Differential pharmacologic sensitivities of phosphodiesterase-3 inhibitors among human isolated gastroepiploic, internal mammary, and radial arteries.
Systematic investigations of the actions of phosphodiesterase (PDE)-3 inhibitors on different human vascular tissues have not been performed. We investigated the effects of specific PDE-3 inhibitors (olprinone, milrinone, and amrinone) on contracted human gastroepiploic arteries (n = 70), internal mammary arteries (n = 72), and radial arteries (n = 70) harvested from a total of 134 patients, all of whom were undergoing coronary artery bypass surgery. Each of these PDE-3 inhibitors dose-dependently diminished the contractile responses to 10(-6) mol/L norepinephrine and to either 10(-9) or 10(-8) mol/L of the thromboxane A2 analog U46619. In inducing vasorelaxations, these inhibitors were significantly more potent in norepinephrine-contracted rings than in those contracted with U46619. Further, at concentrations similar to the maximum therapeutic plasma concentrations (10(-7) mol/L olprinone; 10(-6) mol/L milrinone; 10(-5) mol/L amrinone) olprinone and milrinone were more potent at inducing relaxations than amrinone in gastroepiploic arteries and radial arteries, whereas in internal mammary arteries milrinone was more potent than the others. These results suggest different activities for the three PDE-3 inhibitors among human arteries located in different regions and may be informative about the effectiveness of these inhibitors in preventing spasms in the various arterial grafts used in revascularization.


CONCLUSIONS
Because three phosphodiesterase-3 inhibitors (milrinone, olprinone, and amrinone) differed in their vasodilator potencies (against the contractile response to either norepinephrine or a thromboxane A2 analog) among human arteries removed from different parts of the body, their vascular relaxation profiles should be considered before they are used clinically.
Onomoto
Masanori
M
*Department of Anesthesiology and Critical Care Medicine, †Second Department of Surgery, Kagoshima University School of Medicine, Kagoshima, Japan.
Tsuneyoshi
Isao
I
Yonetani
Arata
A
Suehiro
Shoich
S
Matsumoto
Kazuhisa
K
Sakata
Ryuzo
R
Kanmura
Yuichi
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000676:Amrinone / Q000493:pharmacokinetics / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004730:Endothelium, Vascular / Q000502:physiology; D024405:Gastroepiploic Artery / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008323:Mammary Arteries / Q000187:drug effects* / Q000502:physiology; D020105:Milrinone / Q000493:pharmacokinetics / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology; D017534:Radial Artery / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; C059498:olprinone; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D000676:Amrinone