Pravastatin administration does not induce detrimental effects on hemodynamics and collaterals of portal hypertensive rats.
OBJECTIVE
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor can enhance endothelial nitric oxide synthase expression and induce vasodilatation. The vasodilatory effect may be detrimental to portal-systemic collaterals due to aggravating the shunting degrees. The present study investigated the effects of pravastatin, a HMG-CoA reductase inhibitor, on the collateral vascular responsiveness to endothelin-1 (ET-1) and portal-systemic shunting in portal hypertensive rats.


METHODS
The partial portal vein-ligated (PVL) rats received either pravastatin (25 mg/kg per day) or distilled water since 2 days prior to until 7 days after ligation. On the 8(th) day following hemodynamic measurements, the collateral vascular responsiveness to ET-1 was evaluated by an in situ collateral perfusion model. The shunting degrees of collaterals were evaluated by constructing vascular flow-pressure curves and color microsphere study, respectively. PVL rats underwent pre-incubation with: (i) Krebs solution (control); or Krebs solution plus (ii) 2 x 10(-5) M pravastatin; (iii) pravastatin + N(omega)-nitro-L-arginine (10(-4) M); and (iv) pravastatin + indomethacin (10(-5) M), followed by ET-1 (10(-10)-10(-7) M) administration to evaluate the collateral vascular responsiveness.


RESULTS
In chronic study, pravastatin did not modify systemic and portal hemodynamics and collateral vascular responsiveness to ET-1. The resistances of flow-pressure curves and the microsphere study demonstrated similar shunting degrees between both groups. Furthermore, pravastatin pre-incubation didn't reduce collateral perfusion pressure to ET-1.


CONCLUSIONS
Chronic pravastatin administration does not induce detrimental effects on hemodynamics and collaterals in PVL rats, nor does it influence the shunting degree. In addition, it does not modify the vasoconstrictive effect of ET-1 on the collaterals of PVL rats.
Chang
Ching-Chih
CC
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Wang
Sun-Sang
SS
Huang
Hui-Chun
HC
Lee
Jing-Yi
JY
Lee
Fa-Yauh
FY
Lin
Han-Chieh
HC
Lee
Shou-Dong
SD
D000818:Animals; D003097:Collateral Circulation / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006975:Hypertension, Portal / Q000378:metabolism / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D011168:Portal System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D017035:Pravastatin; D007213:Indomethacin