The Sub-Division of Alpha-Adrenoceptors in Vascular Smooth Muscle

O'Brien, Jacqueline W (1985) The Sub-Division of Alpha-Adrenoceptors in Vascular Smooth Muscle. PhD thesis, University of Glasgow.

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1) The aim of this study was to examine the sub-division of alpha-adrenoceptors in vascular smooth muscle. These studies were carried out on the pithed rat and isolated rat aorta preparations. 2) Various parameters were investigated in an attempt to discover the physiological conditions which might be optimal for activation of the alpha-adrenoceptor subtypes. In the pithed rat, the influence of blood gases and the differential effects of calcium-entry blockade on the alpha1 - and alpha2-adrenoceptor-mediated pressor responses were examined. The isolated rat aorta was used to study more closely the calcium dependency of the alpha receptor response, in vascular smooth muscle. 3) The influence of blood gases on the alpha-adrenoceptor subtype-mediated pressor response was studied in the pithed rat by varying the inspired gas mixture or the ventilation volume. Acidosis was found to favour the peak responses to the alpha2-adrenoceptor agonist, xylazine, while alkalosis favoured the peak responses to the alpha1-adrenoceptor agonist, phenylephrine. A combination of hypoxia and hypercapnia greatly depressed the alpha1 response to phenylephrine whereas the alpha2 response to xylazine remained relatively unaffected. When PaO2 was varied in either acidotic or alkalotic conditions, the response to phenylephrine increased as PaO2 increased. 4) To prevent hypoxia in air ventilated rats , large stroke volumes were required. This caused alkalosis and hence decreased responsiveness to xylazine. Consequently, air ventilated pithed rats gave poorer responses to xylazine than did those ventilated on 100% O2. The results show that alpha1- and alpha2-adrenoceptor mediated pressor responses can be differentially affected by blood gases. The relative contribution of alpha1- and alpha2-adrenoceptors to vascular tone may be either under- or over-estimated depending on the arterial blood gases. 5) The pithed rat was also used to study the effect of the calcium-entry blocker, nifedipine, on the alpha1- and alpha2-adrenoceptor pressor responses. To do this, alpha1 and alpha2 agonists were either bolus injected or infused into the pithed rat's blood stream. It was found that nifedipine could inhibit the response initiated by both types of agonist, usually for both the bolus and infusion responses. Calcium-entry blockade was significantly greater on the more prolonged, secondary component of the pressor responses; whether produced by alpha1 or by alpha2 receptor activation. This demonstrates that calcium-entry occurs during the secondary component of the alpha response and can be initiated by either alpha1- or alpha2-adrenoceptor subtypes. 6) The shape of the response produced by infusing the alpha-agonists varied greatly. Most alpha1 agonists, with the exception of SGD 101/75, did not achieve a plateau during the 20 minute infusion time. The alpha2 agonists, on the other hand, readily attained a plateau which was maintained throughout the remainder of the infusion. Phenylephrine and noradrenaline produced pressor responses which reached a maximum and then declined during the remainder of the infusion. These results indicate a difference in the mode of action by which the various alpha-agonists produce their infusion pressor responses. 7) The levels of noradrenaline in the rat arterial and venous plasma were measured during the infusion of noradrenaline, by an HPLC system. Arterial noradrenaline levels rose throughout the infusion whereas venous levels remained relatively unaffected. 8) The isolated rat aortic ring produced a biphasic, contractile response when stimulated by noradrenaline. The initial transient component (ITC) was relatively resistant to the removal of calcium from the external buffering saline and to calcium-entry blockade by nifedipine. It was therefore thought to be the result of mobilization of internal calcium. The slower secondary component (SSC) was reduced by the removal of calcium from the external buffering saline and by calcium-entry blockade, when carried out under reduced calcium conditions. It was considered to be the result of calcium-entry into the cell. The inorganic calcium-entry blocker, cadmium, and the intracellular calcium blocker, dantrolene sodium, were both found to reduce the ITC and the SSC equally well. These results indicate that calcium-entry is involved in both components of the response to noradrenaline. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Physiology
Date of Award: 1985
Depositing User: Enlighten Team
Unique ID: glathesis:1985-77379
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 09:10
Last Modified: 14 Jan 2020 09:10

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