Angiotensin-converting enzyme inhibitor enhances liver regeneration following partial hepatectomy: involvement of bradykinin B2 and angiotensin AT1 receptors.
Angiotensin-converting enzyme (ACE) inhibitor enhances the liver regeneration in rats after partial hepatectomy (PH), though the precise mechanisms are unknown. To determine the roles of bradykinin and angiotensin II in the ACE inhibitor-induced enhancement of liver regeneration, we investigated effects of lisinopril (ACE inhibitor), candesartan and losartan (angiotensin II type 1 (AT1) receptor antagonists) and icatibant (bradykinin B2 receptor antagonist) on the hepatic regenerative response to 70% PH in the rat. The liver regeneration was evaluated by measuring the frequency of 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte nuclei 48 h after PH. We found that administration of candesartan or losartan, as well as lisinopril, enhanced BrdU incorporation after PH, and the lisinopril-induced enhancement was inhibited in part (40%) by icatibant. PH induced the expression of hepatocyte growth factor (HGF) mRNA in remnant liver, and this PH-induced up-regulation of HGF mRNA was further enhanced not only by lisinopril but also by candesartan and losartan. Administration of icatibant inhibited up to 40% of the lisinopril-induced up-regulation of HGF mRNA. These results suggest that the blockade of the renin-angiotensin system by either ACE inhibitor or AT1 receptor antagonist enhances the hepatic regenerative response to PH, probably through an augmentation of hepatic HGF production. In addition to this mechanism, the activation of B2 receptors may also be involved in the ACE inhibitor-induced enhancement of hepatic regenerative response.
Yayama
Katsutoshi
K
Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University.
Sugiyama
Kaori
K
Miyagi
Ryoko
R
Okamoto
Hiroshi
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D001973:Bromodeoxyuridine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006498:Hepatectomy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D017706:Lisinopril / Q000494:pharmacology; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065094:Bradykinin B2 Receptor Antagonists; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D013777:Tetrazoles; D017228:Hepatocyte Growth Factor; C065679:icatibant; D017706:Lisinopril; D001973:Bromodeoxyuridine; D019808:Losartan; C081643:candesartan; D001920:Bradykinin