VASOCONSTRICTOR-MEDIATED INCREASE IN MUSCLE RESTING THERMOGENESIS IS INHIBITED BY MEMBRANE-STABILIZING AGENTS

Norepinephrine and angiotensin II are potent vasoconstrictors and stim ulate thermogenesis (oxygen uptake) as well as lactate and glycerol ef flux in the constant-flow perfused rat hind limb at rest. However, the mechanism by which oxygen uptake ((V) over dot o(2)) is increased is unknown, and it is not clear whether vasoconstriction is required for the increase in (V) over dot o(2) by the hind limb. In the present stu dy the association between vasoconstriction and (V) over dot o(2) was further investigated, and a chance observation that high-dose proprano lol selectively blocked vasoconstrictor-induced increase in (V) over d ot o(2) was further explored. The norepinephrine-mediated increase in (V) over dot o(2) was totally blocked by either 50 mu M (+)-propranolo l or 50 mu M (-)-propranolol (active beta-blocking enantiomer), but on ly (+)-propranolol reduced the vasoconstriction. Similarly, 100 mu M ( +/-)-propranolol (a dose likely to cause plasma membrane stabilizing e ffects involving interruption and (or) prevention of action potentials ) blocked increases in (V) over dot o(2), lactate, and glycerol efflux by 5 nM angiotensin II (a nonadrenergic vasoconstrictor) with only ma rginal effects on pressure development. (+/-)-Propranolol (100 mu M) h ad no effect on postequilibration red blood cell washout mediated by a ngiotensin II, a putative indicator of vasoconstrictor-induced redistr ibution of flow. Quinidine (260 mu M) (an antiarrhythmic agent with me mbrane-stabilizing activity) inhibited only the increase in (V) over d ot o(2), but neither nadolol (300 mu M) nor atenolol (300 mu M) (beta- blockers without membrane-stabilizing activity) inhibited (V) over dot o(2) or perfusion pressure increases produced by 5 nM angiotensin II. Veratridine (a membrane labilizer that is capable of evoking plasma m embrane depolarization by maintaining voltage-gated Na+ channels in th eir open state) increased (V) over dot o(2) without vasoconstriction, and the increase in (V) over dot o(2) was blocked by 100 mu M (+/-)-pr opranolol. It is concluded that the increase in hind-limb (V) over dot o(2) results from a destabilization of skeletal muscle plasma membran es. This can be achieved directly by veratridine or indirectly by angi otensin II, involving vasoconstriction and redistribution of flow. The findings suggest a novel mechanism for resting muscle thermogenesis.