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Mechanics of Cardiovascular Deconditioning

Principal Investigator:
Artin A. Shoukas, Ph.D.

Johns Hopkins University School of Medicine

The primary cardiovascular effect after long-term space travel is a drop in blood pressure caused by a decrease in cardiac output, or blood flow, when astronauts go from a supine to standing position. Dr. Artin A. Shoukas is exploring the change in cardiac output as a function of the heart’s venous filling pressure since the heart is extremely sensitive to this filling pressure. In turn, the filling pressure depends on the amount of blood in the venous system as well as the size of the blood vessels in the system. His earlier studies have shown that veno-constriction by the nervous system, particularly the carotid sinus baroreceptor reflex system, plays an important role on the regulation of cardiac output. Dr. Shoukas is determining whether alterations in the veno-constriction by the nervous system can explain the changes in cardiac output experienced by astronauts. His research will advance the overall understanding of circulatory adjustments made during long-term space flight and provide for countermeasures for astronauts to reduce the incidence of low pressure and possibility of fainting.

NASA Taskbook Entry

Technical Summary

Specific Aims:
  1. To determine mechanisms of impaired stroke volume response (SV) in a rat model of micro-gravity. The impaired stroke volume response seen in HLU rats could result from either functional and/or structural changes in the myocardium.
    (a) With the goal of determining the role of myocardial contractility and loading conditions in the impaired SV response, we hypothesized that the impaired SV response is secondary to both altered loading and impaired myocardial contractile reserve.
    (b) With the goal of determining the role of cardiac atrophy in cardiovascular de-conditioning, we hypothesized that micro-gravity is associated with a significant loss of cardiac mass.
  2. To determine molecular mechanisms of vascular (systemic and pulmonary arterial, and venous) hyporesponsiveness in a rat model of micro-gravity. Our data demonstrates impaired contractile responses in both arterial, venous, and pulmonary vascular beds, and an increase in venous capacitance in HLU rats.
    (a) To determine the role of abnormalities in vascular smooth muscle Ca2+ influx/release and myo-filament Ca2+ sensitivity in vascular hypo-responsiveness, we hypothesized that abnormalities in Ca2+i and/or myo-filament Ca2+ sensitivity in smooth muscle may contribute to the endothelial independent mechanism of vascular contractile dysfunction.
    (b) To determine the role of the endothelium in vascular contractile hypo-responsiveness, we hypothesized that enhanced endothelial dependent vasodilator signaling contributes to vascular smooth muscle hypo-responsiveness.
  3. To test pharmacologic countermeasures based on mechanisms that impair both SV responses and vascular hypo-responsiveness in a rat model of micro-gravity. We hypothesize those pharmacologic countermeasures that enhance vascular smooth muscle contraction by modulating signal transduction pathways, can be used as countermeasures to treat orthostatic intolerance associated with cardiovascular de-conditioning.

Summary of Accomplishments:
Our proposed experiments test the overall hypothesis that alterations in venous capacitance function and arterial resistance by the carotid sinus baroreceptor reflex system are an important determinant of the cardiac output and blood pressure response seen in astronauts after returning to earth from long term exposure to microgravity. This hypothesis is important to our overall understanding of circulatory adjustments made during long term space flight. It also provides a framework for investigating countermeasures to reduce the incidence of orthostatic hypotension caused by an attenuation of cardiac output. We continue to use hind limb un-weighted (HLU) rat model to simulate the patho-physiological effects as they relate to cardiovascular de-conditioning in microgravity. We have used this model to address the hypothesis that microgravity induced cardiovascular de-conditioning results in impaired vascular responses and that these impaired vascular responses result from abnormal alpha-1 AR signaling. The impaired vascular reactivity results in attenuated blood pressure and cardiac output responses to an orthostatic challenge.

We have used in-vitro vascular reactivity assays to explore abnormalities in vascular responses in vessels from HLU animals and cardiac output (CO), blood pressure (BP) and heart rate (HR) measurements to characterize changes in hemodynamics following HLU. Overall, we have been able to show that our model of microgravity exposure is associated with a decrease in sympathetic neurotransmission (SN). This in turn is associated with a decrease in alpha-1 AR number and signaling as well as vessel smooth muscle mass (trophic effects of NE). Upon return to gravity, attenuated vascular contractility occurs secondary to end organ hypo-responsiveness, despite normal or accentuated sympathetic neurotransmission. We have found that the impaired venular and arteriolar responses to catecholamine stimulation result in impaired stroke volume, cardiac output and blood pressure responses.

These accomplishments have allowed us to refine mechanisms, begin to test countermeasures - specifically Midodrine - and bridge the gap between animal models and human subjects in our understanding of microgravity-induced orthostatic intolerance.


Earth Applications

These studies have direct application to orthostatic intolerance seen in the elderly population, particularly in females. Similar countermeasures that have been proposed for astronauts in a microgravity environment are also currently being tested in the female elderly population.

This project's funding ended in 2004