Stimulation and inhibition of resting muscle thermogenesis by vasoconstrictors in perfused rat hind limb

Angiotensin (AII) and serotonin (5-HT) are both vasoconstrictors of the con stant-flow perfused rat hind limb that have opposite effects on thermogenes is, possibly the result of differing effects on vascular flow distribution between nutritive and non-nutritive pathways. In the present study interact ion between the two opposing agents was examined with the expectation that the combined presence would show additive effects on pressure and mutually neutralizing effects on thermogenesis. Thus doses of All and 5-HT that gave similar, but opposite, quantitative effects on thermogenesis were infused alone, in combination one after the other, or in combination with the order reversed, and the effects an perfusion pressure (PP) and thermogenesis (ox ygen uptake, (V) over dot o(2)) were compared. ATT (3 nM) alone increased P P by 15 +/- 1 mmHg (1 mmHg = 133.3 Pa) and (V) over dot o(2) by 3.1 +/- 0.2 mu mol h(-1) g(-1), whereas 5-HT (1 mu M) alone increased PP by 75 +/- 6 m mHg and inhibited (V) over dot o(2) by 3.9 +/- 0.2 mu mol h(-1) g(-1). When added in combination, the outcome depended on the order of addition. Follo wing All, infusion of 5-HT further increased PP by 160 +/- 11 mmHg and decr eased (V) over dot o(2) by 6.3 +/- 0.2 mu mol h(-1)g(-1). Following 5-HT, i nfusion of AII further increased PP by 28 +/- 4 mmHg and increased (V) over dot o(2) by only 1.8 +/- 0.3 mu mol h(-1) g(-1). The prior presence of 5-H T (1 mu M) Shifted the All dose-response curves for (V) over dot o(2) and p ressure to the right and left, respectively. The prior infusion of AII incr eased the dose-dependent response to 5-HT in terms of both the inhibition o f (V) over dot o(2) and the increase in PP At low doses of 5-HT (10(-8)-10( -7) M), but not alpha-methyl serotonin (alpha MT), there was a marked vasod ilatation-associated inhibition of All-mediated increase in (V) over dot o( 2). Overall the data show that the combined effect of AII and 5-HT differed from the simple addition of each separately. Since the order of addition a ppears to be critical in terms of thermogenic outcome, it is concluded that each vasoconstrictor exerts a specific hemodynamic action to affect access of the other to vascular receptor sites. These findings are consistent wit h the previously reported effects of these vasoconstrictors on substrate an d insulin access to muscle of the perfused rat hind limb.