CURRENT RESEARCH- Artin A. Shoukas

Our research will test the hypothesis, that, the arterial compliance is an important determinant of cardiac output during reflex induced changes of vascular capacitance and total peripheral resistance.

Sprague-Dawley (SD) or Wistar Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats, which have very different arterial compliances, have opposite cardiac output responses. Initially, we measure the arterial pressure, venous pressure, cardiac output, heart rate, ascending aortic flow, stroke volume and dP/dT/P_max in the three strains of rat when carotid sinus pressure is changed. We test the carotid baroreceptor reflex responses on the above variables in conscious chronically instrumented rats and in the same rats after they have been anesthetized. We test the hypothesis that the cardiac output and stroke volume response to carotid sinus stimulation in conscious SD or WKY rats are different in magnitude and direction then in SHR rats and then test the hypothesis that the cardiac output and stroke volume responses in anesthetized SD or WKY and SHR rats respond similarly to conscious rats of the same strain. We then  test whether the bi-lateral carotid sinus baroreceptor reflex gain on arterial pressure is the same in SD, WKY and SHR rats.

Currently, there are two major methods to measure the total systemic vascular compliance,  the cardiopulmonary bypass technique with constant flow and the mean systemic filing pressure (MSFP) technique. Our laboratory is in a unique position to measure the systemic capacitance changes caused by the reflex system using our newly developed cardio-pulmonary bypass technique and in the same rats, apply the MSFP technique to determine the primary differences in reported values from these two techniques. We also test if the pressure-diameter relationships of micro-vascular venules is the same. We measure the arterial compliances using both linear and non-linear systems theory.

We also test for the equality of contractility changes in the three strains. In the same rats we will perform reflex control experiments and then beta block the heart to determine if the response in cardiac output and stroke volume were dependent on changes in contractile state. We simultaneously measure dP/dT/P_max and end-systolic pressure volume relationship (ESPVR) in the three strains using intraventricular pressure measurements and a volume conductance catheter.

We have developed a negative/positive feedback servo system by which we are able to increase and decrease the apparent arterial compliance. We will find at what level of arterial compliance to venous compliance ratio that will significantly attenuate and/or reverse the cardiac output response when carotid baroreceptor are activated.

We hypothesize that the mechanism for the differences in cardiac output responses and the changes in the inverse slope of the Venous Return Curve,  the resistance to venous return, caused by the carotid reflex system are attenuated when the arterial compliance is smaller as in SHR rats.

Changes in cardiac output can occur for two reasons: the altered contractility of the heart or through changes in venous filling pressure of the heart via the Frank Starling mechanism.  The observed changes in cardiac output after long term long term space flight cannot be entirely explained through changes in contractility or heart rate alone.  Therefore, changes in filling pressure mediated through changes in systemic venous capacitance function may be an important determinant of cardiac output after long term space flight. Our laboratory has previously shown the importance of veno-constriction by the carotid sinus baroreceptor reflex system on overall circulatory homeostasis and in particular the regulation of cardiac output.

Our proposed experiments will test our overall hypothesis, that, alterations in venous capacitance function by the carotid sinus baroreceptor reflex system is an important determinant of the cardiac output 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 as well as to provide for counter measures to reduce the incidence of ortho static hypotension caused by an attenuation of cardiac output.  We will use the tail suspended rat model to simulate the pathophysiological effects as they relate to cardiovascular deconditioning in microgravity.  We will study the baroreceptor reflex control from the organism level to the level of venous micro vessels and the adrenergic receptors responsible for veno constriction.  This proposal also advances a novel hypothesis: orthostatic intolerance following microgravity exposure is due in part to changes in function of intestinal (splanchnic) capacitance vessel alpha-1 adrenoreceptors (ARs). This hypothesis is based on: 1) our preliminary animal and human data which demonstrate that inhibition of a single alpha-1 AR subtype results in both blockade of sympathetically mediated splanchnic capacitance vessel constriction and orthostatic intolerance, and 2) published studies which document intact efferent sympathetic responses to postural stress (norepinephrine (NE) release) in returning astronauts, possibly pointing to a vascular smooth muscle insensitivity as contributing to orthostatic intolerance. This proposal will test the hypothesis that simulated microgravity  produces alterations in alpha 1 AR-mediated control of splanchnic capacitance vessel tone. 

A chronic rat model and in vivo and in vitro microvessel bioassay will be used to investigate effects of simulated microgravity on splanchnic vessel responses to adrenergic stimulation.  These studies will provide important new data concerning normal capacitance vessel function in compensating for postural blood volume redistribution, test our novel hypothesis regarding the pathogenesis of orthostatic intolerance following microgravity exposure, and provide insights into potential countermeasures and therapies to prevent problematic postural hypotension on reentry.