Modulation of Noradrenaline Release in the Pithed Rabbit

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Abstract
The pithed rabbit with electrically stimulated sympathetic outflow (spinal region, T-8; 3 Hz) was studied to determine the contribution of the renin-angiotensin system to noradrenaline [norepinephrine] release in vivo. The noradrenaline release rate (spillover) into the plasma was determined from the endogenous plasma noradrenaline level and the simultaneously determined noradrenaline plasma clearance. In the pithed rabbit, angiotensin II (0.1 .mu.g/kg per min i.v.) infusion failed to increase the noradrenaline release rate and only slightly increased blood pressure. Conversely, the angiotensin-converting enzyme inhibitor captopril (1 mg/kg i.v.) decreased blood pressure and the noradrenaline release rate. Bilateral nephrectomy was performed to reduce endogenous angiotensin II formation; and infusion of angiotensin II markedly increased the noradrenaline release rate and blood pressure, whereas captopril had no effect. Angiotensin II apparently modulates noradrenaline release in vivo through activation of facilitatory prejunctional angiotensin II receptors. In the pithed rabbit these receptors are probably maximally activated by endogenously synthesized angiotensin II. The actions of angiotensin II on noradrenaline release open the possibility that blood pressure increases in the pithed rabbit, by decreasing renin release via intrarenal baroreceptors and hence decreasing angiotensin II formation, may lead to decreased noradrenaline release. Phenylephrine (6 .mu.g/kg per min i.v.), a selective .alpha.1-adrenoceptor agonist, and adrenaline (1 .mu.g/kg per min i.v.), an .alpha.1/.alpha.2-agonist were used to investigate this. Both drugs increased blood pressure and decreased the noradrenaline release rate. After a bilateral nephrectomy, the inhibitory effect of phenylephrine on noradrenaline release was abolished, whereas that of adrenaline was maintained. The release-inhibiting effect of adrenaline was blocked by the .alpha.2-selective antagonist yohimbine (1 mg/kg + 0.2 mg/kg per h i.v.). Apparently, adrenaline directly activates inhibitory presynaptic .alpha.2-adrenoceptors at sympathetic terminal axons. The release-inhibiting effect of phenylephrine is indirect, requires the kidney, and probably involves renin secretion suppression and less activation of facilitatory presynaptic angiotensin II receptors.

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