Pharmacokinetics of regional angiotensin-II: a novel biologic response modifier.
BACKGROUND
The splanchnic vasoconstrictor angiotensin-II (A-II) has been shown to redistribute blood flow to hepatoma during systemic infusions. The hepatoma tumor derives all blood flow from the hepatic artery, whereas the normal liver has a dual blood supply from both the portal vein and the hepatic artery. We hypothesized that the pharmacokinetics of regional intrahepatic arterial A-II infusion could favorably distribute blood flow to the tumor while preserving portal flow to normal liver.


METHODS
ACI rats had 10(6) cultured H4IIE cells inoculated into the liver 10-14 days before study. Both systemic and splanchnic hemodynamics were measured by the radio-labeled microsphere technique during intrahepatic arterial or intravenous infusion of angiotensin-II or normal saline. The tumor-to-normal liver hepatic artery blood flow ratio was calculated.


RESULTS
Regional A-II produced a proportionately less systemic effect than did intravenous infusion. The tumor vasoconstrictive response to A-II was minimal, and the tumor-to-normal blood flow ratio was greater with intrahepatic arterial or intravenous A-II infusion than with normal saline. Cardiac output and portal vein flow were decreased dramatically during intravenous, but not during intrahepatic, arterial A-II.


CONCLUSIONS
Intrahepatic arterial A-II exhibits saturation kinetics with a system effect observed only after hepatic receptor saturation. Furthermore, the pharmacokinetics of intrahepatic arterial versus intravenous A-II indicate that intrahepatic arterial A-II will preferentially redistribute arterial blood flow to the tumor while synchronously preserving portal blood flow to the normal liver.
Wu
Y
Y
Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Sitzmann
J V
JV
D000804:Angiotensin II / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D004333:Drug Administration Routes; D006439:Hemodynamics / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011912:Rats, Inbred ACI; D014662:Vasoconstrictor Agents / Q000493:pharmacokinetics* / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D000804:Angiotensin II