The Origin of the Decline in the Vasopressor Response to Infused Noradrenaline in the Pithed Rat

Abstract

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. * Henry Head Fellow.

Blockade by nifedipine of responses to intravenous bolus injection or infusion of α1‐and α2‐adrenoceptor agonists in the pithed rat

“…The non-sustained nature of the pressor response to infusions of phenylephrine and NA was similar to an earlier observation with NA (Gillespie & Muir, 1967).…”

The Effect of Infusing Noradrenaline or of Stimulating the Sympathetic Nerves on the Blood Pressure Response to Indirect Sympathomimetics

“…The effect of tyramine on the blood pressure continues to 'be potentiated at a time when the peripheral vascular response is maximal, assuming the limb is representative of other vascular beds. This suggests that the noradrenaline dose-response curve for cardiac muscle may be displaced to the right along the abscissa compared with that for vascular smooth muscle and would be consistent with the suggestion made in the previous paper (Gillespie & Muir, 1967b) that the density of receptors in this tissue is less than in smooth muscle.…”

“…This will occur both in the arterial smooth muscle determining the peripheral resistance and in the heart; either or both could be the site responsible for the increased responses. The presence of potentiation at each site was examined in the perfused limb preparation (Gillespie & Muir, 1967b). The pressure response in the limb perfused by means of a constant volume output pump gives a measure of the peripheral resistance uncomplicated by changes in cardiac output.…”

“…perfused limb preparation (Gillespie & Muir, 1967b). The pressure response in the limb perfused by means of a constant volume output pump gives a measure of the peripheral resistance uncomplicated by changes in cardiac output.…”

The Influence of Propranolol Pretreatment on Acute Tolerance to Norepinephrine Effects on the Systemic and Pulmonary Circulations in Dogs

“…Therefore, the The Influence o f P ro p ran o lo l P retreatm ent ... 2 2 3 decline in systemic blood pressure from its maximal effect is caused by the decrease in peripheral vascular resistance. This holds true for norepinephrine infusions of relatively low dose and short duration only, since during prolonged infusions of norepi nephrine in large dosage the cardiac output declines [Moss et a!., 19(56;Gomez and Yard, 1968;Gillespie and Muir, 1967] as a con sequence of cardiac muscle deterioration [Moss el al., 1966].…”