Cardiac impairment and nitric oxide synthase activity in the chronic portal vein-stenosed rat

Battarbee, Harold D.; Zavecz, James H.; Grisham, Matthew B.; Maloney, Ronald E.; Chandler, L. Judson; Mercer, John; Cady, Francois M.

doi:10.1152/ajpgi.1999.276.2.g363

Cited by 8 publications

(8 citation statements)

References 42 publications

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“…33 In hearts of 4-week CBDL models, Liu et al recently showed cytokine activation of iNOS and improvement of papillary muscle contractility when the enzyme was inhibited. 34 This result is in contrast with the increase in eNOS without activation of iNOS observed in aortic rings by the same group 35 and others 36 and with the results in the partial portal vein ligation rat heart 37 in which NOS expression and activity and endproducts resulting from NO pathway did not differ from those in sham hearts. An intriguing aspect of the present results is the mechanism of the persistently increased synthesis of NO by eNOS in isolated hearts.…”

Section: Coronary Vasodilationmentioning

confidence: 63%

Left Ventricular Hypertrophy in Rats With Biliary Cirrhosis

et al. 2003

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Portal hypertension induces neuroendocrine activation and a hyperkinetic circulation state. This study investigated the consequences of portal hypertension on heart structure and function. Intrahepatic portal hypertension was induced in male Sprague-Dawley rats by chronic bile duct ligation (CBDL). Six weeks later, CBDL rats showed higher plasma angiotensin-II and endothelin-1 (P < .01), 56% reduction in peripheral resistance and 73% reduction in pulmonary resistance (P < .01), 87% increase in cardiac index and 30% increase in heart weight (P < .01), and increased myocardial nitric oxide (NO) synthesis. In CBDL rats, macroscopic analysis demonstrated a 30% (P < .01) increase in cross-sectional area of the left ventricular (LV) wall without changes in the LV cavity or in the right ventricle (RV). Histomorphometric analysis revealed increased cell width (12%, P < .01) of cardiomyocytes from the LV of CBDL rats, but no differences in myocardial collagen content. Myocytes isolated from the LV were wider (12%) and longer (8%) than right ventricular myocytes (P < .01) in CBDL rats but not in controls. CBDL rats showed an increased expression of ANF and CK-B genes (P < .01). Isolated perfused CBDL hearts showed pressure/end-diastolic pressure curves and response to isoproterenol identical to sham hearts, although generated wall tension was reduced because of the increased wall thickness. Coronary resistance was markedly reduced. This reduction was abolished by inhibition of NO synthesis with N-nitro-L-arginine. Expression of eNOS was increased in CBDL hearts. In conclusion, portal hypertension associated to biliary cirrhosis induces marked LV hypertrophy and increased myocardial NO synthesis without detectable fibrosis or functional impairment. This observation could be relevant to patients with cirrhosis. (HEPATOLOGY 2003;38:589-598.) H yperdynamic circulation is a common feature in human and experimental portal hypertension, with or without cirrhosis. This is also called hyperdynamic circulatory syndrome and is the consequence of splanchnic and systemic vasodilatation, manifested by increased heart rate, cardiac output, and regional blood flow with decreased mean arterial pressure and systemic vascular resistance (SVR). 1 The mechanism of systemic and splanchnic vasodilatation is multifactorial. Many studies have suggested a prominent role for increased biosynthesis of nitric oxide (NO), 2 which is due to increased endothelial nitric oxide synthase (eNOS) activity. 3,4 It has been shown that NO inhibition attenuates the hyperdynamic circulation observed in portal hypertensive rats. 5,6 Other studies have shown an increased splanchnic production of carbon monoxide in portal hypertension 7 as well as an increased release of splanchnic vasodilatory peptides, such as glucagon. 8,9 Vasoconstrictor systems are also up-regulated, probably as a counter-regulatory response to the hyperdynamic state. 10 Sympathetic nervous and renin-angiotensin aldosterone systems are enhanced, and the plasma levels of vasopressin and endot...

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Section: Coronary Vasodilationmentioning

confidence: 63%

Left Ventricular Hypertrophy in Rats With Biliary Cirrhosis

et al. 2003

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“…Portal hypertension with portosystemic shunting was produced by calibrated constriction of the portal vein as previously described [2,12,24,25]. Briefly, Sprague-Dawley derived rats were anesthetized with ketamine, 100 mg kg -1 ip, the portal vein was isolated, and a silk ligature was placed around it.…”

Section: Portal Vein Stenosismentioning

confidence: 99%

The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy

Zavecz

Battarbee

2010

Cardiovasc Toxicol

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Marked hemodynamic changes occur in humans and experimental animals with cirrhotic liver disease. In the heart, basal contractility, responsiveness to beta-adrenoceptor activation, and excitation-contraction coupling (ECC) are negatively affected in models of cirrhosis and portal hypertension with portosystemic shunting (PVS), and comprise what has been called cirrhotic cardiomyopathy. These effects are accompanied by elevated circulating levels of bile acids. We investigated whether elevated bile acids act as a myocardial toxicant by exposing cardiac muscle in vitro to bile acids and compared these results with two models of cirrhotic cardiomyopathy with elevated bile acids: CCl4-induced cirrhosis and PVS. Cholic acid, a lipophilic bile acid, produced a decrease in basal cardiac contractility and responsiveness to beta-adrenoceptor activation, both of which appeared to result from altered ECC. beta-Adrenoceptor density and signaling were unaffected. Acutely, ursodeoxycholic acid, a more hydrophilic bile acid, had no effect. Cirrhosis produced a decrease in basal force, depressed beta-adrenoceptor responsiveness, and altered ECC similar to cholic acid. However, cirrhosis also altered beta-adrenoceptor signaling including decreases in cyclic AMP formation, expression of the stimulatory G protein, GS, and beta-adrenoceptor density. Displacement of lipophilic bile acids by chronic administration of ursodeoxycholic acid to rats during the development of cirrhotic cardiomyopathy produced by PVS produced attenuation of the effect on ECC. These results suggest a possible role for lipophilic bile acids in some, but not all of the myocardial consequences of chronic portal vein stenosis and CCl4-induced cirrhosis.

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“…Specifically, these parameters were found to be unaltered in PVS rats, whereas membrane L-type Ca# + channels and sarcoplasmic reticulum caffeine-sensitive calcium stores appeared to be dysfunctional [96]. Given the considerations described above, it is interesting to note that Battarbee and colleagues [94] found no evidence of iNOS or even NO activation in their PVS rats. Even serum levels of nitrites\nitrates were unaltered in their PVS rat model.…”

Section: No In Cirrhotic Cardiomyopathymentioning

confidence: 92%

“…Battarbee and colleagues [94] have recently reported their investigations of NO activity in a rat model of prehepatic portal hypertension due to graded stenosis of the portal vein [portal vein stenosis (PVS) rats]. This rat model does not have any intrinsic liver disease, but mimics the human situation of portal vein obstruction with a ' pure ' presinusoidal portal hypertension.…”

Section: No In Cirrhotic Cardiomyopathymentioning

confidence: 99%

Nitric oxide and renal and cardiac dysfunction in cirrhosis

Garcı́a-Estañ¹,

ORTIZ²,

LEE³

2002

Clinical Science

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Nitric oxide (NO) has diverse physiological and pathophysiological effects. The roles of NO in the renal and cardiac dysfunction found in cirrhosis are reviewed. In the kidneys of experimental animals with cirrhosis, several lines of evidence speak in favour of an enhanced production of NO, through the activation of both endothelial constitutive and inducible isoforms of NO synthase. In contrast with the situation in normal animals, inhibition of NO synthesis in rats with cirrhosis improves sodium and water excretion via blood pressure-dependent and -independent mechanisms, which indicates that the renal sodium and water retention of cirrhosis is related to an excess of NO production. The deleterious effect of excessive NO on the kidney may be mediated by peroxynitrite, a potent oxidant that is readily formed whenever superoxide anions and the *NO radical are produced together. The peroxidation of arachidonic acid by peroxynitrite leads to the formation of F(2a)-isoprostanes, which are powerful renal vasoconstrictors. F(2a)-isoprostane levels are correlated with the severity of liver injury during cirrhosis. However, whether peroxynitrite or F(2a)-isoprostanes are the elusive mediator of the NO-induced renal alterations in cirrhosis remains to be firmly established. NO is also involved in cardiac contractility, probably in the normal heart as well as in disease conditions such as non-cirrhotic and cirrhotic cardiomyopathy. In the latter state, evidence suggests that inducible NO synthase attenuates ventricular contractility, mediated by cGMP. Another gas that transduces its signal through cGMP, carbon monoxide, is also likely to play a role in cirrhotic cardiomyopathy, but the nature of the interaction between NO and carbon monoxide in this syndrome remains unclear.

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Cardiac impairment and nitric oxide synthase activity in the chronic portal vein-stenosed rat

Cited by 8 publications

References 42 publications

Left Ventricular Hypertrophy in Rats With Biliary Cirrhosis

Left Ventricular Hypertrophy in Rats With Biliary Cirrhosis

The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy

Nitric oxide and renal and cardiac dysfunction in cirrhosis

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