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Large-conductance calcium-activated potassium channels modulate vascular tone in experimental cirrhosis
Aina Rodríguez-Vilarrupla1, Mariona Graupera, Vasilica Matei
1Hepatic Hemodynamic Laboratory, Liver Unit, Institut Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ciberehd, Barcelona, Spain.
Insights
Large-conductance calcium-activated potassium (BK(Ca)) channels are overexpressed in cirrhotic rat livers. This suggests BK(Ca) channels may compensate for increased hepatic vascular tone in cirrhosis.
Area of Science:
- Physiology
- Pharmacology
- Hepatology
Background:
- Large-conductance calcium-activated potassium (BK(Ca)) channels are key regulators of vascular tone.
- Activated hepatic stellate cells (HSC) express BK(Ca) channels.
- Cirrhosis is associated with altered liver vascular tone.
Purpose of the Study:
- To investigate the role of BK(Ca) channels in regulating vascular tone in normal and cirrhotic rat livers.
- To assess BK(Ca) channel expression in cirrhotic livers.
Main Methods:
- Portal perfusion pressure (PP) was measured in response to vasoconstrictors and vasodilators.
- BK(Ca) channel blockers (Iberiotoxin) and openers (NS1619) were used.
- BK(Ca) mRNA and protein expression in HSC was quantified.
Main Results:
- BK(Ca) channel blockade increased baseline PP and exacerbated vasoconstriction in cirrhotic livers.
- BK(Ca) channel activation had a mild effect on baseline PP but attenuated hyperresponse to vasoconstrictors.
- Both BK(Ca) mRNA and protein levels were upregulated in cirrhotic livers.
Conclusions:
- BK(Ca) channels are overexpressed in carbon tetrachloride-induced cirrhosis.
- Overexpression of BK(Ca) channels may represent a compensatory mechanism against increased hepatic vascular tone in cirrhosis.
Background:
Large-conductance calcium-activated potassium (BK(Ca)) channels regulate vascular tone in different vascular systems. Moreover, activated hepatic stellate cells (HSC) contain BK(Ca) channels. The aim of this study was to evaluate the role of BK(Ca) channels in the regulation of vascular tone in control (CT) and carbon tetrachloride-cirrhotic (CH) rat livers.
Methods:
Changes in intrahepatic vascular resistance were assessed by evaluating the portal perfusion pressure (PP) response to methoxamine (Mtx) in the presence of Iberiotoxin (Ibtx; a BK(Ca) channel blocker), NS1619 (a BK(Ca) channel opener), Ibtx plus the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine (L-NNA) or L-NNA alone. In addition, in CH livers, PP dose-response curves to the NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), were performed after pre-incubation with Ibtx or its vehicle. BK(Ca) mRNA expression was assessed in liver homogenates, and BK(Ca) protein expression in HSC isolated from CT and CH livers.
Results:
In CH livers, Ibtx significantly increased baseline PP and exacerbated the PP response to Mtx. Conversely, NS1619 induced a mild nonsignificant decrease of baseline PP and attenuated the hyperresponse to Mtx. CH livers exhibited an upregulation of both mRNA and protein of the alpha-subunit of BK(Ca).
Conclusion:
Large-conductance calcium-activated potassium channels are overexpressed in CH livers and might represent a compensatory mechanism modulating the increased hepatic vascular tone of cirrhosis.
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