Karlman Wasserman - US grants

Our objectives are to learn how the cardiorespiratory system normally couples to cell metabolism during exercise and how the coupling is modified by disease states. We aim to: 1) describe the gas exchange responses to exercise and recovery and how the components of the cardiorespiratory system interact to meet the cellular gas exchange needs, 2) demonstrate how disease states disrupt the normal coupling between external and internal respiration during exercise and how this information can be used, diagnostically, 3) develop the clinical applications of the anaerobic threshold, 4) compare metabolic markers of the cell redox state to the continuous, noninvasive, gas exchange techniques for measuring metabolic acidosis, 5) learn the mechanisms by which ventilation is controlled during exercise and how it relates to dyspnea, and 6) use the learned physiologic principles to modify therapy. Using the most advanced measurement systems available and computer technology, breath-by-breath ventilation and gas exchange measurements are made and processed to obtain a quantitative analysis of the dynamic components of gas exchange during exercise and recovery. The kinetics of respiration, circulation and metabolism in response to exercise perturbations, as well as to manipulation of factors affecting gas exchange, provide boundary conditions for the metabolic and ventilatory control mechanisms. In addition, arterial blood analyzed for PO2, PCO2, pH and metabolites which reveal the redox state of the cells define the effectiveness of the ventilatory and circulatory homeostatic mechanisms. The mechanism of the exercise hyperpnea, in man, will be studied within the frame of reference of new clues by which humoral and cardiac changes during exercise link to the ventilatory control mechanism. This project utilizes the disciplines of physiology, biochemistry and computer technology in studies on man and animals to determine the mechanisms which control the dynamics of gas exchange and ventilation during exercise, and to use this knowledge to understand pathophysiology, diagnose and treat patients with exercise limitation and dyspnea.

This research has as its focus the coupling of external to cellular respiration during exercise. The ability to perform exercise depends on the dynamic responses of the cardiorespiratory system. These support normal oxygen utilization by the muscle cells, elimination of its CO2 and also acid-base regulation. Recent advances in measurement technology now makes it possible to examine the details of the dynamics of alveolar O2 and CO2 transport in response to exercise. Conceptually there are three functional components of gas exchange dynamics in response to exercise: the cardiodynamic phase (first 25 sec, phase I), the period of increasing O2 extraction and CO2 loading into venous blood (15 sec to approx 3-4 min, phase II), and the period beyond 3-4 min where gas exchange achieves a steady-state below the lactate threshold, but continues to rise above the threshold (phase III). Three major hypotheses will be examined in this project: 1) Alveolar O2 transport dynamics can be used to characterize the state of cardiovascular function during exercise, 2) O2 consumption during heavy work has a component which seems to be linked to mechanisms of lactate metabolism and which causes the O2 cost of the exercise to increase, 3) CO2 output kinetics can be used to measure exercising muscle respiratory quotient and the rate of bicarbonate buffering of metabolic (lactic) acid. For the first hypothesis, we will study normal subjects or patients with particular physiological defects which should interfere with the normal coupling of external to cellular respiration. To test the second hypothesis, we will explore factors which modulate the phase III VO2 during heavy work. To examine the third hypothesis, measurement of lactate, HCO3 and CO2 exchange dynamics in normal subjects will be used as the basis of model analysis of the determinants of CO2 output, both above and below the lactate threshold. These studies utilize the skills of physiologists, physicians, computer scientists and engineers. The time-related changes in O2 uptake and CO2 output in response to exercise are manifestations of specific cardiovascular and metabolic mechanisms. Abnormalities of the response patterns therefore provide important information regarding the site(s) of functional impairment. Understanding these mechanisms is likely to provide the basis for a more rational approach to diagnosis and treatment of patients with exercise limitation.

respiratory function; muscle metabolism; exercise; cardiovascular function; malates; oral administration; clinical trials; drug administration rate /duration; magnesium; clinical research; human subject;

The purpose of this project is to measure double product in normal subjects, using a new blood pressure measuring device, and to compare the double product breakpoint with the anaerobic threshold, measured by gas exchange. The studies are to be done on 10 non-smoking, young, adult, normal subjects, under conditions of air breathing with and without increasing the carboxyhemoglobin to about 10-12%, the level of the heavy cigarette smoker.