Effects of isozyme-selective phosphodiesterase inhibitors on rat aorta and human platelets: smooth muscle tone, platelet aggregation and cAMP levels.
The inhibitors of the cGMP-inhibited, low-Km cAMP phosphodiesterase--milrinone and OPC 3911--and an inhibitor of a non-cGMP-inhibited low-Km cAMP phosphodiesterase--rolipram--were used to evaluate the functional importance of the two cAMP phosphodiesterase activities in vascular smooth muscle and in platelets. Vinpocetine, an inhibitor of a calcium-calmodulin-dependent phosphodiesterase was also studied. OPC 3911 and milrinone relaxed the contracted rat aorta, inhibited ADP-induced platelet aggregation and also enhanced isoprenaline-induced relaxation as well as the antiaggregatory effects of adenosine. In platelets, OPC 3911 and milrinone increased cAMP levels, but in the rat aorta the increase was significant only for milrinone (OPC 3911 P = 0.062). In both tissues OPC 3911 and milrinone enhanced the increase in cAMP caused by activators of adenylate cyclase (isoprenaline/adenosine). Rolipram had no effects on aggregation or cAMP levels in platelets and no overadditive effects in combination with adenosine. Rolipram had little effect on relaxation and cAMP levels, did not alter isoprenaline-induced relaxation of guanfacin-contracted rat aorta, but showed synergistic effects with isoprenaline in raising cAMP levels. In PGF2 alpha-contracted aorta rolipram enhanced relaxation caused by isoprenaline. Vinpocetine had a relaxant effect without affecting cAMP levels, but had no effect on platelets. These results support the concept that the cGMP-inhibited phosphodiesterase is an important modulator of vascular smooth muscle tone and platelet function. The role of the non-cGMP-inhibited phosphodiesterase in these tissues is less obvious.
Lindgren
S H
SH
Department of Clinical Pharmacology, University Hospital, Lund, Sweden.
Andersson
T L
TL
Vinge
E
E
Andersson
K E
KE
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D016316:Guanfacine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone; D009129:Muscle Tonus / Q000187:drug effects*; D009130:Muscle, Smooth / Q000201:enzymology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014748:Vinca Alkaloids / Q000494:pharmacology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011728:Pyridones; D015363:Quinolones; D014748:Vinca Alkaloids; D016316:Guanfacine; C013983:vinpocetine; C060853:OPC 3911; D000242:Cyclic AMP; D020105:Milrinone; D007545:Isoproterenol