ROLE OF KININS AND NITRIC-OXIDE IN THE EFFECTS OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS ON NEOINTIMA FORMATION

Marked neointima formation occurs after balloon injury to the intima o f rat arteries. Angiotensin II has been implicated as a growth factor in this process, since angiotensin converting enzyme (ACE) inhibitors block neointima formation after injury. However, ACE is an important k ininase, and its inhibitors may act in part by a kinin-mediated mechan ism. Kinins are also known to stimulate synthesis of endothelium-deriv ed relaxing factor/nitric oxide (EDRF/NO) and prostacyclin, both of wh ich have antigrowth effects. To determine whether the effect of ACE in hibitors on neointima formation is due to blockade of angiotensin II s ynthesis alone and/or inhibition of kinin inactivation, we followed tw o approaches. First, we compared the inhibition of neointima formation induced by the AT1-type angiotensin II receptor antagonist losartan w ith that caused by the ACE inhibitor ramipril. We also studied whether a kinin receptor antagonist, Hoe 140, blocks the effect of two differ ent ACE inhibitors, ramipril and enalapril, on neointima formation. In addition, we studied whether the effect of ramipril is blocked by an NO synthesis inhibitor, N(omega)-nitro-L-arginine-methyl ester (L-NAME ). Although both ramipril and losartan significantly reduced neointima formation, ramipril had a more marked effect (p < 0.05 for ramipril v ersus losartan). The kinin antagonist Hoe 140 reduced the inhibitory e ffect of ramipril and enalapril by 73% and 62%, respectively. The rema ining effect of the ACE inhibitors was now similar to that of losartan . Inhibition of neointima formation by ramipril was also blocked by th e NO synthesis inhibitor L-NAME. Therefore, we suggest that the protec tive effect of ACE inhibitors is due to both blockade of angiotensin I I formation and kinin degradation. We also suggest that NO may mediate the effect of kinins. The fact that L-NAME blocked the effect of rami pril on neointima formation suggests that NO may play a major role in the inhibitory effect of ACE inhibitors.