The calcemic and phosphaturic effects of parathyroid hormone in the normal and uremic dog

The responsiveness of bone and kidney to highly purified bovine PTH was evaluated in normal (N) and uremic dogs. One group of uremic dogs (uremic-constant solute intake; U-CSI), maintained on a diet containing 1500 mg of phosphorus (P) daily developed the adaptive increases in phosphate excretion (FE_PO4) and PTH levels characteristic of uremia. A second group of uremic dogs (uremic-proportional reduction of solute; U-PRS), in which dietary P intake was reduced in proportion to the reduction in GFR, exhibited normal FE_PO4 and PTH values. During PTH infusion tubular reabsorption of phosphate per nephron mass decreased 2.5 mg/100 ml in U-PRS but only 1.4 in U-CSI (p < .001) and 1.1 in N (p < .001). After PTH the calcemic response was significantly and equally decreased in both U-CSI and U-PRS compared to N. In conclusion, the blunted calcemic response to PTH in uremia does not appear to be the only or predominant factor in the pathogenesis of hyperparathyroidism since the uremic dog treated with proportional reduction of phosphorus intake, which maintains a normal PTH level, also demonstrates this abnormality. The PTH-induced rise in phosphate excretion in the uremic nephron depends on the pre-existing degree of inhibition of renal tubular phosphate reabsorption. Finally, the uremic animals in which an adaptive phosphaturia was prevented (U-PRS) exhibited a magnified response in phosphate excretion per nephron to exogenous PTH infusion.     

Evidence for in vivo compartmentation of amino acids between blood cells and plasma in man with liver disease during constant infusion of L (U-14C) tyrosine

L (U-¹⁴C) tyrosine tracer was infused at a constant rate for 8 hrs in a series of five patients with liver disease on two occasions, the first when diet consisted of intravenous glucose, and the second when aminoacids were added. Plateau labelling of both plasma and intracellular blood cell free tyrosine was obtained by 6 hr of each infusion. However, the intracellular specific activities were on average 50% lower (p < 0.05) when diet was glucose alone, and 54% lower (p < 0.01) when glucose and aminoacids were given. Change in diet did not significantly affect these differences. The results provide evidence for significant in-vivo compartmentation of aminoacids between plasma and blood cells in man with liver disease, and indicate that whole blood cannot be used in the conventional measurement of whole body protein     

Response to pyridoxine hydrochloride in refractory anemia due to myelofibrosis

Eleven of 14 patients with primary myelofibrosis were given a therapeutic trial with 250 mg of pyridoxine hydrochloride daily because of refractory anemia. The effect on the hemoglobin level and the hematocrit value was studied and compared to that in a group of untreated patients with the same degree of anemia. Six of 11 treated patients responded within three months with a rise in the hemoglobin level (at least 3 g/100 ml) and/or an increase in the hematocrit value (at least 10 per cent), and transfusions were no longer required. Deliberate discontinuation of pyridoxine treatment in one responding patient was followed by a relapse of the anemia; resumption of therapy once again induced an erythropoietic response. Spontaneous remissions of anemia were not observed in the untreated group. It is concluded that a trial with pyridoxine is warranted in patients with myelofibrosis and refractory anemia.     

Adaptation to high altitude hypoxia as a factor preventing development of myocardial ischemic necrosis

Adaptation to high altitude hypoxia reduces the mortality rate in rats with a ligated coronary artery by 5 or 6 times and the size of ischemic necrosis by 35 percent. This adaptation also minimizes the disturbances of the heart's contractile function in ischemic myocardial necrosis. The deficit in the contractile force during maximal load on the heart is 4.4 times smaller in rats adapted to hypoxia than in rats not so adapted. The primary factor contributing to the preventive effect of adaptation to high altitude hypoxia in ischemic necrosis is an increased capacity of the oxygen transport and utilization (mitochondrial) systems in the heart muscle of the adapted animals.     

Effects of ouabain on the electrophysiological properties of subendocardial Purkinje fibers surviving in regions of acute myocardial infarction

We compared the effects of ouabain 2.5 × 10^?8 M. on the electrophysiological properties of minimally-depressed subendocardial Purkinje fibers surviving in regions of acute myocardial infarction with its effects on subendocardial Purkinje fibers in adjacent normal regions and in anatomically identical regions of noninfarcted hearts. Experiments were carried out in vitro on left ventricular tissue preparations dissected from the hearts of dogs 24 hours after coronary artery ligation and from normal canine hearts. Ouabain had no effect on maximum diastolic potential, action potential upstroke, or V_max of Purkinje fibers in normal or infarcted regions. It prolonged the action potential duration in infarcted but not in normal regions. In infarcted tissue preparations ouabain increased conduction velocity and failed to alter the effective and functional refractory periods, while in normal tissue preparations the drug did not affect conduction velocity or the effective refractory period but caused an increase in the functional refractory period. Ouabain did not cause spontaneous activity in normal tissue preparations. In infarcted preparations it resulted in spontaneous activity in six of eight preparations studied. This was due to the development of oscillatory afterpotentials in three preparations and phase 4 depolarization in one; in the other two preparations the mechanism was uncertain. Thus, Purkinje fibers surviving in infarcted regions are more sensitive than normal fibers to the direct electrophysiological effects of digitalis.     

Evidence for autonomous secretion of prolactin in some alcoholic men with cirrhosis and gynecomastia

Prolactin responses to provocative thyrotropin releasing hormone (TRH) stimulation were evaluated in 20 cirrhotic men with gynecomastia. Fifteen of these cirrhotic men had normal responses with a minimum doubling of the prolactin concentration above basal in response to TRH. Five had abnormal (autonomous) responses in that they failed to double their basal level or had a paradoxical decrease from basal in response to TRH. Moreover, these same five men failed to have a sleep-related increase in plasma prolactin. Three of them also failed to respond to chlorpromazine stimulation. Such abnormal responses are generally associated with the presence of a prolactin secreting pituitary tumor. Basal plasma levels of prolactin were measured in all 20 men studied. The five men who failed to respond to TRH had significantly greater basal prolactin concentrations (80.5 ± 18.7 ng/ml) than did the 15 men who responded normally (33.7 ± 4.3 ng/ml) (p < 0.01), although all 20 had increased prolactin levels relative to that of controls (10.8 ± 0.9 ng/ml) (both p < 0.01).     

Influence of elevated plasma free fatty acids on the glucagon response to hypoglycemia in normal and in pregnant women

We investigated the influence of an insulin-induced hypoglycemia on plasma glucagon in nonpregnant healthy young women and in women during the last month of gestation. Both groups were tested either in the basal state or during a period where free fatty acid plasma levels were increased by infusion of a lipid emulsion supplemented with heparin. Regular insulin was injected intravenously at the dose of 0.1 U/kg body wt in controls and 0.3 U/kg in pregnant women in order to obtain a similar lowering of blood glucose in all groups. In controls, the increase in plasma glucagon was maximum 30 and 45 min after insulin injection and averaged 130 pg/ml; the infusion of triglycerides and heparin which raised plasma FFA to about 1300 μEq/liter decreased basal plasma glucagon levels and reduced, by about 70%, the glucagon response to hypoglycemia. During the last month of pregnancy, the glucagon response to insulin-induced hypoglycemia was reduced by 60% (mean maximal increase 52 pg/ml); furthermore, raising plasma FFA to about 1500 μEq/liter completely abolished the glucagon rise induced by the insulin hypoglycemia. These results support the view that the glucagon release from A-cells can be modulated by the level of circulating plasma FFA.     

Ultrasonic pattern of ventricular rhabdomyoma in two infants

Two infants with ventricular septal rhabdomyoma were studied with ultrasound. An abnormal cluster of echoes in the vicinity of the ventricular septum corresponded to the angiographic location of the tumor in each case. Disappearance of these echoes after successful surgical resection lends further support to the conclusion that the abnormal cluster of echoes was indeed related to the intracavitary portion of the tumor in both cases.     

Hereditary orotic aciduria: types I and II

A follow-up study of the propositus for type II orotic aciduria, deficient in orotidine-5′-monophosphate decarboxylase (ODCase), is reported. The subject demonstrated excessive excretion of both orotidine and orotic acid. He responded to uridine replacement therapy with a progressive decrease in orotate phosphoribosyltransferase (OPRTase) activity. His heterozygous mother also excreted excess orotic acid and orotidine. In contrast, heterozygotes for type I orotic aciduria, deficient in both OPRTase and ODCase, excreted excess orotic acid but not orotidine.A frequency distribution study of human erythrocyte OPRTase and ODCase activities revealed a distribution skewed to its lower range. More than one modal value was suggested. Activities of OPRTase and ODCase in erythrocytes from subjects heterozygous for hereditary orotic aciduria types I and II overlapped with those at the lower end of the control group. The coordinate relationship between OPRTase and ODCase activities was maintained throughout the distribution, including the heterozygotes.     

Dose-response relation of antianginal activity of isosorbide dinitrate

Eleven men with angiographic evidence of coronary heart disease and stable, exercise-induced angina pectoris were given placebo (P) or isosorbide dinitrate (ISDN) in a daily dose of 30, 120, 240 or 480 mg, in a randomized single-blind trial. The daily doses were administered 6 times a day as single oral doses of 5, 20, 40 and 80 mg. Each dose or placebo was given for 7 days. Before therapy was begun, and on the seventh day of each treatment period, an exercise ECG with standardized level and duration of exercise was recorded. Subsequently, a 4-week treatment period with 480 mg/day was carried out at the end of which another stress test was performed. The was followed by a final 2-week placebo period. The frequency of anginal attacks per week tended to decrease with increasing nitrate doses, but decreased significantly only after the highest dose (480 mg/day) compared with placebo. Continuation of therapy with 480 mg/day maintained the reduced rate of anginal attacks. The ischemic response, expressed as the sum of ST-segment depressions in the exercise ECG, revealed a dose-dependent reduction of 26% (30 mg/day), 39% (120 mg/day) (p less than 0.01), 63% (240 mg/day) (p less than 0.01) and 72% (480 mg/day) (p less than 0.01), respectively. At the end of the 4-week treatment period with 480 mg/day, antianginal efficacy was found to be moderately reduced, showing a 56% reduction of ischemic response compared to the placebo trial. The time of onset of angina during exercise testing was also delayed in relation to the dosage given.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipolysis and the antilipolytic effect of insulin in adipocytes from rats adapted to a high-protein diet

Free fatty acid (FFA) mobilization during fasting was investigated in rats fed a high-protein, carbohydrate-free (HP) diet (70% casein, 8% fat, wt/wt) or a balanced diet (66% carbohydrate, 17% casein, 8% fat) for 30 to 40 days. In vivo, rats on the HP diet showed reduced rates of plasma FFA increase during fasting. Their blood sugar remained unchanged and was higher than that of control rats 24 hours after removal of food. In the fed state, serum insulin levels were smaller in HP-fed rats but did not differ significantly in the two experimental groups during fasting. In vitro, the rates of glycerol and FFA release by epididymal fat pads obtained from fasted rats were similar in rats consuming the HP diet. Fat cells isolated from rats on the HP diet also had reduced rates of basal lipolysis. Furthermore, they showed a significant increase in responsiveness to the lipolytic action of noradrenaline and an increase in both sensitivity and responsiveness to the inhibitory effect of insulin on noradrenaline-stimulated lipolysis. Adipocytes from HP-fed and control rats had mean diameters of 51 and 60 mu, respectively, and estimated average volumes of 90 and 142 pL. On the basis of existing data on the correlation between size and lipolytic activity of fat cells, the smaller size of the adipocytes from HP-fed rats might account for the lower rate of basal lipolysis but not for the increased response to the hormones. The increased sensitivity of fat cells to the antilipolytic action of insulin may have been an important factor in the reduced lipomobilization during fasting in rats under the high-protein regimen.     

Calcium channel blocking drugs for chronic, stable angina

The slow channel calcium blocking drugs have been shown to be efficacious in patients with chronic stable angina. They provide effective first alternative therapy to beta-blockers in preventing recurrent episodes of myocardial ischemia in patients who do not tolerate treatment with beta-blocking drugs because of, for example, pulmonary bronchospasm or hypoglycemia. The calcium blocking drugs often provide an additive effect in reducing anginal episodes when combined with beta-blocking agents and sometimes provide effective relief of chronic stable angina when beta-blocking drugs are unsuccessful. Diltiazem, nifedipine and verapamil are important additions to our therapeutic armentarium for the treatment of exercise-induced angina pectoris.