Effects Of Isosorbide Dinitrate Research Articles

Isosorbide DiNitrate Effect on Hemodynamic Profile, Liver Stiffness, and Exercise Tolerance in Fontan Circulation (The NEET Clinical Trial)

After Fontan operation, decreased venous capacitance and venoconstriction are adaptive mechanisms to maintain venous return and cardiac output. The consequent higher venous pressure may adversely impact end-organ function, exercise capacity and result in worse clinical outcomes. This pilot study evaluated the safety and effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after 4 weeks of therapeutic treatment with ISDN. Primary aims were to assess the safety of ISDN and the effect on maximal exercise. We also aimed to evaluate the effect of ISDN on ultrasound-assessed liver stiffness, markers of submaximal exercise, and PVP at rest and peak exercise. Repeated measures t-tests were used to assess change in variables of interest in response to ISDN. Mean age was 23.5 ± 9.2years (range 11.2-39.0years), and 10/15 (67%) were male. There was no statistically significant change in peak VO2 (1401 ± 428 to 1428 ± 436mL/min, p = 0.128), but VO2 at the anaerobic threshold increased (1087 ± 313 to 1115 ± 302mL/min, p = 0.03). ISDN was also associated with a lower peak exercise PVP (22.5 ± 4.5 to 20.6 ± 3.0mmHg, p = 0.015). Liver stiffness was lower with ISDN, though the difference was not statistically significant (2.3 ± 0.4 to 2.1 ± 0.5m/s, p = 0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Treatment with ISDN for 4weeks is well-tolerated in patients with a Fontan circulation. ISDN is associated with an increase in VO2 at anaerobic threshold, lower peak PVP, and a trend toward lower liver stiffness. Larger, longer durationstudies will be necessary to define the impact of ISDN on clinical outcomes in the Fontan circulation.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT04297241.

Abstract 11838: Isosorbide Dinitrate Effect May Improve Exercise Tolerance, Venous Pressure and Liver Stiffness in Patients With Fontan Circulation (The NEET Clinical Trial)

Introduction: After the Fontan operation, decreased venous capacitance (venoconstriction) and elevated central venous pressure may result in worse clinical outcomes, worse exercise capacity, and increased liver stiffness. This pilot study evaluated the acute effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. Methods: In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after four weeks of treatment with ISDN. Cardiopulmonary exercise testing was performed to assess exercise tolerance, with a primary outcome of peak oxygen consumption (peak VO 2 ). The secondary outcome included VO 2 at the anaerobic threshold (AT VO 2 ), PVP at rest and peak exercise and liver stiffness measured by ultrasound prior to the exercise test. Repeated measure t-test was used to test for differences in outcomes in response to ISDN. Results: The mean age was 23.5 ± 9.2 years (range 11.2-30.6 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO 2 from baseline (1401±428 to 1428±436 ml/min, p=0.128), but there was an improvement in AT VO 2 (1087 ± 313 to 1115 ±302 mL/min, p= 0.03). Treatment with ISDN was associated with lower peak exercise PVP (22.5 ±4.5 to 20.6 ± 2.99 mmHg, p=0.015) without a notable difference in the resting PVP (p=0.357). There was a trend towards lower liver stiffness with ISDN (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p=0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Conclusions: Treatment with ISDN for 4 weeks is well-tolerated except for headache and appears safe in patients with a Fontan circulation. ISDN therapy was associated with improvements in certain exercise and hemodynamic parameters as well as a trend towards lowering liver stiffness. Larger studies will be necessary to validate these physiologic findings and further evaluate the effects of nitrates on meaningful clinical outcomes.

Can isosorbide dinitrate oral spray serve as an immediate bridging therapy for a mass cyanide poisoning?

Objective In this proof-of-concept study, the aim was to evaluate the short-term clinical effectiveness of isosorbide dinitrate (ISDN) oral spray in non-anaesthetized cyanide-poisoned swine. Methods A comparative study was conducted using domestic swine. Animals were intravenously poisoned with potassium cyanide (KCN), either 2 mg/kg or 4 mg/kg dose. Two control groups (one for each cyanide dose) were not further treated. Two other groups (one for each cyanide dose) were treated within 1 min after poisoning with ISDN oral spray: 3 spray actuations (averaging a total of 3.75 mg) after the lower cyanide dose and 4 spray actuations (averaging a total of 5.0 mg) after the higher dose. The study outcomes were clinical score, time to death, and blood tests including pH, lactate, and methemoglobin levels. Results All the animals started to convulse within 20 to 30 sec after KCN poisoning, then became unresponsive and hemodynamically depressed after another 20 to 30 sec. After the KCN 2 mg/kg dose, 3 of 4 control animals survived, while all treated animals survived. Compared with control animals, ISDN-treated animals displayed significantly better clinical scores starting 5 min after KCN poisoning. Acidosis was significantly more pronounced in the untreated animals. After the KCN 4 mg/kg dose, similar survival rates were observed for control and ISDN-treated groups (1/4), but treated animals had longer time to death and better pH and lactate levels. Conclusion ISDN oral spray administration following KCN poisoning in this porcine model did not result in statistically significant increased survival. However, based on clinical scores and clinical laboratory values, ISDN may benefit as a bridging countermeasure until currently-available specific cyanide antidotes can be administered. Further research is warranted to better characterize this potential role of ISDN in cyanide poisoning.

The effect of isosorbide dinitrate on cardiac function after cardiopulmonary resuscitation in a porcine model

Objective To assess the effect of isosorbide dinitrate on the improvement of cardiac function after cardiopulmonary resuscitation (CPR) by regulating myocardial cells apoptosis.. Methods Total of 30 domestic pigs were divided into three groups randomly (random mumber) after anesthetization: the sham group (n=6), the control group (n=12), and the isosorbide dinitrate group (n=12). Cardiac arrest of ventricular fibrillation was induced by programed electrical stimulation in the control and isosorbide dinitrate groups. Isosorbide dinitrate was infused at the rate of 2 μg/(kg·min) in the isosorbide dinitrate group. Coronary perfusion pressure (CPP) and cardiac output (CO) were recorded at baseline, 2, 6, 12 and 24 h after restoration of spontaneous circulation (ROSC). Myocardial enzyme and heart fatty acid binding protein (H-FABP) was tested at the same time points. At 24 h after ROSC, the animals were sacrificed to obtain the myocardium for pathological section and Western blot. The expression of Bcl-2, Bax and activated Caspase-3 were tested and apoptosis was tested by TUNEL and apoptosis index was calculated. Results Right atrial pressure (RAP) increased after ROSC and decreased in the isosorbide dinitrate group compared with the control group (P<0.05). CPP at 12, 24 h after ROSC and CO at 24 h after ROSC in the isosorbide dinitrate group increased significantly compared with the control group (both P<0.05). HE staining revealed that the injury of myocardial cells was ameliorated in the isosorbide dinitrate group. Apoptosis index of the isosorbide dinitrate group significantly decreased than the control group [(37.8±15.5)% vs (13.1±0.5)%, P<0.05]. The expression of Bax and activated Caspase-3 decreased while Bcl-2 and Bcl-2/Bax increased after ROSC in the isosorbide dinitrate group compared with the control group (all P<0.05). Conclusions Isosorbide dinitrate could improve the ischemia/reperfusion injury and cardiac function after ROSC by inhibiting apoptosis regulated with Caspase-3 pathway. Key words: Cardiac Arrest; Cardiopulmonary Resuscitation; Isosorbide Dinitrate; Cardiac Function; Myocardial Enzyme

Effect of Ibuprofen on Skeletal Muscle of Dysferlin-Null Mice.

Ibuprofen, a nonsteroidal anti-inflammatory drug, and nitric oxide (NO) donors have been reported to reduce the severity of muscular dystrophies in mice associated with the absence of dystrophin or α-sarcoglycan, but their effects on mice that are dystrophic due to the absence of dysferlin have not been examined. We have tested ibuprofen, as well as isosorbide dinitrate (ISDN), a NO donor, to learn whether used alone or together they protect dysferlin-null muscle in A/J mice from large strain injury (LSI) induced by a series of high strain lengthening contractions. Mice were maintained on chow containing ibuprofen and ISDN for 4 weeks. They were then subjected to LSI and maintained on the drugs for 3 additional days. We measured loss of torque immediately following injury and at day 3 postinjury, fiber necrosis, and macrophage infiltration at day 3 postinjury, and serum levels of the drugs at the time of euthanasia. Loss of torque immediately after injury was not altered by the drugs. However, the torque on day 3 postinjury significantly decreased as a function of ibuprofen concentration in the serum (range, 0.67-8.2 µg/ml), independent of ISDN. The effects of ISDN on torque loss at day 3 postinjury were not significant. In long-term studies of dysferlinopathic BlAJ mice, lower doses of ibuprofen had no effects on muscle morphology, but reduced treadmill running by 40%. Our results indicate that ibuprofen can have deleterious effects on dysferlin-null muscle and suggest that its use at pharmacological doses should be avoided by individuals with dysferlinopathies.

Effectiveness of isosorbide dinitrate in cyanide poisoning as a function of the administration timing

BackgroundBetter and safer antidotes against cyanide poisoning are needed. Prior study has shown a favorable effect of isosorbide dinitrate (ISDN) on the survival of cyanide-poisoned rabbits when administered as early as 1 min after poisoning. The aim of the current study was to further evaluate the efficacy of intravenous ISDN administered in clinically relevant timing for first responders.MethodsA comparative animal study using 24 rabbits in 4 randomized study groups was performed. Animals were poisoned with intravenous potassium cyanide (1 mg/kg). Animals in Group 1 served as controls and received no treatment. Groups 2–4 animals were treated intravenously with ISDN (50 μg/kg) after poisoning; one group after 3 min, another group after 5 min and the last after 7 min. Animals were observed for 30 min after poisoning. The study endpoints included survival rate, clinical status, blood pressure, pulse per minute, blood lactate and pH.ResultsFive of 6 animals (83.3%) from every treatment group survived the whole observation period while all control untreated animals died. All the rabbits collapsed immediately after exposure, showing rapidly deteriorated vital signs with lactic metabolic acidosis (peak blood lactate levels of 18.1 to 19.0 mmol/L on average at 10 min post exposure). Vital signs, clinical scores, and blood gases of treated rabbits gradually improved.ConclusionPoisoned rabbits showed improved short-term survival following the administration of ISDN up to 7 min after lethal cyanide poisoning of. We see a potential for ISDN as an antidote against cyanide poisoning.

Isosorbide dinitrate inhibits mechanical stress-induced cardiac hypertrophy and autophagy through downregulation of angiotensin II type 1 receptor.

Mechanical stress can induce cardiac hypertrophy and autophagy. Recently, it has been reported that nitric oxide donors inhibited autophagy in human chondrocytes. Therefore, the effect of isosorbide dinitrate (ISDN) on cardiac hypertrophy and autophagy induced by mechanical stress was investigated in this study. A 48-hour mechanical stretch and a 4-week transverse aortic constriction were performed to induce cardiomyocyte hypertrophy in vitro and in vivo, respectively, before the assessment of myocardial autophagy using LC3b-II. ISDN was found to significantly reduce mechanical stretch-induced LC3b-II upregulation. Furthermore, mechanical stress was shown to upregulate angiotensin II (AngII) type 1 (AT1) receptor expression in both cultured cardiomyocytes and in mouse hearts, whereas ISDN was demonstrated to significantly suppress the upregulation of the AT1 receptor. It was concluded that ISDN could inhibit mechanical stress-induced cardiac hypertrophy and autophagy through the downregulation of AT1 receptor expression.

Early administration of isosorbide dinitrate improves survival of cyanide-poisoned rabbits

Context. More effective, rapidly delivered, safer antidotes are needed for cyanide poisoning. Previous study has demonstrated a beneficial effect of isosorbide dinitrate on the survival of cyanide-poisoned mice. Objective. To evaluate the effectiveness of isosorbide dinitrate compared with that of sodium nitrite in cyanide poisoning. Materials and methods. A comparative animal study was performed using 18 rabbits, randomized into 3 study groups. Animals were poisoned intravenously with potassium cyanide (1 mg/kg). The first group was not given any further treatment. The second and third groups were treated intravenously 1 min after poisoning with sodium nitrite (6 mg/kg) and isosorbide dinitrate (50 μg/kg), respectively. The primary outcome was short-term survival of up to 30 min. Secondary outcomes included time to death, a clinical score, mean blood pressure, pulse, blood pH, and lactate and methemoglobin levels. Results. Rabbits treated with isosorbide dinitrate or sodium nitrite survived while only one untreated rabbit survived. Median time to death of the 5 poisoned and untreated animals was 10 min. All the animals collapsed soon after poisoning, exhibiting rapidly disturbed vital signs and developed lactic metabolic acidosis; average peak blood lactate levels were 15.5–19.1 mmol/L at 10 min after poisoning. The treated animals improved gradually with practically full recovery of the clinical scores, vital signs, and blood gas levels. Sodium nitrite administration raised methemoglobin to an average peak of 7.9%, while isosorbide dinitrate did not change methemoglobin levels. Conclusion. Early administration of isosorbide dinitrate improved the short-term survival of cyanide-poisoned rabbits. Isosorbide dinitrate shows potential as an antidote for cyanide poisoning and may exert its effect using a nitric-oxide-dependent mechanism.

The effect of isosorbide dinitrate on uterine and ovarian blood flow during oestrous cycle and early pregnancy in mares

It has been proposed that in mares fertility could be affected by uterine blood flow [Blaich U,et.al,. Pferdeheilkunde 1999;15:547-50].An adequate blood supply is essential for hormonal signalling, uterine contractility, placentation and feto-endometrial interactions (Le Blanc MM, Causey RC. Reprod Domest Anim 2009;44:11-22.The objective of this study was to investigate the effects of the exogenous application of the vasodilator nitric oxide donor isosorbide dinitrate (ISDN) on uterine and ovarianperfusion in cycling mares and early pregnant mares by using transrectal Doppler ultrasonography. Six Trotter mares, aged 7 to 14 years were examined daily during three oestrous cycles. Four of these mares were additionally examined during early pregnancy. Mares were treated with placebo (lactose 60 mg), a low dose of ISDN (30 mg) and a high dose of ISDN (60 mg) orally (one treatment per cycle, in random order) every 12 h from Day 1 to 11 of the cycle (Day 0 1⁄4 day of ovulation following prostaglandin-induced luteolysis). Four of these mares were additionally treated with a placebo (lactose 60mg) or ISDN (60mg) orally every 12 h fromDay 1 to 11 after insemination. The uterine and ovarian blood supplies were studied by Doppler ultrasonography of both uterine arteries and both ovarian arteries once a day

Effects of a Sustained-Release Form of Isosorbide Dinitrate on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation

The effects of isosorbide dinitrate (ISDN) have not been sufficiently investigated in conscious dogs with mitral valve regurgitation (MR). The objective was to investigate the effects of a sustained-release form of ISDN (sr-ISDN) on hemodynamics and the autonomic nervous system in dogs with MR. Six healthy Beagles weighing 11.2 ± 2.2 kg (2 years of age; 2 males and 4 females) were used. Experimental, crossover, and interventional study. Dogs with experimentally induced MR were administered placebo, 2, 5, and 10 mg/kg sr-ISDN PO on separate days with a 7-day washout period between randomized dosings. Left atrial pressure (LAP) had been recorded continuously from 30 minutes before administration of sr-ISDN to 12 hours after administration. LAP was significantly decreased after administration in the 5 and 10 mg/kg groups. Significant decrease was observed at 3 and 4 hours after administration in the 5 mg/kg group. In the 10 mg/kg group, significant decrease was observed at 2, 3, 4, 5, 6, 7, 10, and 11 hours after administration. The lowest value was observed at 4 hours after administration in the 5 and 10 mg/kg groups (20.9 ± 4.2 to 15.9 ± 3.9 mmHg, P < .01, and 21.3 ± 4.0 to 13.6 ± 4.2 mmHg, P < .001). Sustained-release form of ISDN showed significant decrease of LAP in the 5 mg/kg and 10 mg/kg groups, and duration of effect was dose related.

The effect of sublingual isosorbide dinitrate on acute urinary retention due to benign prostatic hyperplasia

Acute urinary retention (AUR) is one of the most important long-term compli-cations of benign prostatic hyperplasia (BPH). Nitric oxide (NO) as a transmitter can relax smooth muscles of the bladder neck and external sphincter. Several studies have reported that sublingual isosorbide dinitrate (ISDN), as a NO donor, can lead to significant decrease in resting pressure of the external sphincter, and its rapid onset of action may be useful in the treatment of AUR. This study was designed to asses the effect of ISDN on AUR in patients with BPH. In this clinical trial, 60 men with BPH-induced AUR were randomly selected via a simple sampling method. Participants were randomly divided into case and control groups. Patients in the case group received 200 mg of sublingual ISDN and participants in the control group received placebo. After 20 min, participants were asked to void spontaneously and the urine was collected in scale containers. Following this, urethral catheterization was done on all the participants and the residual urine was measured. Data were analyzed using SPSS version 15. There was no signi-ficant difference in the mean age of the two groups (P-value = 0.28). The mean voided urine volume in the case group was 201 mL and, in the control group, it was 18 mL (P = 0.004). About 30% in the case group and 3.3% in the control group could void spontaneously after receiving ISDN or placebo (P = 0.006). In the case group, there was a significant correlation between voided urine volume and total urine volume in the bladder (P = 0.03) and in the size of the prostate (P = 0.001). Our study shows that ISDN can be effective in the treatment of BPH-induced AUR with decrease in bladder outlet resistance. ISDN is more effective in younger men and in those with smaller prostates.

Effect of single dose oral isosorbide dinitrate tablets on the intraocular pressure

The effect of isosorbide dinitrate (ISORDIL ) on intraocular pressure (IOP)was studied using rabbits as experimental animals. There was a net decrease in IOP following administration of the drug. The study rabbits were divided into 2 groups (the 10mg per day group and the 20mg per day group) of 4 rabbits each. The initial IOP was taken before administration of the drug. The first group was given lml of 10mg/ml solution of the drug orally, once daily for five days and the second group received same regimen orally, but was given 2ml of the 10mg/ml solution. The IOP was monitored for seven days using Schiotz indentation tonometer. Statistical analysis using ANOVA showed significant difference (P>0.05) between the means of various days in the second group. There was no significant difference (P

Divergent Effects of Nitric Oxide Donors on the Biliary Efflux Transporters in Isolated Perfused Rat Livers: Nitric Oxide-Independent Inhibition of ABC Transporters by Sodium Nitroprusside

Rhodamine 123 (RH-123) and its glucuronidated metabolite (RH-Glu) are excreted into the bile via the ABC efflux transporters P-glycoprotein (P-gp) and multidrug resistance-related protein type 2 (Mrp2), respectively. In this study, we investigated the short-term (2 h) effects of a low or high concentration of nitric oxide (NO) donors sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) on the hepatobiliary disposition of RH-123 and its metabolite in an isolated perfused rat liver model. Additionally, the effects of ISDN on the hepatobiliary disposition of 5 (and 6)-carboxy-2', 7'- dichlorofluorescein (CDF), a specific marker of Mrp2, were investigated in the same model. Whereas SNP caused a substantial (85-90%) reduction in the P-gp- and Mrp2-mediated transport of RH-123 and RH-Glu, respectively, ISDN did not affect either of these transporters. However, ISDN reduced the biliary recovery of RH-Glu, most likely because of inhibition of the formation of the metabolite. Further studies showed that the effects of SNP on these transporters are due to a substantial (88%) depletion of hepatic ATP levels by this NO donor. Additionally, studies using CDF revealed an almost identical hepatobiliary disposition of this Mrp2 marker in the presence or absence of ISDN. It is concluded that short-term exposure of rat livers to NO does not affect the functions of the efflux transporters P-gp and Mrp2. The observed inhibitory effects of SNP on the functions of both P-gp and Mrp2 are via an NO-independent mechanism.

Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans.

Current therapies for muscular dystrophy are based on corticosteroids. Significant side effects associated with these therapies have prompted several studies aimed at identifying possible alternative strategies. As inflammation and defects of nitric oxide (NO) generation are key pathogenic events in muscular dystrophies, we have studied the effects of combining the NO donor isosorbide dinitrate (ISDN) and the non-steroidal anti-inflammatory drug ibuprofen. alpha-Sarcoglycan-null mice were treated for up to 8 months with ISDN (30 mg.kg(-1)) plus ibuprofen (50 mg.kg(-1)) administered daily in the diet. Effects of ISDN and ibuprofen alone were assessed in parallel. Drug effects on animal motility and muscle function, muscle damage, inflammatory infiltrates and cytokine levels, as well as muscle regeneration including assessment of endogenous stem cell pool, were measured at selected time points. Combination of ibuprofen and ISDN stimulated regeneration capacity, of myogenic precursor cells, reduced muscle necrotic damage and inflammation. Muscle function in terms of free voluntary movement and resistance to exercise was maintained throughout the time window analysed. The effects of ISDN and ibuprofen administered separately were transient and significantly lower than those induced by their combination. Co-administration of NO and ibuprofen provided synergistic beneficial effects in a mouse model of muscular dystrophy, leading to an effective therapy. Our results open the possibility of immediate clinical testing of a combination of ISDN and ibuprofen in dystrophic patients, as both components are approved for use in humans, with a good safety profile.

UP-3.065: Effects of Isosorbide Dinitrate on the Urinary Flow Rate in Patients with Benign Prostatic Hyperplasia

To compare the immediate effects of a systemic nitric oxide (NO) donor with placebo on the uroflowmetric parameters in patients with benign prostatic hyperplasia (BPH).Eighty patients with the mean age of 61.5 years (range, 49 to 74 years) who suffered from BPH were enrolled in the study. We examined peak flow rate, average flow rate, and residual urine in all the patients. Then, patients were randomized to receive either 20 mg sublingual isosorbide dinitrate (ISDN) (n = 40) or placebo (n = 40) 20 minutes prior to the second uroflowmetry, which was performed one day after the first test.The mean peak flow rate increased from 7.6 ± 0.41 mL/s to 10.2 ± 0.54 mL/s (P = .013) in the ISDN group, while it increased +0.40 mL/s in the placebo group (P > .05). Mean residual urine volume decreased significantly from 51 ± 3.1 mL to 29 ± 2.9 mL and from 56 ± 4.1 to 51 ± 2.6 in the ISDN (P = .02) and the placebo groups (P > .05), respectively. At baseline, the mean arterial pressure was 95 ± 2.1 mmHg and under the influence of the NO-donor, it decreased to 83 ± 1.9 mmHg, which was significant (P < .001). No significant changes of micturition parameters were found in the placebo group.Organic nitrates influence micturition parameters in patients with BPH. This new approach could offer a potential pharmacological option to treat obstructive lower urinary tract symptoms.

EFFECT OF ISOSORBIDE DINITRATE ON GASTRIC BLOOD FLOW IN RATS WITH LIVER CIRRHOSIS DETERMINED BY ANALYZING GASTRIC BLOOD FLOW, PORTAL VEIN PRESSURE AND BLOOD GAS

We investigated the effects of isosorbide dinitrate (IDN) on gastric blood flow (GBF), portal venous pressure (PVP) and blood gas of rats with liver cirrhosis (LC) accompanied by portal hypertension. Thirty male Wistar rats (LC in 17 and normal in 13) were used. Before and after IDN administration, GBF, PVP and blood gas in the femoral artery and portal vein were measured. Portal blood oxygen concentration was estimated by calculating the ratio of PO2 in portal blood and that in arterial blood (PpvO2/PaO2) of each rat. The GBF in the LC rats was significantly lower than that in the normal rats. In the LC group, IDN administration significantly increased the GBF. The PpvO2/PaO2 value in the group with LC was significantly lower after IDN administration than that before IDN administration. In the investigation whether changes in PVP or Ppv/PaO2 contributed more to the change in GBF after IDN administration, a significant correlation was found between rates of change in GBF and PpvO2/PaO2 were significantly correlated (r= -0.733, p <0.05). The effect of IDN on changes in the stomach accompanying portal hypertension is mainly attributable to a decrease in preload, which suppresses inflow to the stomach, as reflected by a decrease in PpvO2/ PaO2, rather than to a decrease in afterload on GBF, as reflected by a decrease in PVP.

Systemic Augmentation of Nitric Oxide: Is There an Immediate Effect on the Urinary Flow Rate in Healthy Men?

Introduction: Nitric oxide (NO) is an important neurotransmitter in the lower urinary tract. Data from experimental studies in animals and humans suggest that NO donors like isosorbide dinitrate could be used to lower the infravesical resistance. Despite the potentially significant clinical benefit of such an effect, it has hardly been studied in vivo in men. We investigated the immediate effect of isosorbide dinitrate on the urinary flow rate and the functional bladder capacity in healthy young men. Patients and Methods: A free urinary flow was measured in 20 healthy male volunteers on two consecutive micturitions. 15–25 min prior to the second micturition, 10 mg of the NO donor isosorbide dinitrate was administered sublingually. Results: We found no significant difference between baseline measurement and the micturition after NO administration with regard to the totally voided volume, the maximal or the average flow rate as well as the flow rate corrected for the voided volume. Conclusion: Systemic augmentation of NO does not produce a relevant immediate effect on the urinary flow rate or the functional bladder capacity in healthy men.

Nitroester drug’s effects and their antagonistic effects against morphine on human sphincter of Oddi motility

To evaluate the effects of nitroester drugs on human sphincter of Oddi (SO) motility and their antagonistic effects against morphine which shows excitatory effect on Oddi's sphincter motility. The effects of these drugs on SO were evaluated by means of choledochofiberoscopy manometry. A total of 67 patients having T-tubes after cholecystectomy and choledochotomy were involved in the study, they were randomly divided into glyceryl trinitrate (GTN) group, isosorbide dinitrate (ISDN) group, pentaerythritol tetranitrate (PTN) group, morphine associated with GTN group, morphine associated with ISDN group and morphine associated with PTN group. Basal pressure of Oddi's sphincter (BPOS), amplitude of phasic contractions (SOCA), frequency of phasic contractions (SOF), duration of phasic contractions (SOD), duodenal pressure (DP) and common bile duct pressure (CBDP) were scored and analyzed. Morphine was given intramuscularly while nitroester drugs were applied sublingually. BPOS and SOCA decreased significantly after administration of ISDN and GTN, BPOS reduced from 10.95+/-7.49 mmHg to 5.92+/-4.04 mmHg (P<0.05) evidently after application of PTN. BPOS increased from 7.37+/-5.58 mmHg to 16.60+/-13.87 mmHg, SOCA increased from 54.09+/-38.37 mmHg to 100.70+/-43.51 mmHg, SOF increased from 7.15+/-3.20 mmHg to 10.38+/-2.93 mmHg and CBDP increased 3.75+/-1.95 mmHg to 10.49+/-8.21 mmHg (P<0.01) evidently after injection of morphine. After associated application of ISDN and GTN, the four indications above decreased obviously. As for application associated with PTN, SOCA and SOF decreased separately from 100.64+/-44.99 mmHg to 66.17+/-35.88 mmHg and from 10.70+/-2.76 mmHg to 9.04+/-1.71 mmHg (P<0.05) markedly. The regular dose of GTN, ISDN and PTN showed inhibitory effect on SO motility, morphine showed excitatory effect on SO while GTN, ISDN and PTN could antagonize the effect of morphine. Among the three nitroester drugs, the effect of ISDN on SO was most significant.

The effects of isosorbide dinitrate on methemoglobin reductase enzyme activity and antioxidant states.

Isosorbide dinitrate (ISDN) has been used in the treatment of ischaemic cardiovascular diseases for many years. ISDN is the most popular nitric oxide donor and causes methemoglobinemia as an important side-effect. The purpose of this study was to examine antioxidant states and methemoglobin reductase activity after giving ISDN and ISDN plus vitamin E. Rats were divided into three groups according to the treatment: control group, ISDN group and ISDN plus vit. E group. We measured reduced glutathione in blood (GSH), plasma malondialdehyde (MDA), erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and NADH-dependent methemoglobin reductase activities. In the ISDN group, plasma MDA levels were significantly high compared to the control and ISDN + vit. E groups (p < 0.001). In the ISDN and ISDN + vit. E groups, blood GSH levels were higher than those of the control group (p < 0.05). Changes of SOD and GPx activities were not significant. In the ISDN and ISDN + vit. E groups the erythrocyte catalase and NADH-dependent methemoglobin reductase activities were significantly higher than that in the control group (p < 0.001). We conclude that oxidant drugs such as ISDN need to be carefully used because of lipid peroxidation and methemoglobinemia. These findings support the notion that vitamine E protects tissues against oxidative stress.

The effect of isosorbide dinitrate, a donor of nitric oxide, on maternal cerebral blood flow in gestational hypertension and preeclampsia

Objective: The purpose of this study was to investigate the effect of a nitric oxide donor on cerebral perfusion pressure and other blood flow index values in the maternal middle cerebral and basilar arteries. Study Design: Sublingual tablets of 5-mg isosorbide dinitrate were administered to 19 hypertensive pregnant patients. Doppler velocimetry of the middle cerebral and basilar arteries was obtained with a transcranial Doppler with the use of the transtemporal and suboccipital approach. Results: The mean (±SEM) flow velocity in the middle cerebral artery significantly decreased from a baseline of 65.9 ± 3.1 cm/s to 55.2 ± 2.2 and 52.0 ± 2.1 cm/s at 10 and 20 minutes (P <.0001). Resistance area product insignificantly increased from a baseline of 2.0 ± 0.1 before isosorbide dinitrate to 2.19 ± 0.11 at 20 minutes. No significant changes were observed in the resistance and pulsatility indices in the middle cerebral artery. The cerebral perfusion pressure did not change significantly after isosorbide dinitrate (84.5 ± 7.3, 80.8 ± 6.6, and 78.5 ± 5.0 mm Hg at 0, 10, and 20 minutes, respectively) nor did the cerebral blood flow index. Conclusion: The results obtained demonstrate that cerebral perfusion pressure is unaltered by isosorbide dinitrate, despite significant changes in maternal blood pressure and in blood flow velocities in the middle cerebral artery.