Vasoconstrictor-mediated increase in muscle resting thermogenesis is inhibited by membrane-stabilizing agents

Norepinephrine and angiotensin II are potent vasoconstrictors and stimulate thermogenesis (oxygen uptake) as well as lactate and glycerol efflux in the constant-flow perfused rat hind limb at rest. However, the mechanism by which oxygen uptake (VO2) is increased is unknown, and it is not clear whether vasoconstriction is required for the increase in VO2 by the hind limb. In the present study the association between vasoconstriction and VO2 was further investigated, and a chance observation that high-dose propranolol selectively blocked vasoconstrictor-induced increase in VO2 was further explored. The norepinephrine-mediated increase in VO2 was totally blocked by either 50 microM (+)-propranolol or 50 microM (-)-propranolol (active beta-blocking enantiomer), but only (+)-propranolol reduced the vasoconstriction. Similarly, 100 microM (+/-)-propranolol (a dose likely to cause plasma membrane stabilizing effects involving interruption and (or) prevention of action potentials) blocked increases in VO2, lactate, and glycerol efflux by 5 nM angiotensin II (a nonadrenergic vasoconstrictor) with only marginal effects on pressure development. (+/-)-Propranolol (100 microM) had no effect on postequilibration red blood cell washout mediated by angiotensin II, a putative indicator of vasoconstrictor-induced redistribution of flow. Quinidine (260 microM) (an antiarrhythmic agent with membrane-stabilizing activity) inhibited only the increase in VO2, but neither nadolol (300 microM) nor atenolol (300 microM) (beta-blockers without membrane-stabilizing activity) inhibited VO2 or perfusion pressure increases produced by 5 nM angiotensin II. Veratridine (a membrane labilizer that is capable of evoking plasma membrane depolarization by maintaining voltage-gated Na+ channels in their open state) increased VO2 without vasoconstriction, and the increase in VO2 was blocked by 100 microM (+/-)-propranolol. It is concluded that the increase in hind-limb VO2 results from a destabilization of skeletal muscle plasma membranes. This can be achieved directly by veratridine or indirectly by angiotensin II, involving vasoconstriction and redistribution of flow. The findings suggest a novel mechanism for resting muscle thermogenesis.