Effect of the nitric oxide donor V-PYRRO/NO on portal pressure and sinusoidal dynamics in normal and cirrhotic mice.
Reduced sinusoidal endothelial nitric oxide (NO) production contributes to increased intrahepatic resistance and portal hypertension after liver injury. We hypothesized that V-PYRRO/NO, an NO donor prodrug metabolized "specifically" in the liver, would reduce portal venous pressure (PVP) without affecting the systemic vasculature. Liver injury was induced in male BALB/c mice by weekly CCl(4) gavage. PVP and mean arterial pressure were recorded during intravenous administration of V-PYRRO/NO. In vivo microscopy was used to monitor sinusoidal diameter and flow during drug administration. Mean PVP was increased in CCl(4)-treated mice compared with sham-treated mice. In dose-response experiments, the minimum dose of PYRRO/NO required to acutely lower PVP by 20%, the amount believed to yield a clinically meaningful outcome, was 200 nmol/kg. This dose decreased portal pressure in cirrhotic (23.4 +/- 2.0%, P < 0.001 vs. vehicle) and sham-treated (19.5 +/- 2.3%, P < 0.001 vs. vehicle) animals by a similar magnitude. This concentration also led to dilation of hepatic sinusoids and an increase in sinusoidal volumetric flow, consistent with a reduction of intrahepatic resistance. The effect of V-PYRRO/NO on mean arterial pressure was significant at all concentrations tested, including the lowest, 30 nmol/kg (P < 0.001 vs. vehicle for all doses). We conclude that V-PYRRO/NO had widespread vascular effects and, as such, is unlikely to be suitable for treatment of portal hypertension. As the potential of this or other similar compounds for treatment of portal hypertension is evaluated, effects on the systemic vasculature will also need to be considered.
Edwards
Claire
C
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Feng
Hong-Qiang
HQ
Reynolds
Christopher
C
Mao
Lan
L
Rockey
Don C
DC
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects*; D002251:Carbon Tetrachloride; D004305:Dose-Response Relationship, Drug; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D017082:Portal Pressure / Q000187:drug effects*; D011759:Pyrrolidines / Q000008:administration & dosage*; D012016:Reference Values; D014664:Vasodilation / Q000187:drug effects*
D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; D002251:Carbon Tetrachloride