The respiratory and pupillary effects of oral l-, d-, and d,l-methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half-life of drug in blood was 22 hr for racemic methadone, 24 hr for l-methadone, and 25 hr for d-methadone. The effects of d-methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l-methadone and 15 mg of d,l-methadone induced intense and sustained respiratory depression and miosis. The changes induced by l-methadone were of longer duration than those of d,l-methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated well with respiratory depression and miosis for l- and d,,l-methadone. The potency ratio of l-methadone to d,l-methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l-methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l-Methadone administered frequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

No abstract

Respiratory and cerebral hemodynamic responses to leg exercise during respiration of air at 1.0 atm. and O2 at 2.0 atm. were studied in relation to changes in arterial and internal jugular venous blood oxygen composition, pH, pCO2 and bicarbonate concentration. The hyperpnea of exercise at 1.0 atm. was accompanied by arterial and venous acidemia and hypocapnia. Oxygen administration during exercise at 2.0 atm. lowered ventilation, restored arterial pH and pCO2 toward resting levels and caused venous pCO2 to rise above the resting level; cerebral venous cH remained elevated in spite of reduction of blood fixed acid concentration. The ventilatory response to exercise showed positive correlations with work load, oxygen consumption, and with changes in arterial and internal jugular venous cH and fixed acid. The observed negative correlations of changes in respiratory minute volume with changes in arterial and internal jugular venous pCO2 and bicarbonate concentration suggest that these factors are functions, rather than primary determinants, of ventilation in exercise. Cerebral hemodynamics and oxygen consumption were not significantly altered by exercise at 1.0 atm. The data suggest either a slight elevation of cerebral blood flow or reduction in the rate of cerebral oxygen consumption during exercise breathing O2 at 2.0 atm., without gross elevation of cerebral venous pO2. Observed changes in cerebral vascular resistance during exercise at .21 and 2.0 atm. inspired pO2 appear related to concomitant alterations in arterial pCO2, with no detectable relationship either to brain oxygen requirement of cerebral venous acid-base composition. Submitted on November 25, 1958

A comparative study is presented on the circulatory dynamics of the renal hypertensive state, the stability (repeatability) of the findings in a given subject, the effect of anemia as a complicating factor and the amount of cardiac hypertrophy present in each animal at the end of the series of observations. The results indicate that in nonanemic renal hypertensive dogs with cardiac hypertrophy the coronary blood flow and cardiac oxygen consumption are the same per unit weight of inyocardial tissue as in normal dogs. However, when a mild chronic anemia is a complicating factor, the coronary blood flow and the myoeardial oxygen uptake are both increased. The coronary sinus venous oxygen saturation is essentially unchanged in the nonanemic hypertensives, whereas in the anemic hypertensives it is significantly lowered. P REVIOUS studies 2 led to the conclusion that rapid digitalization of the lightly anesthetized but otherwise intact normal dog causes a decrease in some of the major cardiac functions such as rate, stroke volume, coronary blood flow and coronary venous oxygen saturation and mechanical efficiency. On the other hand, in a few preliminary experiments with dogs in low-output, congestive heart failure, these same functions were all increased by acute digitalization. The implications of these findings seemed important enough to justify a systematic study, and a series of attempts at producing low-output, congestive failure in dogs were begun. Among the measures employed were renal hypertension, progressive coronary narrowing and traumatic aortic insufficiency.From the Although these procedures, alone and in combination, did not bring about the desired result (low-output, congestive heart failure of adequate stability in a sufficient number of animals), they did provide a series of observations of the behavior of the important cardiac functions during the development of left ventricular hypertrophy in previously normal dogs. This report presents findings in dogs subjected to renal hypertension. It may be said at once that, the major conclusion eonfirms that derived by Bing and his associates 8 from corresponding studies on human subjects in essential hypertension-that coronary flow and cardiac oxygen consumption per unit weight of hypertrophied muscle fall within the range of the normal values. Beyond this, the experiments provided information on the prehypertensive state, the various stages in the development of hypertension, the effect of anemia as a complicating factor, the stability (repeatability) of the findings in a given animal subject and the amount of hypertrophy present in each animal at the end of the series of observations. METHODS Experimental renal hypertension was induced in adult mongrel dogs weighing IS to 30 Kg. by the cellophane perinephritis method of Page. 4 Following the establishment of hypertension, the animals were studied under anesthesia by intramuscular injection of morphine (3 mg./Kg.) followed by intravenous injection of a combination of equal 476

No abstract