Relaxant effects of the selective phosphodiesterase inhibitors milrinone and OPC 3911 on isolated human mesenteric vessels.
Several new positive inotropic drugs with vasodilating properties for which a major mechanism of action is believed to be inhibition of phosphodiesterase (PDE) have been introduced in the treatment of congestive heart failure. Hydrolysis of cyclic nucleotides is catalyzed by multiple forms of PDE, which may vary between organs and cell-types. These enzymes can be selectively inhibited by various agents, theoretically making it possible to produce tissue-selective responses. An enzyme, which belongs to a subclass of cGMP inhibited low Km cAMP PDE, was recently purified from rat adipose tissue. The enzyme was specifically and potently inhibited by the cilostamide derivative OPC 3911 (OPC) and milrinone (mil). We studied the relaxant effects of OPC and mil on isolated human mesenteric arteries and veins in vitro. In preparations contracted by noradrenaline (NA), both agents produced about 60% maximum relaxation; OPC was 3-4 times more potent than mil. Both OPC and mil caused rightward displacement of the NA concentration-response curve and depressed the maximum responses. Arteries, as compared to veins, were more sensitive to this inhibition of NA contraction. Both drugs relaxed arteries contracted by 30 mM K+, but not 127 mM K+; maximum relaxation was between 60 and 70%. OPC was 10 times more potent than mil. The interactions between mil/OPC and isoprenaline, forskolin and ouabain were also studied. In preparations pretreated with isoprenaline or forskolin, the relaxant effects of mil and OPC were additive to those of isoprenaline and forskolin. Ouabain pretreatment did not affect the actions of the phosphodiesterase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
Lindgren
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S
Department of Clinical Pharmacology, University of Lund, University Hospital, Sweden.
Andersson
K E
KE
Belfrage
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P
Degerman
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E
Manganiello
V C
VC
D000328:Adult; D000368:Aged; D002121:Calcium Channel Blockers / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020105:Milrinone; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013152:Splanchnic Circulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D015363:Quinolones; D014665:Vasodilator Agents; D005576:Colforsin; D010042:Ouabain; C060853:OPC 3911; D020105:Milrinone; D007545:Isoproterenol; D011188:Potassium; D009638:Norepinephrine