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Abstract

Perfused hindlimb preparations have been used to investigate vasoconstrictormediated
control of skeletal muscle metabolism, with particular emphasis on the
regulation of oxygen consumption (V0 2) as an index of muscle nonshivering
thermogenesis (NST). The ability of a group of molecules known as vanilloids to
modulate muscle V02 was investigated using hindlimb preparations of hooded Wistar
rats. Both naturally-occurring and synthetic vanilloids were examined. Infused
vanilloids gave dose-dependent V02 changes in association with increased perfusion
pressure (PP). Vanilloid V02 concentration-response curves were biphasic, lower
concentrations stimulating and higher concentrations inhibiting V02.
Nitrovasodilators demonstrated an association between the V02 changes and
vasoconstriction, whilst a- and 13-adrenergic antagonists showed that neither
adrenergic receptors nor secondary catecholamine release were responsible for the
increased V02. The observed effects may have been due to specialised vanilloid
receptors. The data in fact supported two vanilloid receptor subtypes; the putative
higher affinity (VNI) receptor mediated increased V02 and vasoconstriction, and was
dependent on the presence of oxygen and external Ca2+. The putative lower affinity
(VN2) receptor mediated an inhibition of V02 with vasoconstriction, but the
vasoconstriction was independent of external Ca2+ or 02 presence. A range of vanilloid structural analogues were synthesised and used to
construct a structure-activity profile for hindlimb thermogenic action. A distinct set of
structural features required for thermogenic activity (a pharmacophore) was defined.
However, there was no clear distinction between the pharmacophore for
thermogenesis and the structural features deduced by others to be necessary for
antinociceptive action in sensory neurone studies. Complete separation of the
responses attributed to the putative dual vanilloid receptors was not observed,
although there was some evidence of partial selectivity.
The concept of vascular metabolic control in muscle was further examined in a
series of comparative perfusion studies. The first study established a viable technique
for perfining bird lower limbs. Since birds are reported to be devoid of brown adipose
tissue, the perfused chicken lower limb was an appropriate model for examining the potential of skeletal muscle, via vascular metabolic control, as a major contributor to
NST. Infused catecholamines increased PP and gave biphasic V02 concentrationresponse
curves. Low dose V02 stimulation was blocked by prazosin and
nitrovasodilation, but was unaffected by propranolol. The demonstration of potential
muscle NST in another taxon raised the possibility of vascular thermogenic control
being a widespread and perhaps a fundamental NST mechanism.
In a further comparative study, genetically obese (fa/fa) Zucker rats were used
primarily to examine the hypothesis that the obesity was related to a defect in vascular
metabolic control. Differences in basal and noradrenaline-mediatedV0 2 related to
lower muscle content and higher fat content in the obese hindlimb. 5-HT-mediated
V02 inhibition was significantly greater in age-matched lean (Fa/?) hindlimbs, even
when the data were expressed in terms of muscle mass. This may indicate a reduced
potential for vascular metabolic control with possible implications for the whole-body
energy balance of the obese phenotype. In a separate series of experiments measuring
glucose uptake, perfused obese hindlimbs were found to be markedly insulin-resistant
relative to lean counterparts. The possibility of a link between the impaired insulin
effectiveness and altered haemodynamic function is discussed.
The studies undertaken underline the potential significance of altering regional
nutrient and hormone access in regulating skeletal muscle metabolism, and in
particular support a critical role for the vasculature in the control of skeletal muscle
thermogenesis.

Item Type:	Thesis - PhD
Authors/Creators:	Eldershaw, Tristram P. D.(Tristram Peter David)
Keywords:	Musculoskeletal system, Oxygen, Cardiovascular system
Copyright Holders:	The Author
Copyright Information:	Copyright 1996 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).
Additional Information:	Includes bibliographical references. Thesis (Ph.D.)--University of Tasmania, 1997
Item Statistics:	View statistics for this item

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