CONVERTING ENZYME-INHIBITION MODULATES SYMPATHETIC NEUROTRANSMISSION INVIVO VIA MULTIPLE MECHANISMS

We investigated the mechanism(s) by which angiotensin-converting enzym e (ACE) inhibition influences peripheral sympathetic neurotransmission . Thus effects of the angiotensin II (ANG II) receptor antagonist losa rtan (Du Pont 753) were compared with those of the ACE inhibitor benaz eprilat on sympathetic neurotransmission in canine gracilis muscle in situ, with alpha-adrenoceptors either intact or irreversibly blocked b y phenoxybenzamine. Furthermore, effects of the bradykinin receptor an tagonist HOE 140 and the prostaglandin synthesis inhibitor diclofenac were studied after ACE inhibition. Losartan reduced the vasoconstricto r response to exogenous ANG II by 76 +/- 4% at the dose used and lower ed muscle perfusion pressures. ACE inhibition by benazeprilat reduced plasma ANG-(1-8) octapeptide levels (from 8 +/- 2 to +/- 1 pM), mean a rterial pressure, and muscle perfusion pressures. After ACE inhibition , both HOE 140 (at a dose that reduced the vasodilatory response to ex ogenous bradykinin by 80 +/- 3%) and diclofenac elevated basal perfusi on pressures. Losartan reduced the nerve stimulation-evoked overflow o f endogenous norepinephrine (NE) (-14 +/- 6%) and vasoconstrictor resp onses (alpha-adrenoceptors intact). ACE inhibition increased NE overfl ow when a-adrenoceptors were intact (+12 +/- 5%) and tended to reduce it when alpha-adrenoceptors were blocked (-12 +/- 4%). During ACE inhi bition, HOE 140 reduced and diclofenac enhanced the evoked NE overflow . In the absence of ACE inhibition, neither HOE 140 nor diclofenac inf luenced NE overflow. Our findings indicate that ACE inhibition influen ces sympathetic neurotransmission via reduced ANG II formation and enh anced bradykinin and prostaglandin accumulation. The effects of ANG II on sympathetic neurotransmission are, however, small under these in v ivo conditions.