Local Modulation of Noradrenaline Release In Vivo

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Abstract
Isoprenaline bitartrate (0.5 .mu.g/kg per min i.v.) increased the rate of noradrenaline [norepinephrine] release into the circulation of pentobarbitone-anesthetized rabbits. This increase was much greater than that produced by an equihypotensive dose of the vasodilator hydralazine (0.2 mg/kg i.v.), suggesting that it was only partly due to baroreflex activation of sympathetic nerves. This facilitatory effect of isoprenaline was also observed in the nephrectomized, pithed rabbit, with electrically stimulated sympathetic outflow, ruling out CNS and renin-angiotensin effects. ICI 118,551 HCl [erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol hydrochloride] (0.3 mg/kg + 0.1 mg/kg per h i.v.) blocked the isoprenaline-induced hypotension, but did not affect the isoprenaline-induced tachycardia, suggesting that it selectively blocked .beta.2-adrenoceptors. ICI 118,551 totally abolished the isoprenaline-induced increase in noradrenaline release, suggesting a .beta.2-effect. Atenolol (0.3 mg/kg + 0.1 mg/kg per h) blocked the isoprenaline-induced tachycardia, a .beta.1-effect, but only slightly attenuated the isoprenaline-induced increase in noradrenaline release. Atenolol by itself decreased heart rate and arterial pressure, but there was no reflex rise in the noradrenaline release rate, which suggests that atenolol impairs baroreceptor activation of sympathetic nerves. In another series of experiments, also in the pentobarbitone-anesthetized rabbit, adrenaline was released into the circulation by splanchnic nerve stimulation. This resulted in prolonged increases of adrenaline levels in heart tissue. After the plasma adrenaline levels had returned to prestimulation values, the rate of noradrenaline release into the plasma was enhanced. This increase was not observed in rabbits treated with either desipramine hydrochloride (1 mg/kg i.v.) or propranolol hydrochloride (2 mg/kg i.p.). A possible explanation is that adrenaline released from the adrenal gland is accumulated in sympathetic nerves. Upon its release from the nerves, adrenaline may activate presynaptic .beta.-adrenoceptors and enhance noradrenaline release. In vivo, noradrenaline release may be modulated through facilitatory .beta.-adrenoceptors on sympathetic nerve endings. These receptors are of the .beta.2-subtype and are possible physiological sites of action of adrenaline.