The origin of the decline in the vasopressor response to infused noradrenaline in the pithed rat.

In several species, including man, the continuous infusion of noradrenaline always results in an eventual steady decline from the initial pressor level (Nickerson, 1962; Rosenthale & Dipalma, 1963; Beyth & Gutman, 1965). This reduction in response is usually attributed to desensitization or tachyphylaxis. Our interest in this phenomenon arose during attempts to modify that preparation of the anaesthetized rat described by Straughan (1958) as an assay method for acetylcholine. To overcome the large reflex depressor artefact which accompanies any intravenous injection in this preparation, the rat was pithed and the normal neurally maintained vascular tone mimicked by infusing noradrenaline continuously in amounts sufficient to raise the blood pressure to about 120 mm Hg. A highly sensitive and artefact-free preparation in which the effect of 0.25 ng of acetylcholine could be recognized was obtained. However, within 5 10 min of beginning the infusion both the blood pressure and the sensitivity to acetylcholine began to fall. Two points seemed of interest. First, if this were due to desensitization to noradrenaline, it was not specific for one substance. Secondly, although the noradrenaline infused was limited to that required to match the neurally released transmitter in restoring the blood pressure to normal levels, desensitization still occurred. Previous investigations of this phenomenon have employed animals with an intact vasoconstrictor outflow in which the infused noradrenaline raised the blood pressure above normal. The present paper reports the results of an investigation into the causes of these changes. The literature contains few reports which allow the contribution of the peripheral vascular smooth muscle to the fall in blood pressure to be separated from that of the heart. To do this, a modification of the technique of Bygdeman (1963) was used, in which the isolated vascular bed of one lower limb was perfused in situ with the animal's own arterial blood. The perfusion pressure gave a measure of the response of the vascular smooth muscle uncomplicated by cardiac efficiency. The blood pressure response of the whole animal, excluding the perfused limb, gave an integrated picture of both the peripheral vascular response and the ability of the heart to maintain its output in face of any increase in peripheral resistance.