PHOSPHODIESTERASE-III AND PHOSPHODIESTERASE-V INHIBITORS ON PULMONARY-ARTERY FROM PULMONARY HYPERTENSIVE RATS - DIFFERENCES BETWEEN EARLY AND ESTABLISHED PULMONARY-HYPERTENSION

Milrinone and 8(methylamino)imidazo[1,2a]pyrazine-2-carbonitrile [SCA4 0; 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 e xposed to hypoxia (10% O-2; 1 or 4 weeks) to induce pulmonary hyperten sion. Each drug fully relaxed preparations precontracted submaximally with phenylephrine. In the absence of endothelium or the presence of t he nitric oxide synthase inhibitor, L-NAME, responses to zaprinast, bu t 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 co rresponding control values (6.05; 5.88; 6.65; 5.64) but in early pulmo nary hypertension (1-week hypoxic rats), all except IBMX had reduced p otency. The potency of the adenylate cyclase activator, forskolin, was reduced in arteries from both groups of rats. In early, but not estab lished, pulmonary hyper tension, arteries had inherent tone, spontaneo us 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 inhibitor s are not compromised in established pulmonary hypertension, and (c) d ata on pulmonary vascular function obtained in 1-week hypoxic rats do not necessarily reflect data in rats exposed to hypoxia for longer per iods.