Michael B. Maron

Excessive sympathetic nervous system activity decreases myocardial contractility

Abstract The objective of this study was to determine whether myocardial contractility is depressed by intense activation of the sympathetic nervous system. A massive sympathetic discharge was produced by injecting veratrine or sodium citrate into the cisterna magna of anesthetized rabbits (n = 10). Two and one-half hr later, the hearts were isolated and their left ventricular (LV) performance evaluated and compared with the LV performance of hearts isolated from control animals (n = 10). LV performance was evaluated from steady-state peak isovolumic systolic and end-diastolic pressures that were generated at various end-diastolic volumes (LV function curves). The relationship between peak LV systolic pressure (or the average peak developed LV wall stress) and LV end-diastolic volume was rotated downward (P < 0.01) in the hearts removed from rabbits treated with veratrine or citrate. The LV end-diastolic pressure or LV end-diastolic wall stress of these hearts was not different from control at any end-diastolic volume. The diminished ability of the experimental hearts to develop systolic pressure or wall stress suggests that intense sympathetic activation depressed contractility. Severely damaged myofibers, located largely in the subendocardium, were found in these hearts. Furthermore, the depressed contractility was not related to pulmonary edema since only 2 of 10 rabbits developed edema.

Role of Prostaglandins in Blood-Induced Vasoconstriction of Canine Cerebral Arteries

We tested the hypothesis that the vasoconstriction produced by the application of blood to the adventitial surfaces of the vessels of an isolated perfused canine circle of Willis preparation was mediated by products of prostaglandin metabolism. In this preparation (perfused at constant flow and outflow pressure), topical application of blood produced an average 16.6 ± 1.8 (SE) mm Hg increase in inflow pressure. This response could be prevented with four structurally dissimilar cyclooxygenase inhibitors (aspirin, indomethacin, ibuprofen, and meclofenamate), suggesting that the blood-induced increase in vascular resistance was mediated by prostaglandins. Imidazole, an inhibitor of thromboxane synthetase, had no effect on the blood response. Further support for the involvement of prostaglandins in this response was provided by additional experiments in which either arachidonic acid, prostaglandin E2 (PGE2), or PGF2α were administered. All three treatments produced vasoconstriction. These results suggest that the vessels of this preparation are capable of synthesizing vasoconstrictor prostaglandins and indicate that they are reactive to known vasoactive prostaglandins.

β-adrenoceptor stimulation of alveolar fluid clearance is increased in rats with heart failure

The alveolar epithelium plays a critical role in resolving pulmonary edema. We thus hypothesized that its function might be upregulated in rats with heart failure, a condition that severely challenges the lungs ability to maintain fluid balance. Heart failure was induced by left coronary artery ligation. Echocardiographic and cardiovascular hemodynamics confirmed its development at 16 wk postligation. At that time, alveolar fluid clearance was measured by an increase in protein concentration over 1 h of a 5% albumin solution instilled into the lungs. Baseline alveolar fluid clearance was similar in heart failure and age-matched control rats. Terbutaline was added to the instillate to determine whether heart failure rats responded to beta-adrenoceptor stimulation. Alveolar fluid clearance in heart failure rats was increased by 194% after terbutaline stimulation compared with a 153% increase by terbutaline in control rats. To determine the mechanisms responsible for this accelerated alveolar fluid clearance, we measured ion transporter expression (ENaC, Na-K- ATPase, CFTR). No significant upregulation was observed for these ion transporters in the heart failure rats. Lung morphology showed significant alveolar epithelial type II cell hyperplasia in heart failure rats. Thus, alveolar epithelial type II cell hyperplasia is the likely explanation for the increased terbutaline-stimulated alveolar fluid clearance in heart failure rats. These data provide evidence for previously unrecognized mechanisms that can protect against or hasten resolution of alveolar edema in heart failure.

Cigarette Smoke Causes Acute Fluctuations in the Cyclic GMP Content of the Isolated Intact Lung

The injection of a single bolus of the gas phase of cigarette smoke into the airway of an isolated, perfused and ventilated, canine lung preparation resulted in a sevenfold increase in lung cyclic GMP content by 2 s after exposure. Recovery of control levels occurred by 2 min after injection. Repeated smoke exposures of the same lung resulted in similar increases. These results indicate that cigarette smoke may activate lung guanylate cyclase when delivered through the airway and suggest that lung cyclic GMP levels may fluctuate acutely during smoking.

Effect of extreme elevations in venous pressure on reflection coefficient in the lung

We determined whether the solvent drag reflection coefficient (sigma f) for total proteins of a canine perfused left lower lung lobe (LLL) preparation decreases at elevated venous pressures (Pv). We found that sigma f (estimated using the hematocrit-protein technique) remained constant at all Pvs (30-95 mm Hg) evaluated. These results were unanticipated, since previous studies reported increases in protein permeability at Pvs within this range. We conducted two additional studies to better understand the basis for these observations. In the first, we evaluated the effect of high Pv (85 mm Hg) on sigma f of a canine perfused forelimb preparation and found sigma f to be reduced. This difference in response suggests that the normal sigma fs observed in the LLL were not due to high Pv per se, but rather that there is some intrinsic difference between the pulmonary and the systemic circulations that accounts for the difference. The second study was designed to determine whether the normal sigma fs observed in the LLL at high Pvs provide meaningful information about pulmonary vascular endothelial permeability. We damaged LLLs with alloxan, oleic acid, or HCl and obtained near normal estimates of sigma f at high Pv. These results indicated that it is not possible to easily distinguish between a normal and a damaged pulmonary vasculature when sigma f is measured at high Pv. We suggest that the normal estimates of sigma f obtained at high Pv in the LLL results from an increased fraction of the transvascular flow occurring through pathways that exclude macromolecules.

An isolated perfused dog lung preparation for the study of cyclic GMP metabolism: Effects of sodium nitroprusside and oxygen

The intact, isolated perfused dog lung was evaluated as a model for studies directed at defining the role of oxidative modulation of lung cyclic GMP metabolism in pulmonary function. Sodium nitroprusside added to the perfusion blood increased the cyclic GMP content of lung over 4-fold in a dose-dependent manner. Although sodium nitroprusside administration caused changes in lung vascular resistance, these occurred independently of the changes in cyclic GMP. Ventilation of lungs with a high oxygen gas mixture containing 95% O2. 5% CO2 acutely increased the cyclic GMP content of lungs after 15 min from 1.3 +/- 0.06 (mean +/- SE) to 3.4 +/- 0.12 pmol cyclic GMP/mg protein. Cyclic GMP levels returned toward control during continued ventilation with the high oxygen concentration. The oxygen-induced elevation of lung cyclic GMP content was not accompanied by changes in lung vascular resistance. The results indicate that the isolated perfused lung may be useful in studies of cyclic GMP, tissue oxidation and pulmonary function.

The University of California Institute of Environmental Stress Marathon Field Studies.

In 1973, the Institute of Environmental Stress of the University of California-Santa Barbara, under the direction of Steven M. Horvath, began a series of field and laboratory studies of marathon runners during competition. As one of Horvaths graduate students, many of these studies became part of my doctoral dissertation. The rationale for studying runners under race conditions was based on my belief as a marathoner that runners would push themselves much harder while competing than under simulated conditions in the laboratory. Horvaths ready support of the studies likely had its roots in his graduate training at the Harvard Fatigue Laboratory, a laboratory well known for its field studies of individuals working in extreme environments. This report describes the studies of 1973-1975, focusing on how the measurements were made and detailing the learning experiences of a new graduate student. In 1973, blood chemistry and fluid shifts were studied in six runners before and for 3 days after a race. This was the first modern study to systematically examine the recovery process. In 1974, oxygen consumption was measured every 3 mi. in two runners during the race. In 1975, rectal temperature and five skin temperatures were evaluated in the same two runners every 1.4 mi. of the race. The latter two studies were the first to make such measurements under race conditions. The Institute of Environmental Stress marathon studies demonstrated the possibility of making measurements during competition without disrupting performance, enhanced our understanding of human exercise capacity under competitive conditions, and provided new insight into the postrace recovery process.