Changes in blood pressure can occur for two reasons: 1) A decrease in cardiac output resulting from the altered contractility of the heart or through changes in venous filling pressure via the Frank Starling mechanism or; 2) A change in systemic vascular resistance. The observed changes in cardiac output and blood pressure after long term long term space flight cannot be entirely explained through changes in contractility or heart rate alone. Therefore, alterations in filling pressure mediated through changes in systemic venous capacitance and arterial resistance function may be important determinants of cardiac output and blood pressure after long term space flight. Our laboratory has previously shown the importance of veno-constriction mediated by the carotid sinus baroreceptor reflex system on overall circulatory homeostasis and in the regulation of cardiac output.
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 micro-gravity. This hypothesis is important to our overall understanding of circulatory adjustments made during long term space flight. It also provides a framework for investigating counter measures to reduce the incidence of orthostatic hypotension caused by an attenuation of cardiac output. We continue to use hind limb unweighted (HLU) rat model to simulate the pathophysiological effects as they relate to cardiovascular deconditioning in micro-gravity. We have used this model to address the hypothesis that micro-gravity induced cardiovascular deconditioning 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 micro-gravity 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 hyporesponsivenss, despite normal or accentuated sympathetic neurotransmission. Impaired venular and arteriolar responses to catecholamine stimulation results in impaired stroke volume, cardiac output and blood pressure responses. Specifically,
We have demonstrated impaired CO responses to an orthostatic challenge in rats following HLU which recovers in ~60hrs.
We have demonstrated that after HLU, unstressed venous vascular volume is increased following HLU and can no longer decrease in response to sympathetic stimulation. This supports our primary hypothesis and may underlie the mechanisms leading to an exaggerated fall in stroke volume seen in astronauts.
Using cardiopulmonary bypass studies in which cardiac output is fixed, we have demonstrated that venous an total circulatory capacitance is increased following HLU.
We have demonstrated impaired alpha-1-AR and non-alpha mediated responses in large arteries (aorta) of HLU animals. We have also demonstrated that the observed vascular contractile hyporesponsiveness is reversible with time, In addition, alpha-1AR specific abnormalities in mesenteric microvessel responsiveness appear to be present.
We have observed a decrease in alpha-1AR specific radioligand binding in aortic vessels from HLU animals.
We have demonstrated both an endothelial dependent and endothelial independent component which contributes to vascular hyporesponsiveness following HLU.
We have demonstrated vascular hyporesponsiveness in the large pulmonary arteries of the HLU rats. This vascular hyporesponsiveness is obliterated with nitric oxide synthase inhibition suggesting that increased nitric oxide production may be mediating this impaired contractile response.
We have demonstrated an impaired heart rat and blood pressure response to a orthostatic stimulus (transient bilateral carotid occlusion) in a HLU mouse model.
We have developed an external non-invasive mechanical prototype device, in conjunction with the Applied Physics Laboratory of JHU, that peristaltically pumps blood from lower extremities and abdomen towards the heart to maintain stroke volume and cardiac output during an orthostatic challenges. A notice of invention and non-disclosure has been filed with Johns Hopkins University.
In general our data support the hypothesis that vascular and specifically venular hyporesponsiveness is likely to contribute to impaired stroke volume response and blood pressure regulation following microgravity. We have also continued to validate the HLU rat model as a model that recapitulates the cardiovascular changes that occur following microgravity in humans. These accomplishments have allowed us to refine mechanisms, begin to test countermeasures, and bridge the gap between animal models and human subjects in our understanding of micro gravity induced orthostatic intolerance.