Inhibition of the low Km cyclic AMP phosphodiesterase and activation of the cyclic AMP system in vascular smooth muscle by milrinone.
The purposes of the present study were to quantitate the effects of the cardiotonic/vasodilator milrinone on phosphodiesterase (PDE) isozymes isolated from vascular (aortic) smooth muscle from several species, and to quantitate changes in cellular cyclic AMP (cAMP) content, activation of cAMP protein kinase (cAPK) and vasorelaxation by milrinone in isolated guinea pig aortic smooth muscle. With PDE isozymes isolated from rat (Wistar-Kyoto or spontaneously hypertensive rats), guinea pig, monkey or canine aortic smooth muscle, milrinone is a potent (IC50 = 0.16-0.90 microM) and selective (100 times peak III relative to peak I) peak III inhibitor. The potency of milrinone and other vascular peak III PDE inhibitors parallels their potency as vasorelaxants in isolated guinea pig aortic rings (r = 0.86; P less than .01). Vasorelaxation of phenylephrine-contracted (3 microM) guinea pig aortic rings is accompanied by significant increases in cAMP content or cAPK activation with concentrations of milrinone greater than or equal to 10 microM. Temporally, significant increases in cAMP content accompany significant vasorelaxation; however, activation of cAPK is not significantly increased until at least 1 to 2 min after addition of milrinone. Similar concentration and temporal relationships are seen with the cAMP-related vasorelaxants papaverine and forskolin. As with milrinone, a temporal dissociation between increases in cAMP content and increases in cAPK activity ratio is evident.(ABSTRACT TRUNCATED AT 250 WORDS)
Silver
P J
PJ
Department of Pharmacology, Sterling-Winthrop Research Institute, Rensselaer, New York.
Lepore
R E
RE
O'Connor
B
B
Lemp
B M
BM
Hamel
L T
LT
Bentley
R G
RG
Harris
A L
AL
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000242:Cyclic AMP / Q000032:analysis*; D006152:Cyclic GMP / Q000032:analysis; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D008297:Male; D020105:Milrinone; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D011494:Protein Kinases / Q000032:analysis*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects
D007527:Isoenzymes; D011728:Pyridones; D000242:Cyclic AMP; D011494:Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP; D020105:Milrinone