James S. McNeil

Mechanism of Increased Sodium Reabsorption during Propranolol Administration

The mechanism of diminished sodium excretion induced by propranolol was investigated in the dog. Propranolol (0.3 to 5 mg/kg) was given intravenously in a bolus to 16 dogs, eight of which had the renal perfusion pressure controlled by a suprarenal aortic clamp. In another group of six dogs propranolol (0.1 to 5, μg/kg/min) was infused into one renal artery for 45 min. Cardiac output (dye dilution), mean arterial and right atrial pressures, heart rate, renal clearances of inulin, creatinine, and para-aminohippurate, and sodium excretion were measured. Total peripheral resistance, central blood volume, stroke volume, renal plasma flow, renal blood flow, renal vascular resistance, glomerular filtration rate, and filtration fraction were calculated.Intravenous propranolol resulted in significant decreases in cardiac output (−25%) and heart rate (−14%) and increases in total peripheral resistance (28%) and renal vascular resistance (37%). Renal blood flow decreased by 25% and filtration fraction increased 21% as urinary sodium excretion diminished 36%. Glomerular filtration did not change significantly. Infusions of propranolol into one renal artery resulted in either no change in sodium excretion or bilateral changes; thus an intrarenal effect of the drug was not demonstrable.The data suggest that the changes in renal hemodynamics associated with propranolol administration are secondary to alterations in systemic hemodynamics, particularly a decrease in cardiac output. These alterations in renal hemodynamics, including an increase in renal vascular resistance and filtration fraction, most likely account for the decrease in sodium excretion rather than a direct effect of propranolol on sodium reabsorption.

Experimental Acute Renal Failure Induced by Uranyl Nitrate in the Dog

The diminished glomerular filtration rate observed in previous studies of acute renal failure induced by uranyl nitrate has been ascribed to backflow of glomerular filtrate through necrotic tubular epithelium, since renal blood flow was essentially normal. Renal blood flow (133xenon washout) and renal function were studied serially for 96 hours after the administration of uranyl nitrate (10 mg/kg, iv) in unanesthetized dogs with chronic renal artery catheters. Inulin clearance and total renal blood flow decreased to 25% and 52% of control, respectively, by 6 hours and remained depressed. By 3 hours, cortical flow decreased to 330±20 ml/min 100 g-1 (control 507±12 ml/min 100 g−1) and outer medullary flow increased to 147±8 ml/min 100 g−1 (control 97±18 ml/min 100 g-1), indicating intrarenal blood flow redistribution. From 6 hours on, these flow components were no longer separable. The ratio of flow in the outer two-thirds of the renal cortex to that in the whole cortex, determined using 85strontium-labeled microspheres (15μ), decreased to 0.34±0.06 and 0.40±0.04 at 6 and 96 hours, respectively (control 2.21±0.12). Plasma renin activity was 1.8±0.6 ng/ml hour−1 at 3 hours and remained elevated (control 0.6±0.2 ng/ml hour−1). Histological examination revealed minimal tubular change at 6 hours and widespread disruption at 96 hours. The decrease in renal blood flow prior to any significant tubular pathology suggests that alterations in renal hemodynamics, which may be mediated by the renin-angiotensin system, are responsible for the diminished renal function observed in this model of acute renal failure.

Uranyl Nitrate Induced Acute Renal Failure in the Rat: Effect of Varying Doses and Saline Loading

Summary Increasing doses of intravenous uranyl nitrate above 2.5 mg/kg of body weight result in more extensive renal tubular necrosis without increasing azotemia in the rat. Despite a uniform level of azotemia, renal tubular epithelial dysfunction tended to parallel the changes in renal tubular pathology. Saline loading, designed to suppress the renin–angiotensin system, ameliorated the azotemia but not the tubular necrosis or tubular dysfunction after uranyl nitrate. These results suggest that passive backflow of glomerular filtrate through necrotic tubular epithelium is not responsible for the azotemia after uranyl nitrate in the rat. The protection afforded by saline loading further suggests a role for the renin–angiotensin system in the development of uranyl nitrate induced acute renal failure.

The role of prostaglandins in gentamicin-induced nephrotoxicity in the dog.

The effects of chronic gentamicin administration on renal function was studied in dogs receiving 4 mg/kg i.m. of gentamicin b.i.d. for 28 days. Administration of gentamicin resulted in a bimodal change in renal function. A decrease in urine osmolality was first noted on day 6 and declined progressively throughout the study. This decrease in urinary concentrating ability was preceded by a steady rise in urinary prostaglandin E2 (PGE) excretion and followed by a rise in plasma renin activity (PRA). Prior to an increase in azotemia, urinary PGE decreased precipitously while PRA continued to rise throughout the remainder of the study. The precipitous decrease in GFR was accompanied by a significant increase in FENa to seven times control. These studies suggest a dual effect of chronic gentamicin administration on renal function: (1) an early effect manifested by stimulation of urinary prostaglandin production with a concomitant loss of urinary concentrating ability and mild prerenal azotemia, and (2) a late effect, preceded by a decrease in urinary prostaglandin excretion while PRA continues to increase, and manifested by increase fractional excretion of sodium and progressive azotemia.

Natriutetic and phosphaturic response to diuretics after parathyroidectomy in dogs

Intact and acutely parathyroidectomized (TPTX) dogs were studied during hydropenia, volume expansion (VE), volume expansion plus ethacrynic acid (EA), and volume expansion plus acetazolamide (AZ). In intact dogs, VE produced marked increases in both Na+ and phosphate (Pi) excretion; in TPTX dogs, Na+ excretion increased but phosphaturia was minimal. Addition of EA increased Na+ but not Pi excretion in both groups. Discontinuing EA and substituting AZ in intact dogs produced a marked increase in Pi excretion compared to both VE and VE + EA. In TPTX dogs, AZ failed to increase Pi excretion compared to VE alone. The results suggest that increased distal Pi absorption in acutely TPTX dogs is not associated with NaCl reabsorption in the thick ascending loop of Henle or may occur at an alternative nephron site. Furthermore, the increased distal Pi reabsorptive capacity revealed by TPTX can overcome the increased distal Pi delivery produced by the superimposition of AZ on VE.