Bioactivation of nitroglycerin and vasomotor response to nitric oxide are impaired in cirrhotic rat livers.
Nitroglycerin (NTG), a nitric oxide (NO) donor, has been shown to reduce portal pressure in cirrhotic patients. Using the in situ perfusion of normal and cirrhotic rat livers, we compared the vascular relaxation induced by either NTG or the spontaneous nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP). Normal and cirrhotic livers were perfused (40 mL/min, 37 degrees C) with Krebs' solution in a recirculating system. After preconstriction with methoxamine (10(-4) mol/L), a dose-response study was performed using 6 cumulative doses of NTG or SNAP (10(-7) to 3 x 10(-5) mol/L). NO(x) (NO(-)(2) + NO(-)(2) production in the perfusate was measured by chemiluminescence. Cirrhotic livers exhibited lower vasorelaxant responses, compared with normal livers, to both NTG (P <.0001) and SNAP (P =.0020). In normal livers, NTG and SNAP induced similar vasorelaxant responses (P =.44). In cirrhotic livers, NTG induced less vasorelaxation than SNAP (P <.0001). In the presence of NTG (P =.0045), but not SNAP (P =.99), NO(x) production in experiments with cirrhotic livers was lower than in experiments with normal livers. In conclusion, in cirrhotic rat livers, the vasorelaxant response to NTG is impaired owing to both a decreased metabolism of this NO donor and an inability of the hepatic vasculature to respond to NO.
Dudenhoefer
Amy A
AA
Hepatic Hemodynamic Laboratory, VA Medical Center, West Haven, CT 06516, USA.
Loureiro-Silva
Maurício R
MR
Cadelina
Gregory W
GW
Gupta
Tarun
T
Groszmann
Roberto J
RJ
D000818:Animals; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism* / Q000494:pharmacology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology
D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D005996:Nitroglycerin