Felice Manfredi

Effect of hypoxemia on sodium and water excretion in chronic obstructive lung disease

To determine the role of hypoxemia in the pathogenesis of impaired sodium and water excretion in advanced chronic obstructive lung disease, 11 clinically stable, hypercapneic patients requiring long-term supplemental oxygen were studied. The renal, hormonal, and cardiovascular responses to sodium and water loading were determined during five-and-a-half-hour studies on a control day (arterial oxygen tension = 80 +/- 6 mm Hg) and on an experimental day under hypoxic conditions (arterial oxygen tension = 39 +/- 2 mm Hg). Hypoxemia produced a significant decrease in urinary sodium excretion but did not affect urinary water excretion. Hypoxemia also resulted in concomitant declines in mean blood pressure, glomerular filtration rate, and filtered sodium load. Renal plasma flow and filtration fraction were unchanged whereas cardiac index rose. On the control day, plasma renin activity and norepinephrine levels were elevated whereas aldosterone and arginine vasopressin levels were normal; none of these four hormones was affected by hypoxemia. Renal tubular function did not appear to be altered by hypoxemia as there was no significant change in fractional reabsorption of sodium. The concurrent decreases in glomerular filtration rate, filtered sodium load, and mean blood pressure at constant renal plasma flow suggest that the reduction in urinary sodium excretion was due to an effect of hypoxemia on glomerular function, possibly related to impaired renovascular autoregulation.

Atrial natriuretic peptide and the renin-aldosterone axis during exercise in man.

Under non-exercise conditions, atrial natriuretic peptide (ANP) elevation suppresses plasma renin activity (PRA) and aldosterone (PA). A similar effect of ANP on PRA-PA during exercise has been suggested but not demonstrated. We measured ANP, PRA, PA, plasma potassium (K+), and changes in plasma volume (PV) and blood volume (BV) at rest and during incremental cycle ergometer exercise to exhaustion in ten healthy males. Plasma concentrations (mean +/- SE) of hormones and electrolytes increased (P less than 0.05) during exercise: ANP (68 +/- 14 to 207 +/- 48 pg.ml-1), PA (11.2 +/- 2.2 to 18.8 +/- 3.4 ng.dl-1), PRA (5.1 +/- 1.1 to 8.2 +/- 1.6 ng.ml-1.90 min-1), and K+ (4.2 +/- 0.1 to 5.5 +/- 0.1 mEq). PV and BV declined, reaching maximal deflections from baseline during the 100% stage (12.9 +/- 1.5 and 8.4 +/- 0.8% decreases, respectively). There were positive correlations between ANP and PRA (r = 0.58; P less than 0.01), ANP and PA (r = 0.56; P less than 0.01), and PRA and PA (r = 0.80; P less than 0.001). Increases in K+ did not correlate with increases in PA. The fall in PV correlated with elevations in PRA (r = -0.67; P less than 0.01) and PA (r = -0.58; P less than 0.01), and the fall in BV correlated with elevations in PRA (r = -0.62; P less than 0.01) and PA (r = -0.44; P less than 0.02). ANP production was related to exercise intensity (gauged by heart rate response; r = 0.58; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Peptide, Renin and Aldosterone in Obstructive Lung Disease and Heart Failure

Elevations of atrial natriuretic peptide (ANP) in congestive heart failure (CHF) and chronic obstructive lung disease (COLD) are presumably due to atrial hypertension, while secondary hyperaldosteronism in these patients is thought to result from diminished renal perfusion. The responsiveness of the ANP and renin (PRA)-aldosterone (PA) systems to acute increases in right atrial pressure has not been studied in these patients, but in normals a reciprocal relationship between ANP with PRA and PA has been shown. The authors monitored venous pressure (VP, reflective of right atrial pressure), ANP, PRA and PA in 15 stable COLD patients, seven stable CHF patients and three normal controls at baseline and after elevation of VP by antishock trousers. Inflation of the trousers resulted in increased VP and ANP (p less than 0.05): control ANP, 84 +/- 17 to 108 +/- 23 pg/ml; COLD ANP, 176 +/- 5 to 200 +/- 7; and CHF ANP, 388 +/- 20 to 499 +/- 37. PRA and PA were not suppressed by increasing ANP levels and the delta ANP/delta VP ratio was similar among groups. No intergroup differences in resting PRA and PA were noted, but PRA was higher (p = 0.007) and PA tended to be higher (p = 0.08) in a sub-group of six edematous patients, as compared with non-edematous patients and controls. These findings: (1) confirm previously reported ANP differences between COLD and CHF; (2) indicate that the ANP system remains responsive to physiologic manipulations in COLD and CHF; and (3) demonstrate that ANP and the PRA-PA axis are not reciprocally related in either group.

Plasma levels of false neurotransmitters across the brain in portal-systemic encephalopathy

Abstract. Arterial and internal jugular venous levels of false neurotransmitters (FNTs: octopamine, OCT, and phenylethanolamine, PEA), aromatic and branched‐chain amino acids, glutamine, ammonia, and pH were measured in patients with portal‐systemic encephalopathy (PSE) and in appropriate controls to define the role of these parameters in the pathogenesis of hepatic coma. The typical plasma patterns reported in the literature were observed: hyperammonaemia (59 ± 8 μmol/l v. controls 30 ± 4, P < 0.005), elevated OCT (19 ± 3 nmol/l v. 6 ± 1, P < 0.001) and PEA (64 ± 8 nmol/l v. 27 ± 3, P < 0.001), high ratio of aromatic to branched‐chain amino acids (0.92 ± 0.12 v. 0.32 ± 0.04, P < 0.005), and variable glutamine levels (216–734 μmol/l). No consistent net flux into or out of the brain could be demonstrated for any of these substances. The degree of encephalopathy correlated with the level of respiratory alkalosis (r= 0.325, P < 0.05) which, in turn, correlated with the degree of elevation of plasma OCT (r= 0.439, P < 0.05) and PEA (r= 0.489, P < 0.05) as well as with the excess of glutamine efflux from the brain (r= 0.927, P < 0.05).

Hemodynamic, renal, and hormonal responses to lower body positive pressure in human subjects

Studies in healthy human subjects subjected to lower body positive pressure (LBPP) have failed to elucidate many of the physiologic effects of this maneuver. In 7 healthy, well-hydrated men we studied the following responses to LBPP (35 mm Hg, 1 hour, supine position): systemic and renal hemodynamics; urine volume (UV), urine osmolality (Uosm), and urine sodium level (UNaV); free water (CH20) and osmolar (Cosm) clearances; plasma renin activity (PRA); levels of aldosterone (PA), cortisol (CORT), norepinephrine (NE), atrial natriuretic peptide (ANP), and vasopressin (AVP); osmolality (Posm); and serum sodium level. Subjects were restudied on a control day with zero trouser pressure. The recorded changes (p < 0.05) when comparing the LBPP day with the control day were as follows: fractional Na+ reabsorption increased (98.7% +/- 0.2% to 99.3% +/- 0.1%) and UNaV decreased (0.19 +/- 0.03 mEq/min to 0.10 +/- 0.01 mEq/min), with concomitant increases in PRA (1.7 +/- 0.2 ng/ml/90 min to 4.5 +/- 1.8 ng/ml/90 min), PA (7.7 +/- 0.7 ng/dl to 9.3 +/- 1.5 ng/dl), and CORT (13.0 +/- 2.6 mg/dl to 19.2 +/- 3 mg/dl); the increase in blood pressure with LBPP (96 +/- 3 mm Hg to 112 +/- 4 mm Hg) was greater than that during control conditions. Renal plasma flow tended to display an interactive pattern across days, with a slight decline during LBPP (5%) and a slight elevation under control conditions (9%). On the LBPP day only, filtered Na+ declined (15 +/- I mEq/min to 12 +/- 1 mEq/min) as a function of reduced glomerular filtration rate (112 +/- 5 ml/min to 91 +/- 7 ml/min), blood volume decreased (by 2.7% +/- 0.7%), CO decreased (5.5 +/- 0.3 L/min to 4.7 +/- 0.3 L/min), and stroke volume declined (101 +/- 6 ml to 84 +/- 3 ml). On both days, NE increased (control, 221 +/- 23 pg/ml to 340 +/- 33 pg/ml; LBPP, 236 +/- 17 pg/ml to 369 +/- 31 pg/ml) and ANP increased (control, 47 +/- 7 pg/ml to 97 +/- 21 pg/ml; LBPP, 49 +/- 10 pg/ml to 104 +/- 30 pg/ml). We concluded that LBPP reduces renal sodium excretion. The mechanism for this reduction is not known, although it did occur in association with an increase in plasma renin activity, which in turn results from mechanical reduction of renal perfusion, stress-related CORT stimulation, a reflex-based elevation in peripheral vascular resistance leading to a reflex increase in plasma renin activity, or a combination of these.

Oxygen transport during acute alkalosis and hyperphosphatemia in dogs.

Oxygen transport, oxygen utilization, erythrocyte 2,3-diphosphoglycerate (DPG), erythrocytic pH, glycolytic rate, P30, cardiac output, lactate, and pyruvate were determined in 15 dogs, hyperventilated and infused with inorganic phosphate for 6 hours. These dogs were compared with: 1) 10 dogs hyperventilated but not infused; 2) 3 dogs infused but not hyperventilated; 3) 3 dogs ventilated normally. Only dogs hyperventilated and infused with phosphate had a significant increase in DFG during the 6 hours. Both groups of hyperventilated animals had decreases in cardiac output and increases in A-VO2 difference, glycolytic rate, lactate and pyruvate. P30s did not change significantly. The increase in DFG did not augment calculated oxygen transport or utilization. The observed increases in DPG, under these nonhypoxic conditions, may merely reflect substrate stimulation of an intraerythrocytic shunt. The effect of increases in DPG on tissue oxygenation in the presence of proven tissue hypoxia remains to be determined.

Red Blood Cell Alkalosis and Decreased Oxyhemoglobin Affinity

The behavior of the oxyhemoglobin curve was studied in ten patients with respiratory alkalosis (arterial [H+] ≤ 37 nM, pCO2 ≤ 32 mmHg and HCO−3 ≤ 22.0 mEq/L) and ten patients with metabolic alkalosis ([H+] ≤ 34 nM, pCO2 ≥ 37 mmHg and HCO−3 ≥ 28.0 mEq/L) to determine whether different alkalotic states similarly affect the red blood cell [H+] and 2,3-diphosphoglycerate interaction and thus the oxygen affinity of hemoglobin. The findings were statistically indistinguishable in respiratory alkalosis and metabolic alkalosis: a) low plasma [H+], normal red blood cell [H+], and high transmembrane [H+] gradient; b) elevated red blood cell 2,3-diphosphoglycerate inversely proportional to low arterial plasma [H+]; c) decrease in oxygen affinity of hemoglobin when normalized for plasma [H+], but less decreased when normalized for red blood cell [H+]. Other factors capable of affecting the oxygen affinity of hemoglobin were: mean corpuscular hemoglobin concentration; red blood cell adenosine triphosphate; carboxyhemoglobin; and methemoglobin were not significantly different between groups. These results: 1) agree with data previously reported from this laboratory on patients with portal-systemic encephalopathy; 2) underscore the importance of RBC [H+] in defining the oxygen affinity of hemoglobin; 3) suggest the decrease in oxygen affinity of hemoglobin is mediated through the 2,3-diphosphoglycerate elevation; and 4) indicate the high transmembrane [H+] gradient is principally due to the cellular accumulation of [H+] (2,3-diphosphoglycerate ionization). [Am J Med Sci 1982; 284(2):8–16.]

Parameters of oxygen delivery in the species Marmot a flaviventris: At sea level and 12,000 feet

1. n1. Hemoglobin, hematocrit, 2,3-DPG, O2 dissociation curve and plasma pH changes were evaluated in the high altitude native mammal, Marmota flaviventris (yellow-bellied marmot), acclimatized to an altitude of 840 ft for 1 year. n n2. n2. They were then placed in hypobaric chambers at 12,000 ± 500 ft for 5 days and the same parameters again studied. n n3. n3. Increases in all parameters were statistically significant except plasma pH. n n4. n4. It is suggested that this animal should be considered a natural paradigm for further laboratory biochemical, physiological and pharmacological studies of oxygen conductance under conditions of hypoxic stress.