Stabley JN, Dominguez JM 2nd, Dominguez CE, Solis FR, Ahlgren J, Behnke BJ, Muller-Delp JM, Delp MD. Spaceflight reduces vasoconstrictor responsiveness of skeletal muscle resistance arteries in mice. Cardiovascular adaptations to microgravity undermine the physiological capacity to respond to orthostatic challenges upon return to terrestrial gravity. The purpose of the present study was to investigate the influence of spaceflight on vasoconstrictor and myogenic contractile properties of mouse

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... strocnemius muscle resistance arteries. We hypothesized that vasoconstrictor responses acting through adrenergic receptors [norepinephrine (NE)], voltage-gated Ca 2ϩ channels (KCl), and stretch-activated (myogenic) mechanisms would be diminished following spaceflight. Feed arteries were isolated from gastrocnemius muscles, cannulated on glass micropipettes, and physiologically pressurized for in vitro experimentation. Vasoconstrictor responses to intraluminal pressure changes (0 -140 cmH 2O), KCl (10 -100 mM), and NE (10 Ϫ9 -10 Ϫ4 M) were measured in spaceflown (SF; n ϭ 11) and ground control (GC; n ϭ 11) female C57BL/6 mice. Spaceflight reduced vasoconstrictor responses to KCl and NE; myogenic vasoconstriction was unaffected. The diminished vasoconstrictor responses were associated with lower ryanodine receptor-2 (RyR-2) and ryanodine receptor-3 (RyR-3) mRNA expression, with no difference in sarcoplasmic/endoplasmic Ca 2ϩ ATPase 2 mRNA expression. Vessel wall thickness and maximal intraluminal diameter were unaffected by spaceflight. The data indicate a deficit in intracellular calcium release via RyR-2 and RyR-3 in smooth muscle cells as the mechanism of reduced contractile activity in skeletal muscle after spaceflight. Furthermore, the results suggest that impaired end-organ vasoconstrictor responsiveness of skeletal muscle resistance arteries contributes to lower peripheral vascular resistance and less tolerance of orthostatic stress in humans after spaceflight. spaceflight; microgravity; vasoconstriction; skeletal muscle; c57bl/6 mice; orthostatic intolerance THE CARDIOVASCULAR CONSEQUENCES of microgravity exposure are evident in the form of orthostatic intolerance (3, 29, 50), reduced aerobic exercise capacity (19, 40, 50) , elevated heart rate (50), and hypovolemia (31, 50). In particular, up to 64% of astronauts experience orthostatic intolerance after only 2 wk of spaceflight (5), whereas habitation in a microgravity environment for several months or more results in virtually all astronauts experiencing orthostatic intolerance upon return to Earth (26). Early work in humans (5, 29) established that orthostatic intolerance was principally the result of the reduced capacity to elevate peripheral vascular resistance following spaceflight.