Simvastatin effects on portal-systemic collaterals of portal hypertensive rats.
OBJECTIVE
Portal-systemic collateral vascular resistance and vasoconstrictor responsiveness are crucial in portal hypertension and variceal bleeding control. Statins enhance vasodilators production, but their influence on collaterals is unknown. This study aimed to survey the effect of simvastatin on collaterals.


METHODS
Partially portal vein-ligated rats received oral simvastatin (20 mg/kg/day) or distilled water from -2 to +7 day of ligation. After hemodynamic measurements on the eighth postoperative day, baseline perfusion pressure (i.e. an index of collateral vascular resistance) and arginine vasopressin (AVP, 0.1 nM-0.1 microM) responsiveness were evaluated with an in situ perfusion model for collateral vascular beds. RT-PCR of endothelial NO synthase (eNOS), inducible NOS (iNOS), cyclooxygenase-1 (COX-1), COX-2, thromboxane A(2) synthase (TXA(2)-S) and prostacyclin synthase genes was performed in parallel groups for splenorenal shunt (SRS), the most prominent intra-abdominal collateral vessel. To determine the acute effects of simvastatin, collateral AVP response was assessed with vehicle or simvastatin. SRS RT-PCR of eNOS, iNOS, COX-1, COX-2 and TXA(2)-S, and measurements of perfusate nitrite/nitrate, 6-keto-PGF1(alpha) and TXB(2) levels were performed in parallel groups without AVP.


RESULTS
Acute simvastatin administration enhanced SRS eNOS expression and elevated perfusate nitrite/nitrate and 6-keto-PGF1(alpha) concentrations. Chronic simvastatin treatment reduced baseline collateral vascular resistance and portal pressure and enhanced SRS eNOS, COX-2 and TXA(2)-S mRNA expression. Neither acute nor chronic simvastatin administration influenced collateral AVP responsiveness.


CONCLUSIONS
Simvastatin reduces portal-systemic collateral vascular resistance and portal pressure in portal hypertensive rats. This may be related to the enhanced portal-systemic collateral vascular NO and prostacyclin activities.
Huang
Hui-Chun
HC
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Wang
Sun-Sang
SS
Lee
Jing-Yi
JY
Chen
Yi-Chou
YC
Lee
Fa-Yauh
FY
Lin
Han-Chieh
HC
Chang
Ching-Chih
CC
Lee
Shou-Dong
SD
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D003097:Collateral Circulation / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006975:Hypertension, Portal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects; D011168:Portal System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C078129:6-keto-prostaglandin F2alpha; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D013929:Thromboxane B2; D019821:Simvastatin; D015237:Dinoprost; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D013930:Thromboxane-A Synthase