginal episodes and nitroderivative consumption in the more severely affected Polish cohort. Proportions of patients reporting drug-related adverse events were similar on placebo and molsidomine in both cohorts. Most of the adverse events were not severe and resolved spontaneously. Less myocardial ischemia and gender (including height, a confounding covariate) acted positively and negatively, respectively, on the higher exercise capacity of Hungarian versus Polish patients. The once-daily 16-mg molsidomine formulation is effective and has good tolerability in both patient cohorts. Molsidomine does not induce any meaningful tolerance issues in Hungarian or Polish patients with stable angina, despite significant demographic and clinical disparities.

The Prophylactic Effect of L-arginine in Acute Ischaemic Colitis in a Rat Model of Ischaemia/reperfusion Injury

Background/Aims: The decreased synthesis of nitric oxide (NO) during ischaemia/reperfusion (I/R) has been implicated as the major underlying mechanism for the pathogenesis of acute ischaemic colitis (A.I.C.). The aim of this study was to investigate the prophylactic effect of L-arginine, a NO donor, on tissue injury during intestinal I/R, and compare its efficacy with that of exogenous vasodilators (molsidomine) and inert nitrogen-containing molecules (casein). Material and methods: One hundred forty four Wistar rats underwent occlusion of the superior mesentery artery for 30, 60 and 90 min for induction of intestinal ischaemia, followed by 90 min of reperfusion. The rats were randomly assigned to receive L-arginine, molsidomine, or casein hydrolysate. In all groups, apart of the histological study, we determined the levels of serum malondialdehyde (MDA), a reliable marker indicating the degree of the tissue damage after intestinal I/R. Results: Serum MDA levels were significantly lower in the L-arginine group compared to the untreated animals or those that had received molsidomine or casein, after a period of ischaemia of 90 minutes (p < 0.0005), as well as after a period of ischaemia of 60 or 90 minutes followed by a 90 minutes reperfusion (p = 0.011, and p < 0.0005, respectively). In addition, lesser histopathological damage was noted after the use of L-arginine compared to that caused by the administration of molsidomine and casein.Conclusion: These findings support a prophylactic effect of L-arginine in experimentally induced intestinal ischaemia. In short, L-arginine attenuates the degree of tissue damage in intestinal ischaemia and promotes healing of intestinal mucosa.

Nitric oxide donor molsidomine attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801

There is experimental evidence indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies, and ataxia). The present study was designed to investigate the efficacy of the nitric oxide (NO) donor molsidomine in counteracting these MK-801-induced behavioral effects in the rat. In a first study, post-training administration of molsidomine (at 4 but not 2 mg/kg) successfully antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, molsidomine (2 and 4 mg/kg) was shown to be unable to reverse MK-801-induced hypermotility but attenuated stereotypies (continuous movement whole cage, body sway, and head weaving) produced by MK-801. Moreover, at 4 mg/kg this NO donor counteracted MK-801-induced ataxia. Our findings indicate that molsidomine attenuates behavioral effects related to the hypofunction of the NMDA receptor suggesting that NO might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.

Intrarenal Administration of Molsidomine, a Molecule Releasing Nitric Oxide, Reduces Renal Ischemia-Reperfusion Injury in Rats

Ischemia reperfusion (I-R)-induced renal damage is reduced by systemic administration of the NO-dependent vasodilator molsidomine. The aim of this study was to estimate the effect of direct intrarenal molsidomine administration on renal dysfunction and inflammatory reaction after experimental I-R in rats, in order to assess only renal NO effects and to obviate its systemic hemodynamic action. Ischemia was induced by renal pedicle ligation (60 min) followed by reperfusion and contralateral nephrectomy. Molsidomine (4 mg/kg) was infused into the renal artery 15 min before reperfusion and its effects were compared with those of the NO-independent vasodilator hydralazine (2 mg/kg). Survival rates after 7 days were 100% in the sham-operated group and 75% in the I-R rats. Molsidomine treatment almost completely prevented the I-R-induced renal dysfunction, and survival reached 100%. Molsidomine prevented an I-R-induced increase in superoxide anion and reduced plasma levels of pro-inflammatory cytokines (TNF-α, IL-1β and IFN-γ), whereas it enhanced anti-inflammatory cytokines (IL-6 and IL-10). Inflammatory cell infiltration and cell-adhesion molecules (ICAM-1, PECAM-1, VCAM-1 and P-selectin) were lower in the molsidomine-treated kidneys than in the untreated animals. All these protective effects were not observed after hydralazine administration. In conclusion, intrarenal administration of molsidomine before reperfusion improved renal function and decreased inflammatory responses after I-R.

Protection against concanavalin A-induced hepatocyte apoptosis by molsidomine is time-dependent.

Viral hepatitis and autoimmune liver diseases cause hepatocyte apoptosis. Concanavalin A (Con A)-induced hepatitis resembles human viral hepatitis and autoimmune hepatitis. The role of nitric oxide (NO) in liver injury was controversial in different liver injury models. We hypothesize both endogenous and exogenous NO protect liver against Con A-induced liver injury. Molsidomine is metabolized into SIN-1 by the liver, and SIN-1 subsequently generates NO. So, molsidomine was used as a NO donor in this study. To study a protective role of endogenous NO in Con A-induced liver injury, mice were pretreated with a specific inducible nitric oxide synthase (iNOS) inhibitor, L-N(6)-(1-iminoethyl)-lysine (L-NIL), before Con A challenge. To study a time-dependent protection against Con A-induced liver injury, animals were either given molsidomine, a NO donor, before or after Con A administration. Serum alanine aminotranferase (ALT) was analyzed. Liver samples were subjected to DNA fragmentation assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling stain, Western blot analysis, and caspase activity assays. Animals pretreated with L-NIL had significantly increased serum ALT levels compared with those challenged with Con A alone; but pretreatment with molsidomine dramatically decreased ALT levels in L-NIL-pretreated animals or in animals that received Con A alone. Administration of molsidomine 30 minutes before or 1, 2, and 3 hours after Con A injection significantly reduced serum ALT levels and attenuated hepatocyte apoptosis from caspase inactivation. The ALT reduction was associated with inhibition of both caspase-3 and caspase-8 activation and reduction of hepatocyte apoptosis. Endogenous NO plays an important protective role against Con A-induced liver injury by reducing hepatocyte apoptosis. Administration of a NO donor early after Con A injection protects the liver from injury. This is the first study demonstrating a time-dependent inhibition of liver injury induced by Con A administration.

Long-term effect of molsidomine and pentaerythrityl tetranitrate on cardiovascular system of spontaneously hypertensive rats.

We studied the effects of long-term administration of molsidomine and pentaerythrityl tetranitrate (PETN) on the cardiovascular system of spontaneously hypertensive rats (SHR). One control and three experimental groups of 10-week-old animals were used: 1) control Wistar rats, 2) SHR, 3) SHR treated with molsidomine in tap water (100 mg/kg/day, by gavage), and 4) SHR treated with PETN in tap water (200 mg/kg/day, by gavage). After six weeks, the content of cGMP in platelets and NO synthase (NOS) activity in aortas were evaluated in the experimental groups. For morphological evaluation the rats were perfused at 120 mm Hg with a glutaraldehyde fixative and the arteries were processed for electron microscopy. Blood pressure and heart weight/body weight ratio (HW/BW) were increased in all experimental groups with respect to the controls. HW/BW was lower in the molsidomine group in comparison to both SHR and PETN-treated group. The platelet content of cGMP was increased and the activity of NOS in the aortas was decreased in the molsidomine and PETN-treated groups. Wall thickness and cross-sectional area of thoracic aorta, carotid artery and coronary artery were increased similarly in all experimental groups compared to the controls, but there were no differences among the experimental groups. We summarize that long-term administration of exogenous NO donors did not improve pathological changes of the cardiovascular system in SHR.

Contrasting effects of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide.

Among the many actions of nitric oxide (NO) are those on endocrine and feeding behaviour. Based on NO involvement in the GH-releasing effect of the GH-releasing peptides (GHRPs) and the reported orexigenic activity of these compounds, we sought to evaluate the effect of the combined administration of a long-acting NO donor, molsidomine, and the newly synthesized GHRP EP92632 on food intake and GH secretion in rats. Moreover, to verify the specificity of a potential NO involvement, we evaluated whether or not the effects of GHRPs were abolished by a pre-treatment with an inhibitor of NO synthase, N-nitro-arginine-methyl-ester (NAME). In the food intake experiments, adult Sprague-Dawley male rats underwent acute administration of: (1) EP92632 (160 microg/kg, s.c.); (2) molsidomine (100 mg/kg, i.p.); (3) EP92632+molsidomine; (4) l-NAME (40 and 60 mg/kg, i.p.); (5) EP92632+l-NAME (60 mg/kg, i.p.); (6) EP92632+molsidomine+l-NAME (60 mg/kg, i.p.); and (7) 0.9% saline (0.1 ml/kg, i.p.). After treatments, the cumulative food intake in the 6 post-treatment hours was carefully evaluated. In the neuroendocrine experiments, rats were given the same compounds according to the above reported schedule, except for the use of one dose of NAME (60 mg/kg, i.p.) and a lower EP92632 dose (80 microg/kg, s.c.), and were sampled via atrial cannula. EP92632 significantly stimulated food intake, an effect which was further enhanced by molsidomine, though the latter did not elicit per se any orexigenic effect. l-NAME given alone significantly decreased food intake and abolished the orexigenic effect of the GHRP and the enhancing effect of molsidomine. Plasma GH levels increased significantly following administration of EP92632 but, in contrast to the food intake experiments, molsidomine significantly inhibited both basal and EP92632-stimulated GH secretion; moreover, NAME had a biphasic effect on the EP92632-stimulated GH release: initially inhibitory and then, from 45 min on, stimulatory. NAME did not affect basal GH levels but, surprisingly, combined administration of molsidomine and NAME induced a striking inhibition of both basal and the peptide-stimulated GH release. In summary, these data indicate that NO in the rat is physiologically involved in a stimulatory way in the GHRP-mediated effect on food intake, but exerts a dual action, probably stimulatory at hypothalamic and inhibitory at pituitary levels, on basal and GHRP-stimulated GH secretion.

The effects of the nitric oxide donor molsidomine prevent in warm ischemia-reperfusion injury of the rat renal--a functional and histophatological study.

Aim of this experimental study is to verify the protective effect of molsidomine on the renal function and structural modifications in the ischemia-reperfusion rat kidney. Sixty-eight male Sprague-Dawley rats, which were right nephrectomized and occluded left renal artery for 60 minutes were used. Group I (n = 10) Sham-Operated animals, which only underwent right nephrectomy. Group II (n = 20) Untreated ischemic rats, which underwent left renal ischemia by occlusion of the renal artery for 60 minutes before blood flow was restored. Group III (n = 18) Molsidomine treated ischemic rats, Group IV (n = 20) L-NAME (N(G)-nitro-L-arginine methyl ester) treated ischemic rats. Serum creatinine and blood urea nitrogen (BUN) were measured daily and biopsies were obtained from the remaining left kidneys. At seventh day, 55% and 50% of the rats remained alive at the G-II and G-IV respectively. Molsidomine treated rats (G-III) were alive and healthy at day 7. The serum creatinine and BUN levels were significantly higher in G-II and G-IV when compared with the sham-operated group (G-I). G-III rats showed a rapid return to the normal serum creatinine and BUN values on postoperative days 1, 2, 3 and 4. The obtained values in G-II were significantly lower in comparison to the values of G-II and G-IV. The most severe damage (grade 3 to 4) was determined in the kidneys of rats from GII or GIV. The degree of renal tubular damage in GIII was evaluated as grade 1 or 2 tubular damage according to Jablonkski's scale. Our findings suggested that the administration of molsidomine may vanquish the pernicious effects of warm ischemia on kidney structure and function.

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.

Elevation of circulating NO: its effects on hemodynamics and vascular smooth muscle cell proliferation in rats.

Object of our study was to characterize the effects of elevated circulating NO on hemodynamics and vascular smooth muscle cell proliferation in rats. Administration of molsidomine (10, 25, 50 mg/kg, bid p.o.) was followed by pharmacodynamic effects: elevation of plasma nitrite/nitrate levels and reduction of blood pressure (25 and 50 mg/kg, bid p.o.). Under these conditions no antiproliferative activity occurred in a model of "air dried" carotid artery injury. From these results we conclude that NO does not act as an antiproliferative agent under conditions where smooth muscle cell injury predominates.

Cardioprotection by molsidomine and iloprost in myocardial ischemia in anaesthetized cats.

In ten anaesthetized open chest cats the ligation of left descending coronary artery (LLDCA) resulted in 80 percent of mortality with survival time of 40.9 +/- 8.6 min. The death of animals was preceded by premature ventricular contractions which occurred with frequency 7.3 +/- 0.6/min after 2.1 +/- 0.3 min following LLDCA. Molsidomine as a dose of 20 micrograms/kg given i.v. to 10 cats 15 min before LLDCA affected none of the above characteristics of acute myocardial ischemia. The pretreatment with iloprost (2 micrograms/kg given i.v. to 10 cats) diminished frequency of premature ventricular contractions and elongated a period of time required for their occurrence after LLDCA, however, iloprost was also unable to diminish mortality of LLDCA cats. Only a combined administration of molsidomine and iloprost significantly diminished mortality among LLDCA cats down to 20 percent and doubled their survival time as compared to the controls. It is concluded that NO-donors (molsidomine) exert permissive effect towards the cardioprotective action of prostacyclin analogues (iloprost) in cats with myocardial ischemia. LLDCA cats pretreated with molsidomine + iloprost enjoyed a more complete cardioprotection than those pretreated with a high dose (3000 units/kg i.v.) of superoxide dismutase.

Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats

1. A series of experiments was performed in conscious, unrestrained, male, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics. 2. Infusion of glyceryl trinitrate (GTN, 0.1 mg kg-1 min-1, i.v.) for 10 min elicited tachycardia, but no sustained change in mean arterial blood pressure. Renal haemodynamics were unaffected, but there were reductions in hindquarters flow and vascular conductance together with substantial increases in flow and conductance in the mesenteric vascular bed. 3. In the presence of captopril (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) GTN elicited significant hypotension and increases in renal blood flow and vascular conductance, indicating that activation of the renin-angiotension system opposed the dilator effects of GTN in this vascular bed. However, the mesenteric and hindquarters haemodynamic effects of GTN were not affected by captopril. In contrast, in the presence of enalaprilat (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) there was significant enhancement of the mesenteric, as well as renal, haemodynamic effects of GTN. Hence, these results provide no evidence for the sulphydryl groups in captopril exerting a specific effect to enhance the haemodynamic actions of GTN in our experimental protocols. 4. Administration of molsidomine alone (1 mg kg-1, i.v. bolus) elicited tachycardia and hypotension; there were no changes in mesenteric or hindquarters haemodynamics, but renal flow and vascular conductance fell. Thus, the hypotensive effect of molsidomine was probably due to a reduction in cardiac output, consequent upon venodilatation. 5. In the presence of captopril or enalaprilat, molsidomine evoked renal and mesenteric vasodilatations in association with hypotension, indicating that activation of the renin-angiotensin system contributed to the lack of vasodilator responses to administration of molsidomine alone. However, since the effects of enalaprilat were more marked than those of captopril (in spite of the dose of both drugs being supramaximal for inhibition of angiotensin-converting enzyme), other factors must have been involved. 6. In a separate experiment, pretreatment with the nitric oxide synthesis inhibitor, N0-nitro-L-arginine methyl ester (1 mg kg- 1 h-1, i.v.), enhanced the mesenteric vasodilator effect of molsidomine. Collectively, these results are consistent with in vitro data showing that endogenous nitric oxide can inhibit the vasodilator effects of nitric oxide derived from molsidomine, and that the sulphydryl groups of captopril can protect endogenous nitric oxide from inactivation by oxygen-derived free radicals, thereby enhancing the inhibitory effect of endogenous nitric oxide on the vasodilator responses to exogenous nitric oxide derived from molsidomine (or GTN).

Pathophysiological aspects of predominant preload lowering on pulmonary circulation, gas exchange, and the biventricular function in patients with chronic obstructive lung disease.

A group of 21 patients with various degrees of chronic obstructive pulmonary disease underwent radionuclide ventriculography with hemodynamic monitoring to assess the extent to which pulmonary artery pressures and pulmonary vascular resistance can be lowered by the vasodilator molsidomine. Molsidomine (N-carboxy-3-morpholino-sydnonimin-ethylester) is similar to nitroglycerin in its mode of action. After hemodynamic and radionuclide data acquisition, at rest and during submaximal exercise in the steady state, 2 mg molsidomine was injected intravenously. Rest and exercise measurements were repeated 45 min after molsidomine injection. In patients with mild to moderate disease (group 1), pulmonary artery resting pressures decreased by 12% (p less than 0.05) at rest by 22% (p less than 0.01) during exercise after the administration of the drug. Total pulmonary resistance during exercise decreased significantly (p less than 0.01) as a result of marked decrease of pulmonary artery pressure (PAP) compared with a minimal decrease in cardiac index (CI). In patients with severe disease (group 2), only the resting values of PAP decreased while the relationship between pressure and flow was unchanged. During the exercise period, the preload parameters of the right and left ventricles decreased by an average of 30%. With regard to gas exchange, only the arterial PO2 at rest decreased slightly but significantly (p less than 0.05) after molsidomine, while the coefficient of oxygen delivery was not affected by the drug. However, in four patients arterial PO2 was markedly reduced by the drug. Right ventricular ejection fraction increased significantly (p less than 0.01) both at rest and during exercise in group 1 and during exercise in group 2 after administration of molsidomine.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic effects of molsidomine in patients with severe chronic coronary disease.

The haemodynamic effects of a single dose of intravenous molsidomine were assessed in 12 patients with severe coronary disease. The investigation was carried out at rest during angina induced by pacing and after molsidomine during pacing at the rate at which angina had been produced. During angina, left ventricular systolic and end-diastolic pressure rose, left ventricular stroke work fell and coronary flow and myocardial oxygen consumption increased by 58.3% above the control levels. After the administration of molsidomine, atrial stimulation was not followed by angina and there were no significant changes in systolic blood pressure. Left ventricular end-diastolic pressure fell sharply and coronary flow and myocardial oxygen consumption were only 38% and 33% higher, respectively, than the control levels. The beneficial effects of molsidomine in ischaemic heart disease, therefore, are the result of peripheral vasodilation which, by reducing the preload and afterload, lowers the oxygen requirements of the myocardium and thus increase the threshold for angina. A direct action on the coronary network can not be excluded but if such an action does exist it must be very small in the light of the marked systemic effect.