Blockade of ATP-sensitive K+ channels by glibenclamide reduces portal pressure and hyperkinetic circulation in portal hypertensive rats

doi:10.1016/S0168-8278(05)80118-7

Journal of Hepatology

Volume 16, Issues 1–2, 1992, Pages 215-218

https://doi.org/10.1016/S0168-8278(05)80118-7 Get rights and content

Certain results of in vitro studies raise the possibility that blockade of ATP-sensitive K⁺ channels by glibenclamide may induce vasoconstriction. Therefore, this substance might decrease portal pressure and hyperkinetic circulation in animals with portal hypertension. Thus, systemic and regional hemodynamics (radioactive microspheres) were measured before and 20 min after a bolus intravenous injection of glibenclamide (20 mg/kg) in conscious rats with portal vein stenosis. Blood pressure decreased significantly from 14.5±1.5 to 12.2±1.2 (mean±SE). Cardiac index significantly decreased by 24%, portal tributary blood flow by 31%, and hepatic artery blood flow by 35%. Systemic vascular resistance significantly increased by 38%, portal territory vascular resistance and hepatic artery vascular resistance by 61%, each, and renal vascular resistance by 17%. Arterial pressure, heart rate, and renal blood flow were unchanged. Moreover, glibenclamide blunted the vasodilating action of diazoxide (an ATP-sensitive K⁺ channel opener). These results show that in rats with extrahepatic portal hypertension the blockade of ATP-sensitive K⁺ channels by glibenclamide reduces portal pressure and hyperkinetic circulation.

References (7)

QuastU et al.
Moving together: K⁺ channel openers and ATP-sensitive K⁺ channels
Trends Pharmacol Sci
(1989)
StandenNB et al.
Hyperpolarizing vasodilators activate ATP-sensitive K⁺ channels in arterial smooth muscle
Science
(1989)
QuastU et al.
In vitro and in vivo comparison of two channel openers, diazoxide and cromakalim, and their inhibition by glibenclamide
J Pharmacol Exp Ther
(1989)

There are more references available in the full text version of this article.

Cited by (22)

Hydrogen sulfide and the liver
2014, Nitric Oxide - Biology and Chemistry
Citation Excerpt :
One key mechanism for H2S-induced vasorelaxation is the opening of KATP channels [17]. Moreau et al. showed that blockade of KATP channels by glibenclamide reduced portal pressure in portal hypertensive rats [108]. Whether endogenously produced H2S controls the functional status of KATP channels in portal circulation has not been reported.
Hydrogen sulfide (H₂S) is a gasotransmitter that regulates numerous physiological and pathophysiological processes in our body. Enzymatic production of H₂S is catalyzed by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST). All these three enzymes present in the liver and via H₂S production regulate liver functions. The liver is the hub for metabolism of glucose and lipids, and maintains the level of circulatory lipids through lipoprotein metabolism. Hepatic H₂S metabolism affects glucose metabolism, insulin sensitivity, lipoprotein synthesis, mitochondrial biogenetics and biogenesis. Malfunction of hepatic H₂S metabolism may be involved in many liver diseases, such as hepatic fibrosis and hepatic cirrhosis.
Progress in portal hypertension
2009, Gastroenterologie Clinique et Biologique
Chez les malades atteints d’hypertension portale due à une cirrhose, les mécanismes responsables de modifications circulatoires sont assez bien connus. Il existe une augmentation de la résistance vasculaire intrahépatique due en partie à une hyperproduction d’endothéline et une diminution de la production de monoxyde d’azote (NO) dans le foie. L’hypercinésie circulatoire et la vasodilatation systémique et splanchnique dépendent en partie à l’hyperproduction de NO artériel. La présence et le degré de l’hypertension portale peuvent être mesurés par le gradient de pression hépatique mais des techniques non invasives, comme le FibroTest et le FibroScan, devraient permettre d’identifier la présence d’une hypertension portale sévère. Il existe de nombreuses substances capables de diminuer la pression porte soit en diminuant la résistance vasculaire hépatique soit en diminuant le débit sanguin dans le territoire porte. L’association de ces différents médicaments pourrait être à l’avenir le traitement pharmacologique le plus efficace, mais d’autres études hémodynamiques et cliniques sont encore nécessaires.
In patients with portal hypertension due to cirrhosis, the mechanisms responsible for circulatory modifications are well-known. An elevation in intrahepatic vascular resistance related to a hepatic endothelin hyperproduction and an arterial nitric oxide (NO) hyperproduction. The presence and the degree of portal hypertension might be determined by the measurement of the hepatic venous pressure gradient but non-invasive technique as FibroTest or FibroScan might be useful to estimate the presence of severe portal hypertension. Numerous substances decrease portal pressure either by reducing hepatic vascular resistance or by reducing portal tributary blood flow. The combination of both types of substances is probably the best pharmacological treatment of portal hypertension but further hemodynamic and clinical studies are needed.
Pharmacological treatment of portal hypertension: Present and future
1998, Journal of Hepatology
Haemodynamic and hormonal responses to long-term inhibition of nitric oxide synthesis in rats with portal hypertension
1996, European Journal of Pharmacology
In portal hypertension, the role of the vasorelaxant nitric oxide (NO) in long-term splanchnic and systemic vascular tone regulation is unclear. This study examined the effects of long-term administration of a NO synthesis inhibitor on haemodynamics in portal hypertensive rats. Rats were randomly assigned to receive either water (placebo) or 100 mg/kg · day of oral N-nitro-l-arginine methylester (l-NAME) for 28 days. At 14 days, the portal vein was ligated in 10 rats from each group. At 28 days, splanchnic and systemic blood flows were measured in 20 normal and 20 portal vein stenosed rats. Plasma atrial natriuretic peptide (ANP) concentrations as well as plasma and urinary cyclic guanosine monophosphate (cGMP) levels were also measured. Porto-systemic shunts were measured in other portal vein stenosed animals that had or had not received l-NAME. Portal vein stenosed rats that received l-NAME had significantly lower portal tributary blood flow and percentages of portal-systemic shunting (7.3 ± 0.5 versus 3.7 ± 0.2 ml/min · 100 g and 96 ± 1 versus 68 ± 5%, respectively) and higher hepatocollateral vascular resistance (147 ± 10 versus 295 ± 30 dyn · s · cm⁻⁵ · 100 g · 10³, respectively) than placebo portal vein stenosed rats. Portal pressure, ANP and cGMP levels did not differ between the groups. Arterial pressure was significantly higher and cardiac index lower after l-NAME than after placebo. Normal rats had similar but less marked l-NAME-induced responses than portal hypertensive rats. The presence of a long-term l-NAME-induced vasoconstriction in collateral vessels and splanchnic and systemic arterioles in portal vein stenosed rats indicates that a NO-mediated vasodilator tone may contribute to the development and the maintenance of collateral circulation as well as splanchnic and systemic vasodilation in portal hypertension. Moreover, the NO-mediated vasodilator tone in portal hypertensive animals seems to be increased.
Functional evidence for a glibenclamide-sensitive K<sup>+</sup> channel in rat ileal smooth muscle
1994, European Journal of Pharmacology
The motor activity of gastrointestinal smooth muscle is closely related to the membrane potential. Controlling the membrane potential via modulation of K⁺ channels is essential for the action of neurotransmitters on smooth muscle. In the present study the effect of the K⁺ channel activator, lemakalim, on longitudinal smooth muscle of the rat ileum was investigated. Segments of rat ileum were stimulated by the muscarinic receptor agonist, carbachol (10⁻⁶ M). Lemakalim (10⁻¹⁰ to 3 × 10⁻⁵ M) induced a dose-dependent inhibition of the carbachol-induced contraction. This inhibitory effect of lemakalim was not modified by neural blockade with tetrodotoxin (10⁻⁶, n = 9). Glibenclamide (10⁻⁷ to 10⁻⁵ M), a specific blocker of ATP-dependent K⁺ channels antagonized dose dependently the relaxant effect of lemakalim (IC₅₀: 3.4 × 10⁻⁶ M, n = 11, P < 0,001). In contrast, apamin (10⁻⁷ M, n = 9, n.s.) and charybdotoxin (10⁻⁷ M, n = 9, n.s.), specific blockers of Ca²⁺-dependent K⁺ channels and the non-specific K⁺ channel blocker, tetraethylammonium (10⁻⁴ to 10⁻¹ M), had no influence on the inhibitory effect of lemakalim. Contractions induced by the Ca²⁺ channel activator, Bay-K-8644, were completely inhibited by lemakalim (10⁻⁵ M, n = 12). This inhibitory effect was also selectively antagonized by glibenclamide (10⁻⁵ M). Potential non-adrenergic non-cholinergic (NANC) inhibitory mediators like ATP, nitric oxide (NO) or neurotensin showed no sensitivity to glibenclamide. These functional data indicate that the relaxant effect of lemakalim is due to a specific activation of glibenclamide-sensitive K⁺ channels, which in turn can modulate the activity of dihydropyridine-sensitive (voltage-dependent) Ca²⁺ channels. A physiological or pathophysiological role of the glibenclamide-sensitive K⁺ channels in intestinal smooth muscle is discussed; however, they seem not to be involved in the effect of the NANC inhibitory mediators tested.
Altered control of vascular tone by adenosine triphosphate-sensitive potassium channels in rats with cirrhosis
1994, Gastroenterology
Background/Aims: Because the activation of arterial adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channels is known to induce vasodilation, these channels may contribute to baseline vasodilator tone in cirrhosis. This study aimed to examine hemodynamic responses to glibenclamide, a K_ATP channel blocker, and to aprikalim, a vasodilator activating K_ATP channels, in normal and cirrhotic rats. Methods: Splanchnic and systemic hemodynamic responses to glibenclamide (2.5, 5, 20, 30 mg/kg, intravenously) were studied. The arterial pressure response to aprikalim (200 μ/kg, intravenously) was studied with and without glibenclamide pretreatment (20 mg/kg). Results: In cirrhotic rats, glibenclamide (5, 20, 30 mg/kg but not 2.5 mg/ kg) significantly increased vascular resistance in portal and systemic territories. In normal rats, the latter effects occurred with 20 and 30 mg/kg of glibenclamide only. Aprikalim-induced arterial hypotension was significantly less marked in cirrhotic than in normal rats. Following glibenclamide, aprikalim-induced arterial hypotension was significantly less marked in cirrhotic than in normal animals. Conclusions: In rats with cirrhosis, the glibenclamide-induced vasoconstriction indicates that a vasodilator tone due to K_ATP channel opening existed under baseline conditions. Moreover, this study suggests that the control of vascular tone by K_ATP channels is altered in cirrhosis.

View all citing articles on Scopus

View full text

Rapid PublicationBlockade of ATP-sensitive K+ channels by glibenclamide reduces portal pressure and hyperkinetic circulation in portal hypertensive rats

Trends Pharmacol Sci

Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle

Science

In vitro and in vivo comparison of two channel openers, diazoxide and cromakalim, and their inhibition by glibenclamide

J Pharmacol Exp Ther

Rapid Publication
Blockade of ATP-sensitive K⁺ channels by glibenclamide reduces portal pressure and hyperkinetic circulation in portal hypertensive rats

Hyperpolarizing vasodilators activate ATP-sensitive K⁺ channels in arterial smooth muscle