Vasoconstrictor-mediated control of thermogenesis

Vasoconstrictors either stimulate or inhibit oxygen consumption (V02) in perfused, but not in incubated or perifused, skeletal muscle. The mechanism of this phenomenon is not fully understood. This thesis attempted to investigate the implication of vasoconstrictor-mediated control of V02 (thus thermogenesis) in perfused muscle as well as other tissue beds, and the mechanism involved. Effects of vasoconstrictors on V02 were examined in the perfused hindlimbs of rats, Tasmanian bettongs (Bettongia gaimardi) and toads (Bufo marinus) as well as in the perfused rat kidney, intestine and mesenteric artery. In line with in vitro experiments, the effects of adrenergic agonists on thermogenesis were further studied in conscious adult bettongs, an endothermic animal without detectable brown adipose tissue. Norepinephrine (NE) and vasopressin (VP) stimulated, but serotonin (5-HT) inhibited V02 in both constant-flow and constant-pressure perfiised hindlimbs when causing vasoconstriction. In the constant-flow (once-through) perfusion, these changes were blocked by vasodilators (ie. nitroprusside) but not by tubocurarine. Vasoconstrictor-mediated changes in muscle metabolism were observed in the hindlimbs of all the three species. a-Adrenoceptors were shown to be responsible for NE-stimulated increase in V02 . Increasing the perfusion flow by resetting at different rates also stimulated changes in V02 in the constant-flow perfused rat hindlimb, which could be augmented by NE but inhibited by nitroprusside. Similarly, a vasoconstriction-associated increase or decrease in V02 was observed in the constant-flow perfused rat kidney and intestine although the effect of a given vasoconstrictor to stimulate or inhibit V02 was not necessarily the same as that in the perfused hindlimb. In the perfused rat mesenteric artery all vasoconstrictors stimulated increases in V02 in parallel with the increased perfusion pressure. By contrast, in the constant-pressure (recirculated) perfused rat hindlimb, ‚àövº- adrenergic agonists, isoproterenol and BRL3 5135A were also found to stimulate V02 in addition to a-adrenergic agonists and VP. During the induced vasoconstriction or vasodilation, creatine phosphate (CrP), AMP, ADP, ATP and lactate remained normal in all the perfused mammalian tissues. In skeletal muscle, the energy status, as indicated by energy charge, was not significantly different among the normal (both in vivo and control perfusion), perfused (high flow plus NE) and ischemic (for 60 min) muscles. In contrast, CrP and Cr differed in the three oxygenation states. Consistent with the observations in the perfused hindlimbs in vitro, NE and isoproterenol elicited an increase in heat production in the intact bettong. a-Adrenergic agonists, phenylephrine and naphazoline were also found to stimulate heat production which was not blocked by propranolol. These results taken together suggest that skeletal muscle is a potentially thermogenic tissue under the control Of vascular functioning. Vasoconstrictor-mediated V02 seems to be widespread across species and tissues. This control may play an important role in the regulation of non-shivering thermogenesis. The results support the notion that working blood vessels may partially account for vasoconstrictor-stimulated changes in V02. However, the data do not exclude the hypothesis that vasoconstrictors act on site-specific receptors on arterioles to redistribute flow to areas or cells that are metabolically more active. The results of this thesis can not definitively distinguish between these two hypotheses. They may not be mutually exclusive.