Dual nitric oxide mechanisms of cholestasis‐induced bradycardia in the rat

Mani, Ali R.; Nahavandi, Arezo; Moosavi, Maryam; Safarinejad, Reza; Dehpour, Ahmad Reza

doi:10.1046/j.1440-1681.2002.03748.x

Cited by 26 publications

(39 citation statements)

References 24 publications

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“…28 Rats with biliary cirrhosis are bradycardic, 29 and this condition is owing to a significant hyporesponsiveness to the chronotropic effect of catecholamines. 7,8 In the present study, we showed that two independent treatments (N-acetylcysteine and L-NAME), both of which can normalize chronotropic responses to adrenergic stimulation in vitro, also led to normalization of heart rate in vivo (Fig. 2).…”

Section: Discussionsupporting

confidence: 58%

“…Similarly, we have shown that increased NO synthesis in bile ductligated (BDL) rats causes bradycardia by causing impaired responsiveness of cardiac pacemaker cells to adrenergic stimuli. 7,8 Nitric oxide is involved in the modulation of cardiac function in the normal heart, as well as in various cardiac diseases via mechanisms involving NO that are both dependent on and independent of guanylyl cy-clase. 9,10 For example, evidence suggests NO attenuates cardiac pacemaker activity, mediated by cyclic guanosine monophosphate (cGMP).…”

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confidence: 99%

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Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis

et al. 2006

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Acceleration of the heart rate in response to catecholamines is impaired in cirrhosis. In this study, we tested the hypothesis that increased formation of reactive nitrogen species in biliary cirrhosis causes nitration of cardiac proteins and leads to impaired chronotropic function. Bile duct-ligated (rats with cirrhosis) or sham-operated rats were injected daily with either saline, N G -L-nitro-arginine methyl ester (L-NAME), or N-acetylcysteine for 7 days from week 3 to week 4 after surgery. Cardiac chronotropic responsiveness to ␤-adrenergic stimulation was assessed in vitro using spontaneous beating isolated atria. Nitration of cardiac proteins was measured by mass spectrometry and located by immunogold electron microscopy. Marked impairment of chronotropic responses of isolated atria to isoproterenol was seen in rats with cirrhosis, which normalized after the administration of N-acetylcysteine or L-NAME. The levels of protein-bound nitrotyrosine in atrial tissue increased from 16 ؎ 1 to 23 ؎ 3 pg/g tyrosine in rats with cirrhosis, and decreased to 15 ؎ 1 and 17 ؎ 1 pg/g after treatment with L-NAME and N-acetylcysteine, respectively (P < .05). Immunogold electron microscopy demonstrated increased nitration of mitochondrial proteins in the atria of rats with cirrhosis. The plasma nitrite/nitrate levels were elevated in rats with biliary cirrhosis, and decreased after administration of L-NAME but were unchanged by N-acetylcysteine. In conclusion, abnormal cardiac chronotropic function in cirrhosis is associated with increased nitration of cardiac proteins. Two independent treatments (N-acetylcysteine and L-NAME) that decrease nitration of cardiac proteins led to normalization of cardiac responses. Nitration of critical proteins in cardiac tissue may lead to abnormal cardiac function. (HEPATOLOGY 2006;43:847-856.)

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Section: Discussionsupporting

confidence: 58%

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confidence: 99%

Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis

et al. 2006

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“…It is likely that the timing and level of NO production in the healing wound must be carefully balanced to ensure a beneficial effect. [39][40][41][42] This work also demonstrated that human tendon cells have the capacity to synthesize physiologically active NO following transfection of iNOS gene via adenovirus.…”

Section: Discussionmentioning

confidence: 94%

Nitric oxide enhances collagen synthesis in cultured human tendon cells

Xia

Szomor

Wang

et al. 2005

Journal Orthopaedic Research

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Collagen deposition is an important process that occurs during wound healing. We and others have shown that nitric oxide (NO) is important in tendon healing. The mechanisms whereby healing is enhanced are, however, undetermined. The aim of this study was to investigate whether NO could enhance collagen synthesis in cultured human tendon cells via exogenous NO and via an adenovirus containing the gene for inducible nitric oxide synthase (Ad-iNOS). Tendon cells from the torn edge of the tendons of patients undergoing rotator cuff repair surgery were cultured following collagenase digestion, and stimulated with exogenous NO (SNAP), transfected with Ad-iNOS, and treated with the NOS inhibitor, L-NMMA. Total protein and collagen synthesis were evaluated by 3 H-proline and collagenase sensitive 3 H-proline incorporation in human tendon cells. High doses of exogenous NO (SNAP) inhibited collagen synthesis. Lower doses enhanced total protein and collagen synthesis of the tendon cells. Ad-iNOS successfully transfected active iNOS into human tendon cells in vitro and also enhanced total protein and collagen synthesis of the tendon cells. The NOS inhibitor, L-NMMA, inhibited the effects of iNOS on the cells. Our studies show for first time that nitric oxide can enhance collagen synthesis in human tendon cells in vitro. These results may explain, in part, at least, the beneficial effects of NO donors in animal models and during the treatment of tendonopathies in human clinical trials. ß

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“…It is well known that cholestatic liver disease is associated with hypotension [1,2], bradycardia [3][4][5], QT prolongation [6], hyporesponsiveness of cardiovascular system to adrenergic stimulation [7][8][9], and tendency to hypovolemic shock and acute renal failure [10][11][12]. QT prolongation usually increases vulnerability to arrhythmia in congenital and acquired conditions [13].…”

Section: Introductionmentioning

confidence: 99%