Hooman Honar - Academia.edu (original) (raw)
Papers by Hooman Honar
Journal of Gastroenterology and Hepatology, 2007
Background: Following bile duct ligation (BDL) endogenous opioids accumulate in plasma and play ... more Background: Following bile duct ligation (BDL) endogenous opioids accumulate in plasma and play a role in the pathophysiology and manifestation of cholestasis. Evidence of centrally mediated induction of liver injury by exogenous opioid agonist administration, prompts the question of whether opioid receptor blockade by naltrexone can affect cholestasis-induced liver injury.Methods: Cholestasis was induced by BDL and cholestatic and sham-operated rats received either naltrexone or saline for 7 consecutive days. On the 7th day, liver samples were collected for determining matrix metalloproteinase-2 (MMP-2) activity, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content and blood samples were obtained for measuring plasma nitrite/nitrate and liver enzyme activities.Results: Naltrexone-treated BDL animals had a significant reduction in plasma enzyme activity and nitrite/nitrate level. Liver SAM : SAH ratio and SAM level improved by naltrexone treatment in cholestatic animals compared to saline-treated BDL ones. Naltrexone treatment in BDL rats led to a decrease in the level of liver MMP-2 activity, which had already increased during cholestasis.Conclusion: Opioid receptor blockade improved the degree of liver injury in cholestasis, as assessed by plasma enzyme and liver MMP-2 activities. The beneficial effect of naltrexone may be due to its ability to increase liver SAM level and restore the SAM : SAH ratio.
Epilepsia, 2004
Summary: Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and ... more Summary: Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine.Methods: The threshold for the clonic seizures (CST) induced by acute intravenous administration of γ-aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy.Results: At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5–3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine.Conclusions: The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.
Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Al... more Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Alteration in the endogenous opioid system and overproduction of nitric oxide have been implicated in colitis. The possible contribution of opioid receptors and nitric oxide to increased seizure susceptibility was examined in a putative model of intestinal inflammation. Methods : The alterations in clonic seizure threshold, induced by pentylenetetrazole, following the induction of intestinal inflammation by the administration of two consecutive daily oral doses of croton oil, was evaluated in mice. This model was used to evaluate the effects of pretreatment with opioid receptor antagonist naltrexone (10 mg/kg, once daily for 4 days or a single dose on the test day), non-specific nitric oxide synthase inhibitor N G -nitro-L -arginine methyl ester (10 mg/kg, once daily), and specific inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg, once daily) on seizure threshold in intestinal inflammation. Results : A significant decrease in clonic seizure threshold was observed in mice with intestinal inflammation compared to the control group. Chronic pretreatment with naltrexone per se did not cause any significant change in seizure threshold, but it significantly restored the threshold in croton oil-treated mice to that of the control animals. However, acute naltrexone pretreatment (on the test day) could not restore the decreased seizure threshold to control level. Chronic pretreatment with neither N G -nitro-Larginine methyl ester nor aminoguanidine altered the seizure threshold in the control animals and in mice treated with croton oil. Conclusions : Experimental croton oil-induced intestinal inflammation leads to a proconvulsant effect, which may have clinical relevance. Chronic alterations mediated by endogenous opioids may be involved in this process, though a direct opioid-receptor-mediated effect is unlikely. Nitric oxide synthesis, via constitutive or inducible pathways, is not involved in this increased susceptibility.
Importance: Acute kidney injury, a common complication of surgery, is associated with poor outcom... more Importance: Acute kidney injury, a common complication of surgery, is associated with poor outcomes and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however, these effects are uncertain and each intervention has the potential for harm. Objective: To determine whether aspirin compared with placebo, and clonidine compared with placebo, alters the risk of perioperative acute kidney injury. Design, Setting, and Participants: A 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing noncardiac surgery from 88 centers in 22 countries with consecutive patients enrolled between January 2011 and December 2013. Interventions: Patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and were assigned to take oral clonidine (0.2 mg) or placebo 2 to 4 hours before su...
Anesthesiology, 2015
Core temperature patterns in patients warmed with forced air remain poorly characterized. Also un... more Core temperature patterns in patients warmed with forced air remain poorly characterized. Also unknown is the extent to which transient and mild intraoperative hypothermia contributes to adverse outcomes in broad populations. We evaluated esophageal (core) temperatures in 58,814 adults having surgery lasting >60 min who were warmed with forced air. Independent associations between hypothermic exposure and transfusion requirement and duration of hospitalization were evaluated. In every percentile subgroup, core temperature decreased during the first hour and subsequently increased. The mean lowest core temperature during the first hour was 35.7 ± 0.6°C. Sixty-four percent of the patients reached a core temperature threshold of <36°C 45 min after induction; 29% reached a core temperature threshold of <35.5°C. Nearly half the patients had continuous core temperatures <36°C for more than an hour, and 20% of the patients were <35.5°C for more than an hour. Twenty percent of patients had continuous core temperatures <36°C for more than 2 h, and 8% of the patients were below 35.5°C for more than 2 h. Hypothermia was independently associated with both transfusions and duration of hospitalization, although the prolongation of hospitalization was small. Even in actively warmed patients, hypothermia is routine during the first hour of anesthesia. Thereafter, average core temperatures progressively increase. Nonetheless, intraoperative hypothermia was common, and often prolonged. Hypothermia was associated with increased transfusion requirement, which is consistent with numerous randomized trials.
![Research paper thumbnail of [304] OPIOID AND NITRIC OXIDE MODULATION OF PENTYLENETETRAZOLE-INDUCED SEIZURE SUSCEPTIBILITY IN A REVERSIBLE MODEL OF CHEMICAL CHOLESTASIS](https://attachments.academia-assets.com/46187411/thumbnails/1.jpg)
](Journal of Hepatology, 2007
The increment of opioidergic neuromodulation is a systemic phenomenon in cholestatic liver diseas... more The increment of opioidergic neuromodulation is a systemic phenomenon in cholestatic liver disease. Previous studies have revealed the increment of plasma and liver concentrations of opioid peptides in animal models of cholestasis and human cholestatic cirrhosis. The present study was conducted to clarify the effects of chronic opioid administration on liver antioxidant defence and hepatocytes vitality Methods: Mice were divided into four groups: Control group, received vehicle (normal saline); Mor group, received morphine injections at dose of 10 mg/kg; Mor+Nal group, received 10 mgikg morphine and 10 mgikg naltrexone injections. In order to investigate whether morphine-induced oxidative stress contributes to induction of apoptosis in hepatocytes we treated the mice in Mor+NAC group with 500mgikg intragastric dose of N-acetylcysteine, 30 min prior to subcutaneous injection of 10 mgikg morphine. All agents were injected intraperitoneally for 9 consecutive days. The changes in liver glutathione concentration and its synthesis pathway were determined. The activities of hepatic antioxidant enzymes were also measured. Induction of apoptosis was examined by in situ determination of the fragmented DNA. The enzyme activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase were also determined in plasma of mice. Results: Following 9 days of morphine injection hepatocytes apoptosis index and biochemical markers of liver damage increased significantly. Liver glutathione concentration as well as catalase, glutathione peroxidase, and superoxide dismutase activities were significantly decreased in Mor group. Hepatic glutathione biosynthesis pathway was changed in the way to compensate for reduced hepatocytes glutathione concentrations. In Mor+Nal group, co-treatment of mice with naltrexone normalized the aforementioned changes. Interestingly, the pro-apoptotic effects of morphine were antagonized by co-administration of thiol antioxidant in Mor+NAC group. Co-treatment of mice with N-acetylcysteine also normalized other oxidant and hepatotoxic effects of morphine. Conclusion: Since the effects of chronic morphine treatment were opioid receptor-mediated and were antagonized by co-administration of an exogenous thiol antioxidant, our findings propose that chronic opioidergic neuromodulation induces oxidative stress in the liver, which may contribute to induction of apoptosis in hepatocytes. These data are valuable in interpretation of the opioid-dependent liver damage during cholestatic liver disease.
Neuroscience, 2004
Significant potentiation of analgesic effects of opioids can be achieved through selective blocka... more Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach
Supplemental digital content 2, Table 1. Cox model exploring independent association between pote... more Supplemental digital content 2, Table 1. Cox model exploring independent association between potential MINS diagnostic criteria of a peak Troponin T ≥0.04 ng/mL with and without an ischemic feature and 30-day mortality Potential diagnostic criteria Adjusted HR (95% CI) p-value Peak TnT ≥0.04 ng/mL with 1 ischemic feature Peak TnT ≥0.04 ng/mL without an ischemic feature TnT ≤0.01 ng/mL 5.06 (3.55-7.21) 3.33 (2.28-4.87) 1.00 <0.001 <0.001 -CI = confidence intervals; HR = hazard ratio; MINS = myocardial injury after noncardiac surgery; % = percentage; TnT = 4 th generation Troponin T Supplemental digital content 2, Table 2. Cox model exploring the independent association between all considered MINS diagnostic criteria and 30-day mortality Potential diagnostic criteria Number of Patients (%) Adjusted HR (95% CI) p-value Peak TnT ≥0.04 ng/mL with 1 ischemic feature Peak TnT ≥0.04 ng/mL without an ischemic feature Peak TnT = 0.03 ng/mL Peak TnT = 0.02 ng/mL TnT ≤0.01 ng/mL 401 (2.7) 540 (3.6) 259 (1.7) 479 (3.2) 13,386 (88.9) 4.82 (3.40-6.84) 3.30 (2.26-4.81) 4.30 (2.68-6.91) 1.61 (0.91-2.86)
by Sergio Mazzadi, Daniel Sessler, Edyta Niebrzegowska, Theroshnie Kisten, Shirley Pettit, Michelle Graham, Hooman Honar, Atiya Faruqui, Sebastian Ribas, Amal Bessissow, and Giovanna Luratibuse
Neuropharmacology, 2003
The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investi... more The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investigated in mice. Acute intraperitoneal administration of agmatine (5, 10, 20, 40 mg/kg) had a significant and dose-dependent inhibitory effect on pentylenetetrazole (PTZ)-induced seizures. The peak of this anticonvulsant effect was 45 min after agmatine administration. We further investigated the possible involvement of the α 2 -adrenoceptors and l-arginine/NO pathway in this effect of agmatine. The α 2 -adrenoceptor antagonist, yohimbine (0.5-2 mg/kg), induced a dose-dependent blockade of the anticonvulsant effect of agmatine. The nitric oxide synthase (NOS) substrate, l-arginine (60 mg/kg), inhibited the anticonvulsant property of agmatine and this effect was significantly reversed by NOS inhibitor N G -nitro-l-arginine (l-NAME, 30 mg/kg), implying an NO-dependent mechanism for l-arginine effect. We further examined a possible additive effect between agmatine (1 or 5 mg/kg) and l-NAME (10 mg/kg). The combination of l-NAME (10 mg/kg) with agmatine (5 but not 1 mg/kg) induced a significantly higher level of seizure protection as compared with each drug alone. Moreover, a combination of lower doses of yohimbine (0.5 mg/kg) and l-arginine (30 mg/kg) also significantly decreased the anticonvulsant effect of agmatine. In conclusion, the present data suggest that agmatine may be of potential use in seizure treatment.
Nature Clinical Practice Gastroenterology & Hepatology, 2006
Life Sciences, 2005
Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in... more Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P b 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P b 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic 0024-3205/$ -see front matter D stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis. D
Life Sciences, 2004
Acute cholestasis is associated with increased activity of the endogenous opioid system. It is al... more Acute cholestasis is associated with increased activity of the endogenous opioid system. It is also known that opioid receptor agonists like morphine decrease the intestinal transit. The purpose of the present study was to investigate the effect of cholestasis on the small intestine transit and the possible involvement of opioid system in this phenomenon in mice. Cholestasis was induced by bile duct-ligation and intestinal transit was measured with charcoal meal and calculation of percent of transit through small intestine. The effect of chronic administration of naltrexone and acute pretreatment with morphine on intestinal transit was evaluated in bile duct-ligated (BDL) as well as unoperated (CTL) and sham-operated (SHAM) animals. The plasma alkaline phosphatase and alanine aminotransferase activities were also measured. A significant decrease in small intestine transit (%transit) was observed in BDL mice compared to SHAM animals, which was prominent even after 24 h of cholestasis. Chronic pretreatment with an opioid receptor antagonist, naltrexone, (10 mg/kg, i.p for 2, 4 or 6 days) completely restored the cholestasis-induced decrease in %transit to that of control animals. Although the acute administration of morphine (2 mg/kg, s.c.) 20 min before charcoal feeding caused a significant decrease in the intestinal transit of CTL and SHAM animals, it did not decrease the %transit of BDL animals on the day 5 after operation. Our findings show that acute cholestasis is associated with a prominent decrease in small intestine transit in mice and opioid receptors maybe involved in this phenomenon. D
Journal of Hepatology, 2011
Background & Aims: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been bro... more Background & Aims: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been brought to the forefront with several reports of unexpected heart failure following liver transplantation and transjugular intrahepatic portosystemic stent-shunt, but the etiology remains unclear. The present study investigated the role of passive tension regulators -titin and collagen -in the pathogenesis of this condition. Methods: Cirrhosis was induced by bile duct ligation (BDL) in rats, while controls underwent bile duct inspection with no ligation. Four weeks after operation, cardiac mRNA and protein levels of titin, collagen, and protein kinase A (PKA) were determined. Diastolic function was examined in isolated right ventricular cardiomyocytes, while passive tension was examined in right ventricular trabeculae muscles. Results: In BDL animals, diastolic return velocity was significantly decreased, relaxation time increased and passive tension increased. However, no significant difference in mRNA and protein levels of titin was observed. PKA mRNA and protein levels were significantly decreased in BDL animals. Collagen levels were also significantly altered in the BDL group. Conclusions: Therefore, diastolic dysfunction exists in cirrhosis with alterations in titin modulation, PKA levels, and collagen configuration contributing to the pathogenesis of this condition. Ó
Journal of Gastroenterology and Hepatology, 2004
Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Al... more Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Alteration in the endogenous opioid system and overproduction of nitric oxide have been implicated in colitis. The possible contribution of opioid receptors and nitric oxide to increased seizure susceptibility was examined in a putative model of intestinal inflammation. Methods : The alterations in clonic seizure threshold, induced by pentylenetetrazole, following the induction of intestinal inflammation by the administration of two consecutive daily oral doses of croton oil, was evaluated in mice. This model was used to evaluate the effects of pretreatment with opioid receptor antagonist naltrexone (10 mg/kg, once daily for 4 days or a single dose on the test day), non-specific nitric oxide synthase inhibitor N G -nitro-L -arginine methyl ester (10 mg/kg, once daily), and specific inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg, once daily) on seizure threshold in intestinal inflammation. Results : A significant decrease in clonic seizure threshold was observed in mice with intestinal inflammation compared to the control group. Chronic pretreatment with naltrexone per se did not cause any significant change in seizure threshold, but it significantly restored the threshold in croton oil-treated mice to that of the control animals. However, acute naltrexone pretreatment (on the test day) could not restore the decreased seizure threshold to control level. Chronic pretreatment with neither N G -nitro-Larginine methyl ester nor aminoguanidine altered the seizure threshold in the control animals and in mice treated with croton oil. Conclusions : Experimental croton oil-induced intestinal inflammation leads to a proconvulsant effect, which may have clinical relevance. Chronic alterations mediated by endogenous opioids may be involved in this process, though a direct opioid-receptor-mediated effect is unlikely. Nitric oxide synthesis, via constitutive or inducible pathways, is not involved in this increased susceptibility.
International Journal of Gynecology & Obstetrics, 2003
International Journal of Gynecological Cancer, 2004
The aim of this study was to evaluate the probable usefulness of normal beta-human chorionic gona... more The aim of this study was to evaluate the probable usefulness of normal beta-human chorionic gonadotropin (beta-hCG) regression curve in the diagnosis of persistent trophoblastic disease (PTD). A log-value regression curve was developed from the means and 95% confidence limits of serial weekly serum beta-hCG titers of 43 patients with uneventful complete hydatidiform moles and 14 patients, who were previously confirmed as PTD. All 14 PTD patients (100%) had abnormal values, beyond normal range, within 4 weeks. beta-hCG was in its upper values, compared to normal regression curve at 2.29 +/- 0.19 weeks. This was earlier than plateau or rise detection at 4.21 +/- 0.33 weeks (P < 0.001). Within 3 weeks of evacuation, 13 of 14 (92.86%) PTD patients' beta-hCG values exceeded the normal range, whereas only six of 14 (42%) showed a rise or plateau. Our finding indicates that the normal beta-hCG regression curve may be useful for quicker detection of PTD than the plateau or rise of level.
European Journal of Pharmacology, 2008
One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms ... more One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms of which are not yet known. In this study we investigated the effect of chronic lithium (LiCl, 600 mg/l for 30 days) administration on the neurogenic relaxation of isolated rat corpus cavernosum. The corporal strips were precontracted with phenylephrine and electrical field stimulation (EFS) was applied to obtain relaxation. Relaxation to EFS was significantly (P b 0.001) impaired in LiCl-treated rats. The nitric oxide (NO) synthase inhibitor N ω -nitro-L-arginine methyl ester (L-NAME; 100 µM) inhibited the relaxation to EFS in both LiCl-treated and control rats. The NO precursor L-arginine, at per se noneffective concentration (0.1 mM), significantly (P b 0.001) enhanced the EFS-induced relaxation of LiCl-treated corporal strips. The relaxation responses to the NO donor sodium nitroprusside were similar between two groups. These data demonstrate that chronic lithium treatment could impair the NOmediated neurogenic relaxation of rat corpus cavernosum which could be prevented by L-arginine.
European Journal of Pharmacology, 2004
Changes in vascular responsiveness are the basis for some of the cardiovascular complications in ... more Changes in vascular responsiveness are the basis for some of the cardiovascular complications in cholestasis. Since the duration of cholestasis is important in determining the degree of the complications, we investigated the time-course dependent evolution of vascular relaxation responsiveness in the aortic rings of cholestatic rats. Acetylcholine-induced endothelium-dependent relaxation was investigated in the isolated aortic rings of unoperated, sham-operated and two-, five-, seven- and fourteen-day bile-duct ligated rats. There was a significant reduction in acetylcholine-induced relaxation of the aortic rings by the second day after the bile-duct ligation operation, compared to those of unoperated and sham-operated groups, but more reduction still occurs in 5- and 7-day bile-duct ligated groups, reaching a plateau by the seventh day. The relaxation response to sodium nitroprusside in the aortic rings of the unoperated and the 7-day bile-duct ligated rats did not differ, implying the intact smooth muscle component of the relaxation pathway. L-NAME ( N(omega)-nitro-L-arginine methyl ester), a nitric oxide (NO) synthase inhibitor, attenuated the acetylcholine-induced relaxation in both groups (unoperated and bile-duct ligated), while L-arginine prevents this inhibitory effect. Indomethacin potentiated the acetylcholine-induced relaxation in the aortic rings of the bile-duct ligated rats while it has no effect on unoperated controls, providing evidence for the possible role of vasoconstrictor prostanoids in cholestasis-induced reduction in acetylcholine-induced relaxation. These results state that the reduced acetylcholine-induced relaxation in the cholestatic aortic rings during the first week, when no portal hypertension was reported to be present, may be due to the decreased acetylcholine-induced NO release from endothelium or increased NO inactivation.
Journal of Gastroenterology and Hepatology, 2007
Background: Following bile duct ligation (BDL) endogenous opioids accumulate in plasma and play ... more Background: Following bile duct ligation (BDL) endogenous opioids accumulate in plasma and play a role in the pathophysiology and manifestation of cholestasis. Evidence of centrally mediated induction of liver injury by exogenous opioid agonist administration, prompts the question of whether opioid receptor blockade by naltrexone can affect cholestasis-induced liver injury.Methods: Cholestasis was induced by BDL and cholestatic and sham-operated rats received either naltrexone or saline for 7 consecutive days. On the 7th day, liver samples were collected for determining matrix metalloproteinase-2 (MMP-2) activity, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content and blood samples were obtained for measuring plasma nitrite/nitrate and liver enzyme activities.Results: Naltrexone-treated BDL animals had a significant reduction in plasma enzyme activity and nitrite/nitrate level. Liver SAM : SAH ratio and SAM level improved by naltrexone treatment in cholestatic animals compared to saline-treated BDL ones. Naltrexone treatment in BDL rats led to a decrease in the level of liver MMP-2 activity, which had already increased during cholestasis.Conclusion: Opioid receptor blockade improved the degree of liver injury in cholestasis, as assessed by plasma enzyme and liver MMP-2 activities. The beneficial effect of naltrexone may be due to its ability to increase liver SAM level and restore the SAM : SAH ratio.
Epilepsia, 2004
Summary: Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and ... more Summary: Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine.Methods: The threshold for the clonic seizures (CST) induced by acute intravenous administration of γ-aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy.Results: At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5–3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine.Conclusions: The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.
Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Al... more Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Alteration in the endogenous opioid system and overproduction of nitric oxide have been implicated in colitis. The possible contribution of opioid receptors and nitric oxide to increased seizure susceptibility was examined in a putative model of intestinal inflammation. Methods : The alterations in clonic seizure threshold, induced by pentylenetetrazole, following the induction of intestinal inflammation by the administration of two consecutive daily oral doses of croton oil, was evaluated in mice. This model was used to evaluate the effects of pretreatment with opioid receptor antagonist naltrexone (10 mg/kg, once daily for 4 days or a single dose on the test day), non-specific nitric oxide synthase inhibitor N G -nitro-L -arginine methyl ester (10 mg/kg, once daily), and specific inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg, once daily) on seizure threshold in intestinal inflammation. Results : A significant decrease in clonic seizure threshold was observed in mice with intestinal inflammation compared to the control group. Chronic pretreatment with naltrexone per se did not cause any significant change in seizure threshold, but it significantly restored the threshold in croton oil-treated mice to that of the control animals. However, acute naltrexone pretreatment (on the test day) could not restore the decreased seizure threshold to control level. Chronic pretreatment with neither N G -nitro-Larginine methyl ester nor aminoguanidine altered the seizure threshold in the control animals and in mice treated with croton oil. Conclusions : Experimental croton oil-induced intestinal inflammation leads to a proconvulsant effect, which may have clinical relevance. Chronic alterations mediated by endogenous opioids may be involved in this process, though a direct opioid-receptor-mediated effect is unlikely. Nitric oxide synthesis, via constitutive or inducible pathways, is not involved in this increased susceptibility.
Importance: Acute kidney injury, a common complication of surgery, is associated with poor outcom... more Importance: Acute kidney injury, a common complication of surgery, is associated with poor outcomes and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however, these effects are uncertain and each intervention has the potential for harm. Objective: To determine whether aspirin compared with placebo, and clonidine compared with placebo, alters the risk of perioperative acute kidney injury. Design, Setting, and Participants: A 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing noncardiac surgery from 88 centers in 22 countries with consecutive patients enrolled between January 2011 and December 2013. Interventions: Patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and were assigned to take oral clonidine (0.2 mg) or placebo 2 to 4 hours before su...
Anesthesiology, 2015
Core temperature patterns in patients warmed with forced air remain poorly characterized. Also un... more Core temperature patterns in patients warmed with forced air remain poorly characterized. Also unknown is the extent to which transient and mild intraoperative hypothermia contributes to adverse outcomes in broad populations. We evaluated esophageal (core) temperatures in 58,814 adults having surgery lasting &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;60 min who were warmed with forced air. Independent associations between hypothermic exposure and transfusion requirement and duration of hospitalization were evaluated. In every percentile subgroup, core temperature decreased during the first hour and subsequently increased. The mean lowest core temperature during the first hour was 35.7 ± 0.6°C. Sixty-four percent of the patients reached a core temperature threshold of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;36°C 45 min after induction; 29% reached a core temperature threshold of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;35.5°C. Nearly half the patients had continuous core temperatures &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;36°C for more than an hour, and 20% of the patients were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;35.5°C for more than an hour. Twenty percent of patients had continuous core temperatures &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;36°C for more than 2 h, and 8% of the patients were below 35.5°C for more than 2 h. Hypothermia was independently associated with both transfusions and duration of hospitalization, although the prolongation of hospitalization was small. Even in actively warmed patients, hypothermia is routine during the first hour of anesthesia. Thereafter, average core temperatures progressively increase. Nonetheless, intraoperative hypothermia was common, and often prolonged. Hypothermia was associated with increased transfusion requirement, which is consistent with numerous randomized trials.
Journal of Hepatology, 2007
The increment of opioidergic neuromodulation is a systemic phenomenon in cholestatic liver diseas... more The increment of opioidergic neuromodulation is a systemic phenomenon in cholestatic liver disease. Previous studies have revealed the increment of plasma and liver concentrations of opioid peptides in animal models of cholestasis and human cholestatic cirrhosis. The present study was conducted to clarify the effects of chronic opioid administration on liver antioxidant defence and hepatocytes vitality Methods: Mice were divided into four groups: Control group, received vehicle (normal saline); Mor group, received morphine injections at dose of 10 mg/kg; Mor+Nal group, received 10 mgikg morphine and 10 mgikg naltrexone injections. In order to investigate whether morphine-induced oxidative stress contributes to induction of apoptosis in hepatocytes we treated the mice in Mor+NAC group with 500mgikg intragastric dose of N-acetylcysteine, 30 min prior to subcutaneous injection of 10 mgikg morphine. All agents were injected intraperitoneally for 9 consecutive days. The changes in liver glutathione concentration and its synthesis pathway were determined. The activities of hepatic antioxidant enzymes were also measured. Induction of apoptosis was examined by in situ determination of the fragmented DNA. The enzyme activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase were also determined in plasma of mice. Results: Following 9 days of morphine injection hepatocytes apoptosis index and biochemical markers of liver damage increased significantly. Liver glutathione concentration as well as catalase, glutathione peroxidase, and superoxide dismutase activities were significantly decreased in Mor group. Hepatic glutathione biosynthesis pathway was changed in the way to compensate for reduced hepatocytes glutathione concentrations. In Mor+Nal group, co-treatment of mice with naltrexone normalized the aforementioned changes. Interestingly, the pro-apoptotic effects of morphine were antagonized by co-administration of thiol antioxidant in Mor+NAC group. Co-treatment of mice with N-acetylcysteine also normalized other oxidant and hepatotoxic effects of morphine. Conclusion: Since the effects of chronic morphine treatment were opioid receptor-mediated and were antagonized by co-administration of an exogenous thiol antioxidant, our findings propose that chronic opioidergic neuromodulation induces oxidative stress in the liver, which may contribute to induction of apoptosis in hepatocytes. These data are valuable in interpretation of the opioid-dependent liver damage during cholestatic liver disease.
Neuroscience, 2004
Significant potentiation of analgesic effects of opioids can be achieved through selective blocka... more Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach
Supplemental digital content 2, Table 1. Cox model exploring independent association between pote... more Supplemental digital content 2, Table 1. Cox model exploring independent association between potential MINS diagnostic criteria of a peak Troponin T ≥0.04 ng/mL with and without an ischemic feature and 30-day mortality Potential diagnostic criteria Adjusted HR (95% CI) p-value Peak TnT ≥0.04 ng/mL with 1 ischemic feature Peak TnT ≥0.04 ng/mL without an ischemic feature TnT ≤0.01 ng/mL 5.06 (3.55-7.21) 3.33 (2.28-4.87) 1.00 <0.001 <0.001 -CI = confidence intervals; HR = hazard ratio; MINS = myocardial injury after noncardiac surgery; % = percentage; TnT = 4 th generation Troponin T Supplemental digital content 2, Table 2. Cox model exploring the independent association between all considered MINS diagnostic criteria and 30-day mortality Potential diagnostic criteria Number of Patients (%) Adjusted HR (95% CI) p-value Peak TnT ≥0.04 ng/mL with 1 ischemic feature Peak TnT ≥0.04 ng/mL without an ischemic feature Peak TnT = 0.03 ng/mL Peak TnT = 0.02 ng/mL TnT ≤0.01 ng/mL 401 (2.7) 540 (3.6) 259 (1.7) 479 (3.2) 13,386 (88.9) 4.82 (3.40-6.84) 3.30 (2.26-4.81) 4.30 (2.68-6.91) 1.61 (0.91-2.86)
by Sergio Mazzadi, Daniel Sessler, Edyta Niebrzegowska, Theroshnie Kisten, Shirley Pettit, Michelle Graham, Hooman Honar, Atiya Faruqui, Sebastian Ribas, Amal Bessissow, and Giovanna Luratibuse
Neuropharmacology, 2003
The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investi... more The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investigated in mice. Acute intraperitoneal administration of agmatine (5, 10, 20, 40 mg/kg) had a significant and dose-dependent inhibitory effect on pentylenetetrazole (PTZ)-induced seizures. The peak of this anticonvulsant effect was 45 min after agmatine administration. We further investigated the possible involvement of the α 2 -adrenoceptors and l-arginine/NO pathway in this effect of agmatine. The α 2 -adrenoceptor antagonist, yohimbine (0.5-2 mg/kg), induced a dose-dependent blockade of the anticonvulsant effect of agmatine. The nitric oxide synthase (NOS) substrate, l-arginine (60 mg/kg), inhibited the anticonvulsant property of agmatine and this effect was significantly reversed by NOS inhibitor N G -nitro-l-arginine (l-NAME, 30 mg/kg), implying an NO-dependent mechanism for l-arginine effect. We further examined a possible additive effect between agmatine (1 or 5 mg/kg) and l-NAME (10 mg/kg). The combination of l-NAME (10 mg/kg) with agmatine (5 but not 1 mg/kg) induced a significantly higher level of seizure protection as compared with each drug alone. Moreover, a combination of lower doses of yohimbine (0.5 mg/kg) and l-arginine (30 mg/kg) also significantly decreased the anticonvulsant effect of agmatine. In conclusion, the present data suggest that agmatine may be of potential use in seizure treatment.
Nature Clinical Practice Gastroenterology & Hepatology, 2006
Life Sciences, 2005
Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in... more Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P b 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P b 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic 0024-3205/$ -see front matter D stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis. D
Life Sciences, 2004
Acute cholestasis is associated with increased activity of the endogenous opioid system. It is al... more Acute cholestasis is associated with increased activity of the endogenous opioid system. It is also known that opioid receptor agonists like morphine decrease the intestinal transit. The purpose of the present study was to investigate the effect of cholestasis on the small intestine transit and the possible involvement of opioid system in this phenomenon in mice. Cholestasis was induced by bile duct-ligation and intestinal transit was measured with charcoal meal and calculation of percent of transit through small intestine. The effect of chronic administration of naltrexone and acute pretreatment with morphine on intestinal transit was evaluated in bile duct-ligated (BDL) as well as unoperated (CTL) and sham-operated (SHAM) animals. The plasma alkaline phosphatase and alanine aminotransferase activities were also measured. A significant decrease in small intestine transit (%transit) was observed in BDL mice compared to SHAM animals, which was prominent even after 24 h of cholestasis. Chronic pretreatment with an opioid receptor antagonist, naltrexone, (10 mg/kg, i.p for 2, 4 or 6 days) completely restored the cholestasis-induced decrease in %transit to that of control animals. Although the acute administration of morphine (2 mg/kg, s.c.) 20 min before charcoal feeding caused a significant decrease in the intestinal transit of CTL and SHAM animals, it did not decrease the %transit of BDL animals on the day 5 after operation. Our findings show that acute cholestasis is associated with a prominent decrease in small intestine transit in mice and opioid receptors maybe involved in this phenomenon. D
Journal of Hepatology, 2011
Background & Aims: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been bro... more Background & Aims: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been brought to the forefront with several reports of unexpected heart failure following liver transplantation and transjugular intrahepatic portosystemic stent-shunt, but the etiology remains unclear. The present study investigated the role of passive tension regulators -titin and collagen -in the pathogenesis of this condition. Methods: Cirrhosis was induced by bile duct ligation (BDL) in rats, while controls underwent bile duct inspection with no ligation. Four weeks after operation, cardiac mRNA and protein levels of titin, collagen, and protein kinase A (PKA) were determined. Diastolic function was examined in isolated right ventricular cardiomyocytes, while passive tension was examined in right ventricular trabeculae muscles. Results: In BDL animals, diastolic return velocity was significantly decreased, relaxation time increased and passive tension increased. However, no significant difference in mRNA and protein levels of titin was observed. PKA mRNA and protein levels were significantly decreased in BDL animals. Collagen levels were also significantly altered in the BDL group. Conclusions: Therefore, diastolic dysfunction exists in cirrhosis with alterations in titin modulation, PKA levels, and collagen configuration contributing to the pathogenesis of this condition. Ó
Journal of Gastroenterology and Hepatology, 2004
Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Al... more Background : Inflammatory bowel disorders are associated with increased incidence of seizures. Alteration in the endogenous opioid system and overproduction of nitric oxide have been implicated in colitis. The possible contribution of opioid receptors and nitric oxide to increased seizure susceptibility was examined in a putative model of intestinal inflammation. Methods : The alterations in clonic seizure threshold, induced by pentylenetetrazole, following the induction of intestinal inflammation by the administration of two consecutive daily oral doses of croton oil, was evaluated in mice. This model was used to evaluate the effects of pretreatment with opioid receptor antagonist naltrexone (10 mg/kg, once daily for 4 days or a single dose on the test day), non-specific nitric oxide synthase inhibitor N G -nitro-L -arginine methyl ester (10 mg/kg, once daily), and specific inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg, once daily) on seizure threshold in intestinal inflammation. Results : A significant decrease in clonic seizure threshold was observed in mice with intestinal inflammation compared to the control group. Chronic pretreatment with naltrexone per se did not cause any significant change in seizure threshold, but it significantly restored the threshold in croton oil-treated mice to that of the control animals. However, acute naltrexone pretreatment (on the test day) could not restore the decreased seizure threshold to control level. Chronic pretreatment with neither N G -nitro-Larginine methyl ester nor aminoguanidine altered the seizure threshold in the control animals and in mice treated with croton oil. Conclusions : Experimental croton oil-induced intestinal inflammation leads to a proconvulsant effect, which may have clinical relevance. Chronic alterations mediated by endogenous opioids may be involved in this process, though a direct opioid-receptor-mediated effect is unlikely. Nitric oxide synthesis, via constitutive or inducible pathways, is not involved in this increased susceptibility.
International Journal of Gynecology & Obstetrics, 2003
International Journal of Gynecological Cancer, 2004
The aim of this study was to evaluate the probable usefulness of normal beta-human chorionic gona... more The aim of this study was to evaluate the probable usefulness of normal beta-human chorionic gonadotropin (beta-hCG) regression curve in the diagnosis of persistent trophoblastic disease (PTD). A log-value regression curve was developed from the means and 95% confidence limits of serial weekly serum beta-hCG titers of 43 patients with uneventful complete hydatidiform moles and 14 patients, who were previously confirmed as PTD. All 14 PTD patients (100%) had abnormal values, beyond normal range, within 4 weeks. beta-hCG was in its upper values, compared to normal regression curve at 2.29 +/- 0.19 weeks. This was earlier than plateau or rise detection at 4.21 +/- 0.33 weeks (P < 0.001). Within 3 weeks of evacuation, 13 of 14 (92.86%) PTD patients' beta-hCG values exceeded the normal range, whereas only six of 14 (42%) showed a rise or plateau. Our finding indicates that the normal beta-hCG regression curve may be useful for quicker detection of PTD than the plateau or rise of level.
European Journal of Pharmacology, 2008
One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms ... more One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms of which are not yet known. In this study we investigated the effect of chronic lithium (LiCl, 600 mg/l for 30 days) administration on the neurogenic relaxation of isolated rat corpus cavernosum. The corporal strips were precontracted with phenylephrine and electrical field stimulation (EFS) was applied to obtain relaxation. Relaxation to EFS was significantly (P b 0.001) impaired in LiCl-treated rats. The nitric oxide (NO) synthase inhibitor N ω -nitro-L-arginine methyl ester (L-NAME; 100 µM) inhibited the relaxation to EFS in both LiCl-treated and control rats. The NO precursor L-arginine, at per se noneffective concentration (0.1 mM), significantly (P b 0.001) enhanced the EFS-induced relaxation of LiCl-treated corporal strips. The relaxation responses to the NO donor sodium nitroprusside were similar between two groups. These data demonstrate that chronic lithium treatment could impair the NOmediated neurogenic relaxation of rat corpus cavernosum which could be prevented by L-arginine.
European Journal of Pharmacology, 2004
Changes in vascular responsiveness are the basis for some of the cardiovascular complications in ... more Changes in vascular responsiveness are the basis for some of the cardiovascular complications in cholestasis. Since the duration of cholestasis is important in determining the degree of the complications, we investigated the time-course dependent evolution of vascular relaxation responsiveness in the aortic rings of cholestatic rats. Acetylcholine-induced endothelium-dependent relaxation was investigated in the isolated aortic rings of unoperated, sham-operated and two-, five-, seven- and fourteen-day bile-duct ligated rats. There was a significant reduction in acetylcholine-induced relaxation of the aortic rings by the second day after the bile-duct ligation operation, compared to those of unoperated and sham-operated groups, but more reduction still occurs in 5- and 7-day bile-duct ligated groups, reaching a plateau by the seventh day. The relaxation response to sodium nitroprusside in the aortic rings of the unoperated and the 7-day bile-duct ligated rats did not differ, implying the intact smooth muscle component of the relaxation pathway. L-NAME ( N(omega)-nitro-L-arginine methyl ester), a nitric oxide (NO) synthase inhibitor, attenuated the acetylcholine-induced relaxation in both groups (unoperated and bile-duct ligated), while L-arginine prevents this inhibitory effect. Indomethacin potentiated the acetylcholine-induced relaxation in the aortic rings of the bile-duct ligated rats while it has no effect on unoperated controls, providing evidence for the possible role of vasoconstrictor prostanoids in cholestasis-induced reduction in acetylcholine-induced relaxation. These results state that the reduced acetylcholine-induced relaxation in the cholestatic aortic rings during the first week, when no portal hypertension was reported to be present, may be due to the decreased acetylcholine-induced NO release from endothelium or increased NO inactivation.