Manuel Martinez-Maldonado

Effect of expansion of extracellular fluid volume on renal phosphate handling

To examine the specific effect of extracellular fluid (ECF) volume expansion on phosphate excretion studies were performed in thyroparathyroidectomized dogs receiving saline solution intravenously. The natriuresis resulting from ECF volume expansion was consistently accompanied by an increase in phosphate excretion. The possible role of increased filtered load of phosphate was eliminated in experiments in which the filtered load of phosphate was reduced by acute reduction in the glomerular filtration rate. Despite considerable reductions in filtered phosphate, ECF volume expansion resulted in a consistent increase in phosphate excretion. Furthermore, the possible contribution of alteration in blood composition was investigated in experiments in which saline was infused during thoracic inferior vena cava constriction. In these experiments saline infusion failed to increase sodium or phosphate excretion. Cessation of saline infusion and release of caval constriction resulted in a prompt natriuresis and increased phosphate excretion. It is concluded from these studies that extracellular fluid volume expansion results in an increased phosphate excretion in the parathyroidectomized dog. This effect is the specific consequence of ECF volume expansion and is not due to increase in the filtered load of phosphate or alterations in blood composition.

Role of macula densa in diuretics-induced renin release.

Diuretic therapy may enhance renin release by various mechanisms, principally contraction of extracellular fluid volume and its effects, including a fall in arterial pressure. Awake hydropenic or volume-expanded rats received diuretics (amiloride and hydrochlorothiazide) that are known inhibitors of NaCl transport beyond the macula densa; also the well-known Na(+)-K(+)-2 Cl- transport system inhibitor furosemide was administered. We also evaluated the effect of a dose of ethacrynic acid (a drug that shares the same mechanism of action as furosemide but is not diuretic in the rat). The direct action of the diuretics on renin-producing cells was examined in isolated glomeruli; a rise in renin release was observed with the calmodulin inhibitor trifluoperazine (10(-5) M). Renin release in intact hydropenic rats was not altered by diuretic therapy, but furosemide increased plasma renin activity in hydropenic as well as in volume-expanded rats. This demonstrates the importance of furosemide inhibition of transport in the macula densa for its renin secretory action. None of the diuretics (amiloride, hydrochlorothiazide, ethacrynic acid, or furosemide) elicited changes in renin release from glomeruli (10(-6) to 10(-3) M); amiloride and hydrochlorothiazide (10(-4) to 10(-3) M) did not change renin release from slices, but 10(-3) M ethacrynic acid and furosemide increased renin secretion in this preparation. This suggests that an effect on the macula densa is essential in loop diuretic-mediated renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of angiotensin-converting enzyme inhibition on altered renal hemodynamics induced by low protein diet in the rat.

We assessed the role of angiotensin II in mediating the alterations in renal hemodynamics known to result from low protein feeding to normal rats by examining the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril. 2 wk of low protein (6% casein) diet resulted in decreased glomerular filtration rate (normal protein [NP], 1.82 +/- 0.17 vs. low protein [LP], 0.76 +/- 0.01 ml/min; P less than 0.05) and renal plasma flow (NP, 6.7 +/- 0.2 vs. LP, 3.3 +/- 0.3 ml/min; P less than 0.05); renal vascular resistance rose (NP, 8.7 +/- 0.4 vs. LP, 19.8 +/- 1.4 dyn . s per cm5; P less than 0.05). These changes were accompanied by a significant decrease in plasma renin activity (NP, 7.0 +/- 0.7 vs. LP, 4.4 +/- 0.8 ng A I/ml per h; P less than 0.05), plasma aldosterone concentration (NP, 7.0 +/- 0.6 vs. LP, 4.1 +/- 0.7 ng/dl; P less than 0.05), and urinary PGE2 excretion (NP, 3,120 +/- 511 vs. LP, 648 +/- 95 pg/mgCr; P less than 0.05); by contrast renal renin content was significantly increased (NP, 2,587 +/- 273 vs. LP, 7,032 +/- 654 ng A I/mg protein; P less than 0.05). Treatment with captopril (30 mg/kg per d) raised glomerular filtration rate (GFR; LP + capt, 1.6 +/- 0.2 ml/min) and renal plasma flow (RPF; LP + capt, 6.7 +/- 0.7 ml/min), and reduced renal vascular resistance (LP + capt, 9.2 +/- 0.5 dyn/s per cm5) in low protein-fed animals. These values were not different from those measured in untreated and captopril-treated rats fed a normal (23%) protein diet. There were no changes in systemic mean arterial pressure in any group of rats. These data provide evidence that intrarenal angiotensin II mediates the changes in intrarenal hemodynamics induced by protein deprivation. The effects of low protein feeding may be partly potentiated by the reduction in PGE2 synthesis. However, the normalization of GFR and RPF in view of only modest increases in PGE2 excretion after captopril (LP, 648 +/- 95 vs. LP + capt, 1,131 +/- 82 pg/mgCr; P less than 0.05) suggests that if PGE2 is involved in these changes, it plays a permissive but not essential role in the increased renovascular resistance.

Renal and hemodynamic effects of atrial natriuretic peptide in patients with cirrhosis

The effects of anaritide, a 25-amino-acid synthetic analogue of ANP, were evaluated in 28 patients with cirrhosis complicated by ascites and/or edema. Each patient received two doses of the agent, as well as an infusion of placebo. Six different doses were tested ranging from 0.015-0.300 microgram/kg/min. The infusions lasted for 2 hours and were flanked by both baseline and recovery periods. There was a significant effect of placebo on urinary sodium and chloride excretion rates but no effect on urine flow rate. In response to anaritide, the urine flow rate increased at 0.03, 0.06, 0.075, and 0.100 microgram/kg/min. The sodium and chloride excretion rates increased at all doses except the highest dose. There was no definite effect of anaritide on urinary potassium, calcium, and phosphate excretion rates. There was also no significant effect on creatinine clearance. The mean arterial pressure decreased in response to the 0.060, 0.075, and 0.100 microgram/kg/min doses. In addition, five of the patients receiving the highest dose (0.300 microgram/kg/min) had decreases in their systolic pressures to 90 mm Hg or less. In conclusion, anaritide is natriuretic and diuretic in patients with cirrhosis complicated by ascites and/or edema. Its effect, however, on arterial pressure may limit its therapeutic potential in this patient population.

Pathogenesis of systemic hypertension and glomerular injury in the spontaneously hypertensive rat

Weanling and young spontaneously hypertensive rats (SHRs) demonstrate higher plasma renin activity and plasma aldosterone concentration than age-matched normotensive Wistar-Kyoto (WKY) control rats. In addition, this age group exhibits a salt-retaining tendency not seen in WKYs. Nevertheless, when they reach adulthood, these differences between SHRs and WKYs are all but abolished, yet hypertension persists in SHRs. The possible mechanisms leading to these changes in SHRs and to the differences seen with advancing age are discussed. Results of micropuncture studies that help elucidate the glomerular hemodynamic adaptations to elevation in systemic blood pressure in young SHRs are also presented. Evidence is advanced suggesting that increased intraglomerular pressure is responsible for the histologic lesions characteristic of untreated severe hypertension. The salutary effects of treatment with vasodilator drugs that reduce intraglomerular pressure are emphasized.

Role of water balance in the enhanced potassium excretion and hypokalaemia of rats with diabetes insipidus.

1. The role of water balance in the hypokalaemia of rats with diabetes insipidus (DI rats) was studied. 2. After a 3‐day balance study DI rats had a lower muscle potassium content, and plasma [K+], and the urinary excretion of potassium in response to oral KCl loading was reduced when compared to normal rats. The hypokalaemia was found to be associated with elevated concentrations of potassium in renal medulla and papilla when compared to values in normal Long‐Evans rats. 3. During a 9‐day balance study urinary potassium excretion was higher than that of normal rats on days 1‐3, but not different on days 4‐9; this transient elevation was observed in DI rats on normal, high and low potassium diets. On a low potassium diet the urinary potassium excretion of DI rats fell to minimal levels, making unlikely the existence of a renal defect in potassium handling. 4. Muscle potassium content and plasma [K+] were normal after 9 days in metabolism cages. This spontaneous reversal of the hypokalaemia of DI rats was associated with increased water content of renal medulla and papilla, and decreased potassium concentration in these zones. 5. The effect of acute mild dehydration on potassium handling of DI rats was evaluated. Water deprivation for 1‐8 hr was sufficient to raise the urinary potassium excretion of DI rats above that of DI rats drinking ad lib. Renal tissue [K+] was significantly increased after 8 hr of dehydration. Water deprivation also enhanced the response of DI rats to an oral KCl load. Two days of chronic dehydration in the form of water rationing also significantly enhanced the urinary potassium excretion of DI rats. 6. These data suggest that chronic mild dehydration may be responsible for the modest potassium deficiency observed in DI rats via alterations in renal tissue [K+] and consequently in urinary potassium excretion. Correction of dehydration during prolonged periods in metabolism cages may account for the spontaneous reversal of the hypokelaemic condition.

Effect of triamterene on potassium excretion in cirrhotic patients receiving furosemide

In a three‐way erossover study, 23 patients with hepatic cirrhosis, ascites, and dependent edema received 40 mg/day of furosemide alone and combined with triamterene 50 mg/day and triamterine 100 mg/day. Baseline potassium exeretion did not increase when furosemide was given alone, but potassium excretion fell when 50 mg or 100 mg of triamterene was also given. Both doses of triamterene augmented the natriuretic effect of furosemide.

Lenticular rubidium uptake in hypertensive `cataract-prone' salt-sensitive rats

We have previously reported a high incidence of cataract formation in adult hypertensive salt-sensitive rats, suggesting that hypertension may be an important cataractogenic risk factor. Weanling salt-sensitive rats that eventually developed cataracts showed a marked increase in the pressor response to a high-sodium diet compared to salt-sensitive rats that did not develop cataracts. A lens and aqueous fluid electrolyte imbalance occurred in all adult salt-sensitive rats examined, but was greater in the salt-sensitive rats that developed cataracts, suggesting an alteration in lens and/or ciliary ion transport in cataracts associated with hypertension. In the present study, lens 86Rb uptake was measured in adult hypertensive salt-sensitive rats prior to cataract formation. `Cataract-prone salt-sensitive hypertensive rats (increased pressor response to a high sodium diet given at weanling age), salt-sensitive hypertensive rats unlikely to develop cataracts and control salt-resistant rats were studied at the age of 16 weeks. Total and ouabain-insensitive lens 86Rb uptake were measured for the determination of ouabain-sensitive uptake, an index of Na+,K+-ATPase activity. Lens oaubain-sensitive 86Rb uptake was low in adult hypertensive cataract-prone salt-sensitive rats before cataract formation compared with values in control resistant rats. Intermediate values were observed in hypertensive salt-sensitive rats unlikely to develop cataracts. These data suggest that altered ion transport may play a pivotal role in cataractogenesis associated with this model of hypertension. The data are also consistent with the concept of a generalized defect in epithelial ion transport, at least in salt-sensitive hypertension.

Role of Extracellular Fluid Volume Expansion and Diuretics in Renal Handling of Phosphate

One of the more remarkable functions of the kidney is maintenance of the constancy of the composition and volume (ECV) of the extracellular fluid. The understanding of the mechanisms involved in ECV homeostasis has improved colossally over the past two decades. A number of important studies during this period of time have revealed that a major site of salt and water regulation in the nephron is the proximal convoluted tubule (Jacobson and Seldin, 1977). During ECV expansion (ECVE), sodium reabsorption in the proximal convoluted tubule is depressed, whereas reabsorption is enhanced when ECV is contracted. The major determinants of proximal tubular reabsorption, in addition to a component of active sodium transport, are intrarenal hemodynamics and peritubular Starling forces. Although specific transport systems may exist for each of the constituents of glomerular filtrate, under conditions of changing ECV, bulk movement of fluid from lumen to blood or backleak from blood to lumen may take place. Considerable evidence has been presented (Boulpaep and Sackin, 1977) indicating that during ECVE, fluid backleaks through the tight junction or zona occludens of proximal tubules (or through intracytoplasmic channels).

Renal Hemodynamics and Urinary Concentrating Capacity in Protein Deprivation: Role of Antidiuretic Hormone

The role of antidiuretic hormone (ADH) in the renal concentration defect and hemodynamic changes in protein malnutrition was evaluated in rats with diabetes insipidus (DI) after 2 weeks of low protein feeding. Free water reabsorptive capacity (TcH2O), glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured in the protein deprived rats and in DI rats fed a normal protein diet. The effect of urea supplementation of the low protein diet on renal concentrating capacity was also evaluated. In addition, the renal hemodynamic response to acute administration of ADH was measured and correlated with changes in plasma renin concentration and renal renin content (RRC). Protein deprivation in DI rats resulted in reduced urine osmolality and urea excretion, differences which were reversed by urea supplementation. Protein deprivation did not affect free water reabsorptive capacity but did reduce GFR and RPF. Acute ADH administration significantly increased GFR and RPF in protein-deprived rats; these changes were associated with a reduction in RRC and release. These results suggest that dietary protein restriction does not directly affect the tubular capacity to generate and reabsorb free water. The hemodynamic changes seen in protein deprivation are not mediated by ADH and may be secondary to increased intrarenal angiotensin II.