Vascular hyporesponsiveness to vasodilators in rats with cirrhosis

doi:10.1016/S0168-8278(97)80056-6

Journal of Hepatology

Volume 26, Issue 2, February 1997, Pages 382-386

https://doi.org/10.1016/S0168-8278(97)80056-6 Get rights and content

Abstract

Background/Aims: In cirrhosis, the activation of nitric oxide and prostacyclin contributes to vasolidation, and ATP-sensitive K⁺ (K_ATP) channel activation or L-type calcium (Ca²⁺) channel inhibition may also play a role in this process. At the same time in cirrhosis, certain endogenous mechanisms may be stimulated which limit the influence of vasodilator mechanisms on vascular tone, thus altering vascular responses to exogenous substances such as nitric oxide donors, exogenous prostacyclin, K_ATP channel openers or L-type Ca²⁺ channel blockers. The aim of the present study was to examine the arterial depressor to these exogenous substances in normal rats and in rats with secondary biliary cirrhosis.

Methods: Arterial depressor dose-response curves to nitroprusside (a nitric oxide donor, 5–60 μg · kg⁻¹ · min⁻¹), prostacyclin (0.5–5 μg · kg⁻¹) and aprikalim (a K_ATP channel opener, 10–200 μg · kg⁻¹) were obtained in both groups. The effects of different L-type Ca²⁺ channel blockers, i.e. nicardipine (a dihydropyridine, 0.02–0.5 mg · kg⁻¹), diltiazem (a benzothiazepine, 0.5–5 mg · kg⁻¹) and verapamil (a phenylalkylamine, 0.02–0.2 mg · kg⁻¹ · min⁻¹), were also studied.

Results: Cirrhosis produced hyporeactivity to the arterial depressor effect of all doses of nitroprusside, the lowest dose of prostacyclin and the highest doses of aprikalim or diltiazem. Cirrhosis did not significantly change depressor responses to nicardipine or verapamil.

Conclusions: Rats with cirrhosis are hyporeactive to exogenous nitric oxide, prostacyclin, K_ATP channel opener and benzothiapezine (an L-type Ca²⁺ channel blocker). Therefore, cirrhosis-induced mechanisms seem to limit the decrease in vascular tone by most vasodilators. However, these mechanisms appear to be more marked in nitric oxide vasodilation than in other vasorelaxation mechanisms.

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Cirrhosis of the liver and receptor-mediated function in vascular smooth muscle
2001, Pharmacology and Therapeutics
Altered regulation of receptors on the vascular smooth muscle has been proposed as one of the mechanisms that may account for the vascular abnormalities in patients with cirrhosis of the liver. Impaired contractility and down-regulation of contractile receptors have been demonstrated in cirrhotic patients and animal models, although interpretation of the literature is hampered by methodological variation and conflicting results. There is little evidence, however, that receptor down-regulation is the cause of contractile dysfunction in either patients or animal models. Receptor desensitisation may contribute to impaired contraction in human arteries, but further investigation is required to confirm this possibility.
Gallbladder hyporesponsiveness to an exogenous nitric oxide donor, glyceryl trinitrate, in patients with advanced liver cirrhosis
1999, American Journal of Gastroenterology
OBJECTIVE: An increased production of nitric oxide (NO) in liver cirrhosis has been documented. NO could intervene in regulating gallbladder contraction, as suggested by clinical and experimental studies. Our aim was to investigate the influence of an NO donor on gallbladder motility in cirrhotic patients in relation to the severity of liver cirrhosis.
METHODS: The subjects were six controls and 18 patients with liver cirrhosis (six in each Child class). Gallbladder emptying was monitored by ultrasound for 90 min after a mixed meal (14 g fat, 425 kcal). Fasting gallbladder volume, minimal residual volume, ejection fraction, area under emptying curve, and half contraction time of the gallbladder were assessed at 15-min intervals. The patients were evaluated on two consecutive days, with or without perlingual administration of 0.5 mg glyceryl trinitrate (GTN). Statistical analysis was performed by the two-tailed Student’s t test and Pearson’s correlation coefficient.
RESULTS: GTN significantly reduced gallbladder motility in controls and compensated cirrhotics (p < 0.02), but had no effect upon gallbladder emptying in Child class B and C cirrhotics.
CONCLUSIONS: Gallbladder hypocontractility in liver cirrhosis is related to the severity of the disease. This study is the first to show that GTN has no effect upon gallbladder motility in advanced liver cirrhosis when administered in doses that induce relaxation in controls and compensated cirrhosis.
Altered adrenergic responsiveness of endothelium-denuded hepatic arteries and portal veins in patients with cirrhosis
1999, Gastroenterology
Background & Aims: Patients with cirrhosis are characterized by a reduced splanchnic vascular resistance and a hyporeactivity to adrenergic vasoconstrictors. So far, their adrenergic splanchnic vascular responsiveness has not been evaluated in vitro. We compared responses to α₁- and β₂-adrenoceptor stimulation of hepatic arteries and portal veins of patients with cirrhosis undergoing transplantation with those of organ donors. Methods: Isometric contractions of endothelium-denuded vessel rings were induced cumulatively by methoxamine and relaxations by isoproterenol. Results are expressed as percentage of the contraction obtained by 85 mmol/L KCl or of the relaxation obtained by 100 μmol/L papaverine, respectively. Results: Maximal methoxamine-induced contractions were reduced in cirrhotic hepatic arteries (cirrhosis, 51.8% ± 6.8%; donor, 89.9% ± 6.6%; P < 0.01) and portal veins (cirrhosis, 49.2% ± 6.4%; donor, 94.0% ± 5.3%; P < 0.01). In cirrhosis, isoproterenol induced a less marked relaxation of hepatic arteries (cirrhosis, 46.6% ± 3.2%; donor, 100.3% ± 4.4%; P < 0.01) but an increased relaxation of portal veins (cirrhosis, 41.9% ± 6.2%; donor, 26.2% ± 2.8%; P < 0.01). Conclusions: In cirrhosis, endothelium-free hepatic arteries are hyporeactive to α₁- and β₂-adrenoceptor agonists, and portal veins are hyporeactive to α₁- but hyperreactive to β₂-adrenoceptor agonists. These findings support the in vivo findings of a hyporesponsiveness to adrenergic vasoconstrictors in patients with cirrhosis.
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Endothelium-dependent blunted membrane potential responses to ATP- sensitive K<sup>+</sup> channel modulators in aortae from rats with cirrhosis
1999, Journal of Hepatology
Background/Aims: In vivo studies have shown that arterial vasodilation induced by synthetic openers of ATP-sensitive K⁺ (K_ATP) channels is decreased in rats with cirrhosis. Since vasodilation induced by these substances is mediated by membrane potential hyperpolarization in arterial smooth muscle cells, membrane potential hyperpolarization in response to K_ATP channel openers may be altered in cirrhotic smooth muscle cells. The aim of the present study was to investigate the effects of K_ATP channel modulators (i.e. openers and blockers of these channels) on the membrane potential in smooth muscle cells in isolated aortae from cirrhotic and normal rats. The influence of endothelin-1 production by endothelial cells on smooth muscle cells membrane potential responses to K_ATP channel modulators was also studied.
Methods: Cells were impaled in situ (in intact and endothelium-denuded aortae) with a microelectrode that was used to measure membrane potentials. K_ATP channel openers were diazoxide or cromakalim; blockers were glibenclamide or tolbutamide. Bosentan (a mixed endothelin receptor antagonist) and exogenous endothelin-1 were also used. Preproendothelin-1 mRNA was assayed in aortae by RNase protection assay. Aortic wall endothelin-1 concentration was measured by double antibody radioimmunoassay technique.
Results: As expected, in smooth muscle cells in intact normal aortae, K_ATP channel openers induced membrane potential hyperpolarization and K_ATP channel blockers membrane potential depolarization. In smooth muscle cells in intact cirrhotic aortae, K_ATP channel openers and blockers did not significantly change the membrane potential. Endothelium removal or exposure of intact aortae to bosentan restored normal membrane potential responses to K_ATP channel modulators in cirrhotic smooth muscle cells and did not alter the effects of these substances in normal smooth muscle cells. In endothelium-denuded aortae, exposure to exogenous endothelin-1 suppressed membrane potential responses to K_ATP channel modulators. In intact aortae, the abundance of preproendothelin-1 mRNA and endothelin-1 did not significantly differ between normal and cirrhotic rats.
Conclusions: K_ATP channel opener-induced membrane hyperpolarization and K_ATP channel blocker-elicited membrane depolarization are blunted in smooth muscle cells in intact cirrhotic aortae. This blunting is due to the activation of the endothelin-1 pathway in the aortic wall, downstream to the endothelial production of endothelin-1.
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Vascular hyporesponsiveness to vasodilators in rats with cirrhosis

Abstract

J Hepatol

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Hepatology

Intracellular cyclic GMP receptor proteins

FASEB J

The nitrovasodilators. New ideas about old drugs

Circulation

Classification of calcium channels and the sites of action of drugs modifying channel function

Pharmacol Rev

Hemodynamic characterization of chronic bile duct-ligated rats: effect of pentobarbital sodium

Am J Physiol

Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat

Br J Exp Pathol