Dose-Related Hepatic Blood Flow Effects Differentiate Nicorandil, Hydralazine, and Isosorbide Dinitrate in Healthy Subjects.
Dose response on hepatic blood flow of nicorandil (2.5, 5, and 10 mg), isosorbide dinitrate (5, 15, and 40 mg), and hydralazine (10, 25, and 50 mg) was assessed in 18 healthy subjects (6 per drug) using a three-period crossover design. Indocyanine green clearance was used to estimate hepatic blood flow before and at two timepoints after dosing. Greater hepatic blood flow changes occurred 90 (than 30) min after nicorandil and isosorbide dinitrate, and 60 (than 150) min after hydralazine. Nicorandil (mixed vasodilator) decreased hepatic blood flow by minus sign13 plus minus 4% (p < 0.05), minus sign15 plus minus 7%, and minus sign21 plus minus 6% (p < 0.05) (mean plus minus standard error of the mean) after 2.5, 5, and 10 mg, respectively; blood pressure was not reduced and heart rate was unchanged. Individual changes correlated poorly with plasma nicorandil concentrations. Isosorbide dinitrate (predominant venodilator) decreased hepatic blood flow by minus sign23 plus minus 9%, minus sign27 plus minus 5% (p < 0.05), and minus sign26 plus minus 7% (p < 0.05) after 5, 15, and 40 mg, respectively; blood pressure decreased (8--12 mm Hg) and heart rate increased (8 beats min(minus sign1)). Hydralazine (arterial dilator) increased hepatic blood flow by 29 plus minus 16%, 32 plus minus 11% (p < 0.05), and 33 plus minus 26% after 10, 25, and 50 mg, respectively; blood pressure was unchanged and heart rate increased (16 beats min(minus sign1)). Hepatic vascular resistance increased after nicorandil and isosorbide dinitrate but decreased after hydralazine. As assessed by hepatic blood flow response, nicorandil behaves more like a predominant venodilator than a direct arterial dilator. Dose and time variables were important to understanding the overall hemodynamic profile of each drug.
Wolf
Daniel L.
DL
Upjohn Research Clinics, The Upjohn Company, Kalamazoo, USA.
Metzler
Carl M.
CM
Froeschke
Monica O.
MO
Luderer
John R.
JR