Similarities between vasoconstrictor- and veratridine-stimulated metabolism in perfused rat hind limb

Abstract

The vasoconstrictors norepinephrine (NE) and angiotensin II (AII) mediate increases in oxygen uptake (VO2) by the constant flow perfused rat hind limb that are inhibited by quinidine-like membrane-stabilizing effects (involving the interruption of action potential) of (+/-)-propranolol with little effect on vasoconstriction. The membrane labilizer veratridine, 10 microM, which has the capability of maintaining voltage-gated Na+ channels of the plasma membrane in their open state, also increases VO2 but without an increase in pressure. Thus in the present study veratridine was characterized in detail and compared with NE in the same system. Veratridine (3-100 microM) produced a dose-dependent stimulation of VO2 (from 11.8 +/- 0.3 to 20.4 +/- 0.6 mumol.h-1.g-1 (n = 5), p < 0.0001) and lactate efflux (LE) (from 7.4 +/- 0.6 to 23.0 +/- 4.7 mumol.h-1.g-1 (n = 5), p < 0.01). These increases were independent of vasoconstriction at low doses (< or = 10 microM). At higher doses of veratridine the accompanying minor vasoconstriction (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 nor LE was greatly affected. Low Na+ perfusions (25 mM) did not affect the vasoconstrictor action of NE but markedly inhibited increases in VO2 and LE due to either veratridine or NE. Veratridine (10 microM) mediated increases in VO2 and LE were blocked by either (+/-)-propranolol (100 microM) or 150 microM quinidine. It is concluded that vasoconstrictors such as NE, which stimulate VO2 in the perfused rat hind limb, do so by a two-stage process involving an essential nitroprusside-sensitive redirection of flow followed by a mechanism involving increased ion movement across skeletal muscle cell membranes, which is blocked by membrane stabilizers. Veratridine achieves a similar increase in VO2 but may do so by directly destabilizing the skeletal muscle cell membrane without the requirement of a redirection of flow.