Phosphodiesterase III and V inhibitors on pulmonary artery from pulmonary hypertensive rats: differences between early and established pulmonary hypertension.
Milrinone and 6-bromo-8(methylamino)imidazo[1,2a]pyrazine-2-carbonitrile [SCA40; phosphodiesterase (PDE) III inhibitors], zaprinast (PDE V inhibitor), and 3-isobutyl-1-methyl xanthine (IBMX; nonselective PDE inhibitor) were examined on main pulmonary arteries from control rats and rats exposed to hypoxia (10% O2; 1 or 4 weeks) to induce pulmonary hypertension. Each drug fully relaxed preparations precontracted submaximally with phenylephrine. In the absence of endothelium or the presence of the nitric oxide synthase inhibitor, L-NAME, responses to zaprinast, but not the other drugs, were reduced but not abolished. The potencies [negative log median effective concentration (EC50)] of the drugs in 4-week hypoxic rats (established pulmonary hypertension; zaprinast, 5.60; milrinone, 5.64; SCA40, 6.41; IBMX, 5.38) were not different from corresponding control values (6.05; 5.88; 6.65; 5.64) but in early pulmonary hypertension (1-week hypoxic rats), all except IBMX had reduced potency. The potency of the adenylate cyclase activator, forskolin, was reduced in arteries from both groups of rats. In early, but not established, pulmonary hypertension, arteries had inherent tone, spontaneous contractions, and diminished endothelial function. In established, but not early, pulmonary hypertension, arteries had increased overall contractile ability. It is concluded that (a) PDE V inhibitors require cyclic guanosine monophosphate (cGMP) produced by endothelial nitric oxide for optimal effect, (b) the potencies of PDE III and V inhibitors are not compromised in established pulmonary hypertension, and (c) data on pulmonary vascular function obtained in 1-week hypoxic rats do not necessarily reflect data in rats exposed to hypoxia for longer periods.
Jeffery
T K
TK
Department of Physiology and Pharmacology, The University of Queensland, St. Lucia, Australia.
Wanstall
J C
JC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology; D000860:Hypoxia / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020105:Milrinone; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011728:Pyridones; C080660:6-bromo-8-methylaminoimidazo(1,2-a)pyrazine-2-carbonitrile; D005576:Colforsin; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D020105:Milrinone; D015056:1-Methyl-3-isobutylxanthine