SIMILARITIES BETWEEN VASOCONSTRICTOR-STIMULATED AND VERATRIDINE-STIMULATED METABOLISM IN PERFUSED RAT HIND-LIMB

The vasoconstrictors norepinephrine (NE) and angiotensin II (AII) medi ate increases in oxygen uptake (VO2) by the constant flow perfused rat hind limb that are inhibited by quinidine-like membrane-stabilizing e ffects (involving the interruption of action potential) of (+/-)-propr anolol with little effect on vasoconstriction. The membrane labilizer veratridine, 10 mu M, which has the capability of maintaining voltage- gated Na+ channels of the plasma membrane in their open state, also in creases VO2 but without an increase in pressure. Thus in the present s tudy veratridine was characterized in detail and compared with NE in t he same system. Veratridine (3-100 mu M) produced a dose-dependent sti mulation of VO2 (from 11.8 +/- 0.3 to 20.4 +/- 0.6 mu mol.h(-1).g(-1) (n = 5), p < 0.0001) and lactate efflux (LE) (from 7.4 +/- 0.6 to 23.0 +/- 4.7 mu mol.h(-1).g(-1) (n = 5),p < 0.01). These increases were in dependent of vasoconstriction at low doses (less than or equal to 10 m u M). At higher doses of veratridine the accompanying minor vasoconstr iction (from 17 +/- 1 to 30 +/- 2 mmHg (1 mmHg = 133.3 Pa) (n = 5), p < 0.005) was blocked by sodium nitroprusside (NP) while neither VO2 no r LE was greatly affected. Low Na+ perfusions (25 mM) did not affect t he vasoconstrictor action of NE but markedly inhibited increases in VO 2 and LE due to either veratridine or NE. Veratridine (10 mu M) mediat ed increases in VO2 and LE were blocked by either (+/-)-propranolol(10 0 mu M) or 150 mu M quinidine. It is concluded that vasoconstrictors s uch as NE, which stimulate VO2 in the perfused rat hind limb, do so by a two-stage process involving an essential nitroprusside-sensitive re direction of flow followed by a mechanism involving increased ion move ment across skeletal muscle cell membranes, which is blocked by membra ne stabilizers. Veratridine achieves a similar increase in VO2 but may do so by directly destabilizing the skeletal muscle cell membrane wit hout the requirement of a redirection of flow.