ESTROGEN/SYMPATHETIC VASOCONSTRICTION IN SKELETAL MUSCLE

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the applicant's abstract): Activation of the
sympathetic nervous system produces many of the cardiovascular adjustments to
exercise that match blood flow and oxygen delivery to the metabolic demands of
the exercising muscles. In exercising muscle, the normal ability of sympathetic
nerves to cause vasoconstriction is attenuated, a phenomenon termed functional
sympatholysis. Dr. Thomas' previous work demonstrated that a key mediator of
sympatholysis is nitric oxide (NO) derived from the neuronal isoform of NO
synthase (nNOS) which is abundantly expressed in skeletal muscle cells. The
expression of skeletal muscle nNOS is upregulated by the female sex hormone
estrogen. Therefore, the central hypothesis of this application is that
estrogen in females is a key mediator of functional sympatholysis because of
its ability to induce nNOS expression. Dr. Thomas hypothesizes that in
estrogen-deficient states the exercising muscles are ischemic due to decreased
production of skeletal-muscle derived NO leading to unopposed alpha-adrenergic
vasoconstriction. First, she will test the hypothesis that estrogen facilitates
functional sympatholysis. In anesthetized female rats, she will measure
hindlimb blood flow and muscle oxygenation with near infrared spectroscopy to
determine if functional sympatholysis is attenuated in states of
estrogen-deficiency such as sexual immaturity, or surgical ovariectomy. To
determine if functional sympatholysis is similarly attenuated in women who are
estrogen-deficient due to surgical or natural menopause, Dr. Thomas will
measure forearm muscle oxygenation with NIR spectroscopy while recording muscle
SNA with microelectrodes. She also will determine if in estrogen-deficient rats
and humans, functional sympatholysis is restored by estrogen replacement, but
not by progesterone replacement. Second, she will test the hypothesis that
increased skeletal muscle expression of nNOS is a major mechanism mediating the
beneficial effect of estrogen on functional sympatholysis. In rats, she will
determine the effect of pharmacologic inhibition of NOS on functional
sympatholysis in estrogen-replete versus estrogen-deficient animals. Dr. Thomas
also will determine if skeletal muscle nNOS expression is reduced by
ovariectomy or by an estrogen receptor antagonist, and is increased by estrogen
replacement in ovariectomized rats. Finally, in female nNOS knockout mice she
will determine if functional sympatholysis is attenuated and refractory to
restoration by estrogen treatment. These rodent and human studies may elucidate
a novel cardiovascular benefit of estrogen to enhance skeletal muscle perfusion
and oxygenation in exercising muscles by opposing alpha-adrenergic
vasoconstriction, thus providing further rationale for estrogen replacement
therapy in women.
StatusFinished
Effective start/end date5/1/004/30/01

Funding

  • National Heart, Lung, and Blood Institute: $234,000.00

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