PARTICIPATION OF PROSTAGLANDINS AND BRADYKININ IN THE EFFECTS OF ANGIOTENSIN-II AND CONVERTING ENZYME-INHIBITION ON SYMPATHETIC NEUROTRANSMISSION IN-VIVO

We investigated the mechanism(s) by which angiotensin converting enzym e (ACE)-inhibition and angiotensin (Ang) II influence peripheral sympa thetic neurotransmission in canine gracilis muscle in situ, with alpha -adrenoceptors either intact or irreversibly blocked by phenoxybenzami ne. ACE-inhibition by ramiprilat reduced, and subsequent infusion of A ng II (30 ng kg(-1) min(-1) i.v.) markedly increased arterial plasma A ng-(1-8)octapeptide levels, basal muscle perfusion pressures and mean arterial pressure. Local intra-arterial bolus injection of Ang II caus ed marked vasoconstriction followed by vasodilation. This vasoconstric tor response was enhanced and the ensuing vasodilation was abolished f ollowing prostaglandin synthesis inhibition by diclofenac. The vasocon strictor response to low frequency (0.5 Hz) sympathetic nerve stimulat ion was also enhanced by diclofenac. The nerve stimulation-evoked nora drenaline (NA) overflow was reduced by ramiprilat when alpha-adrenocep tors were blocked (-11 +/- 3%, P < 0.05), but increased when alpha-adr enoceptors were intact (+28 +/- 14%, P < 0.05). During ACE-inhibition, effective bradykinin receptor antagonism by HOE 140 reduced stimulati on-evoked NA overflow irrespective of alpha-adrenoceptor blockade (i.e . by 25 +/- 5 and 20 +/- 3% in the absence and presence of alpha-adren oceptor blockade, respectively, P < 0.01). Diclofenac increased stimul ation-evoked NA overflow in the absence of alpha-adrenoceptor blockade (+19 +/- 4%, P < 0.05). I.v. infusion of Ang II failed to enhance sti mulation-evoked NA overflow both before and after diclofenac. In concl usion, the results support the ideas that local formation of Ang II an d bradykinin facilitate, and of prostaglandins inhibit NA release, and that ACE inhibition influences sympathetic neurotransmission through all of these mechanisms in skeletal muscle in situ; the net result dep ends on the degree of prejunctional alpha-adrenergic feedback inhibiti on. Circulating Ang II may enhance the local formation of vasodilatory prostaglandins, but does not seem to modulate NA release even after p rostaglandin synthesis inhibition in this model. Our data suggest that circulating AngII may not reach the perivascular sympathetic nerves t o a significant extent in skeletal muscle in vivo.