Michael D. Bailie

Effects of Indomethacin on Furosemide-lnduced Changes in Renal Blood Flow

Summary The effects of indomethacin on furosemide induced changes in renal blood flow were determined in dogs. Furosemide alone caused an increase in total renal blood flow while indomethacin alone decreased renal blood flow. When furosemide was administered to animals pretreated with indomethacin the increase in renal blood flow was blocked. Changes in intrarenal blood flow distribution were also measured using radioactive microspheres. The pattern of blood flow distribution after furosemide was modified in some of the animals pretreated with indomethacin. Stimulation of renin secretion occurred after furosemide in indo-methacin-treated animals. The data suggest that the changes in renal blood flow produced by furosemide may be modulated by the prostaglandin system. The authors acknowledge the technical assistance of Ms. Tonie Thiel and Mr. Keith Crosslan.

Control of renin secretion in the dog. Effects of furosemide on the vascular and macula densa receptors.

Experiments were undertaken to investigate further the effect of furosemide on rennin secretion in the anesthetized dog. To separate the effects of the macula densa and the baroreceptor mechanisms, experiments were conducted in kidneys made nonfiltering by combining 2.5 hours of renal ischemia with ureteral ligation. Furosemide, in a dose of 5 mg/kg, increased renin secretion and decreased renal resistance in dogs with a nonfiltering kidney. Prior dilation of the nonfiltering kidney with either acetylcholine or papaverine prevented changes in both resistance and renin secretion. However, following dilation of the intact filtering kidney with acetylcholine, furosemide caused an increase in rennin secretion. Infusion of d, l-propranolol decreased renin secretion in both the filtering and the nonfiltering kidneys. Following propranolol treatment, furosemide increased rennin secretion in the filtering kidney but had no effect on renal resistance. These experiments indicate that furosemide stimulates renin secretion by both the macula densa and the baroreceptor mechanisms. The data suggest that stimulation of the sympathetic nervous system may alter renin secretion by modulating the renal baroreceptor, but sympathetic innervation does not appear to be involved in the macula densa mechanism.

In vitro analysis of transport of 2,4,5-trichlorophenoxyacetic acid by rat and dog kidney

Renal transport of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) was studied quantitatively in vitro using renal cortical slices from dogs and rats, in an attempt to explain species differences in the biological half-life of the compound. Addition of 2,4,5-T to slices of rat renal cortex competitively inhibited active transport of p-aminohippuric acid without altering transport of the organic cation, N-methylnicotinamide. Renal cortical slices from rats and dogs actively accumulated 2,4,5-T. Accumulation was oxygen dependent and saturable, and was reduced in the presence of other anions (p-aminohippurate and probenecid). A reduction in the potassium concentration of the medium reduced accumulation of 2,4,5-T by rat tissue but not by dog tissue. Acetate in the medium increased accumulation of the herbicide in dog but not in rat tissue. Finally, the ability of renal tissue from newborn rats to accumulate 2,4,5-T was significantly less than that of adult tissue. It is concluded that the primary route of renal elimination of 2,4,5-T is active secretion of the compound. The greater ability of adult rat tissue to transport PAH explains the shorter biological half-life of 2,4,5-T in this species.

Effects of Asphyxia on Cardiac Output and Organ Blood Flow in the Newborn Piglet

Summary: Experiments were performed on newborn piglets 6–96 hr of age. When the respiratory dead space was increased arterial pO2 decreased and pCO2 increased. During this time cardiac output was unchanged (Fig. 1), while heart rate, respiratory rate, and blood pressure increased (Figs. 2 and 3). After 90 min of asphyxia blood flow to the stomach and small and large intestines decreased. Changes in blood flow were associated with dilatation of segments of the small and large intestine with scattered areas of hemorrhage. Pathologic examination revealed scattered areas of mucosal necrosis (Fig. 6).Speculation: Asphyxia causes both physiologic and pathologic changes in the gastrointestinal tract. Asphyxia appears to be one of the factors involved in the genesis of necrotizing enterocolitis.

Effect of paraquat treatment of rats on disposition of 5-hydroxytryptamine and angiotensin I by perfused lung.

Abstract Rats were injected with the herbicide, paraquat dichloride (25 mg/kg, i.p.), and their lungs were perfused 2–28 days later. Isolated lungs from rats treated with paraquat (PQ) 3 or 4 days before perfusion removed significantly less perfused 5-hydroxytryptamine (5-HT) than did saline-injected controls. This effect was not caused by PQ directly, since perfusion of lungs from untreated animals with PQ did not alter removal of co-perfused 5-HT. Monoamine oxidase activity of600 g supernatan fractions of homogenates of lungs from PQ-treated rats was also reduced compared to controls. Although removal of perfused angiotensin I (1 ng/ml) by isolated lungs was not altered by PQpretreatment, antgiotensin-converting enzyme activity in 600 g supernatant fractions of lung homogenates was reducedd significantly. These results suggest that PQ damages pulmonary endothelium and impairs the metabolic function of lung.

The renal handling of 2,4,5-trichlorophenoxy-acetic acid (2,4,5-T) in the dog

Abstract The herbicide 2,4,5-T is actively transported by renal cortical slices of dogs and rats, suggesting that the compound should be rapidly eliminated from the body via the kidneys. The prolonged plasma half-life of 2,4,5-T in the dog (77 hr) indicates that factors other than secretion into the urine are important determinants of elimination in the dog. This study was designed to determine the renal handling of 2,4,5-T in anaesthetized dogs, and an attempt was made to increase excretion of the herbicide with sodium acetate. Injection of 2,4,5-T decreased clearance of p -aminohippurate in a dose-dependent manner, suggesting that the compound was actively secreted. The clearance of the herbicide, however, was exceedingly low, being less than 1% of inulin clearance. The clearance of 2,4,5-T was increased by sodium acetate and by acetazolamide. Additional studies with mannitol, sodium bicarbonate and ammonium chloride demonstrated that clearance of 2,4,5-T was related to urinary pH, but only when the pH exceeded 6, and was not affected by changes in urine volume. Addition of plasma inhibited the transport of 2,4,5-T by renal cortex slices in vitro , suggesting that the low clearance in vivo was due to very tight binding of the herbicide to plasma protein.

Mechanism of Renal Handling of Angiotensin II in the Dog

The mechanism of renal handling of angiotensin II was studied in vivo in the renal circulation of the intact anesthetized dog and in vitro in whole blood using 14C-5-Ile-angiotensin II, l-Asp-125I-angiotensin II, and d-Asp-125I-angiotensin II. Seventy-five percent of a 600-pmole bolus of 14C-angiotensin II was degraded in a single passage through the kidney as measured by radioactive tracer and radioimmunoassay techniques. The metabolic products were 14C-5-Ile (59%), 5-Ile-8-Phe (15%), and 3-Val-8-Phe (2%); recovery of the injected radioactive material was 99%. The degradation rate of 14C-angiotensin II in whole dog blood in vitro was only 17%/min. Similar metabolic patterns were seen in vivo and in vitro. Sixty-six percent of the injected l-Asp-125I-angiotensin II was metabolized, but only 23% of the d-Asp-125I-angiotensin II was metabolized in a single passage through the kidney. These observations indicate that, under the conditions of these experiments, (1) angiotensin II is rapidly metabolized in the dog kidney by multiple enzymes, including an aminopeptidase, (2) circulating plasma enzymes do not account for the renal handling of angiotensin II, and (3) angiotensin II is not sequestered in the kidney.

Effects of Asphyxia on Renal Function in the Newborn Piglet

Summary: This investigation was undertaken to determine the nature of acute alterations in renal function following the production of hypoxemia, hypercarbia, and acidosis in newborn piglets 6–96 hr of age. After completion of the surgical procedure piglets were allowed to recover from the effects of anesthesia. When respiratory dead space was increased arterial oxygen tension decreased whereas arterial carbon dioxide tension and hydrogen ion concentration increased. There was little change in glomerular filtration rate. Total renal blood flow decreased and renal vascular resistance increased significantly (504 ± 78 mm Hg/liter/mm/m2 to 1422 ± 504). There was no change in distribution of intrarenal blood flow. Sodium excretion and urinary flow rate demonstrated significant parallel increases following the increase in dead space. Plasma renin concentration increased from 67 to 110 ng/ml.Speculation: Hypoxia, hypercarbia, and acidosis produced changes in renal function in newborn piglets. Therapeutic approaches to the newborn human with respiratory distress must consider the potential for modifications of renal function which may be detrimental to the infant.

Control of renin release. Effects of d-propranolol and renal denervation on furosemide-induced renin release in the dog.

We determined the effects of </-propranolol and renal denervation on furosemide-induced renin release in the anesthetized dog. rf-Propranolol possesses only membrane-stabilizing properties, whereas the /-isomer produces beta adrenergic blockade. To separate the vascular and macula densa mechanisms of the juxtaglomerular apparatus effectively, nonfiltering kidneys were produced by combining 2.5 hours of renal ischemia with ureteral ligation. In some dogs, renal denervation was accomplished by relocating the nonfiltering kidney into the neck during the 2.5-hour ischemic interval. Administration of d-propranolol in a priming dose of 1 mg/kg, iv, followed by an intravenous infusion of 1 mg/kg per hour decreased renin release in both the filtering and nonfiltering kidney. Subsequent furosemide injection (5 mg/kg, iv) failed to increase renin release in the nonfiltering kidney. Similarly, after the infusion of lidocaine into the renal artery of the nonfiltering kidney (1 mg/kg per hour), furosemide did not alter renin release. In the denervated nonfiltering kidney, furosemide in a dose of 5 mg/kg, iv, increased renin release and decreased renal resistance. Treatment with dor rf,/-propranolol decreased renin release in five out of six denervated nonfiltering kidneys. Following propranolol, furosemide failed to increase renin release. These results demonstrate that the ability of </,/-propranolol to decrease renin release may be due partially to the membranestabilizing activity of the rf-isomer. Stimulation of renin release by furosemide occurs at both the vascular and macula densa sites which may act independently in the control of renin release. The data demonstrate that, whereas renal sympathetic innervation may modulate renin release under a variety of circumstances, this innervation is not an absolute requirement for renin release at the juxtaglomerular apparatus.

Release of active and inactive renin by the porcine kidney.

We studied the relative rates of release of active and inactive renin by the kidney in anesthetized pigs. Renin concentration was determined in arterial and renal venous plasma as follows: (1) before and after stimulation of renin release with isoproterenol or furosemide, (2) after suppression of renin release by extracellular fluid volume expansion, and (3) after administration of propranolol or indomethacin. Inactive renin was activated by dialysis of plasma at pH 3.3 for 24 hours. Renin concentration was estimated by radioimmunoassay determination of angiotensin I after a 3-hour incubation with excess homologous renin substrate. Following isoproterenol, the release of active renin increased from 8 ± 4 (SEM) to 58 ± 34 ng/min, and inactive renin increased from 53 ± 33 to 321 ± 136 ng/min. Similarly, furosemide stimulated the release of both active and inactive renin. Both forms of renin were suppressed by propranolol or indomethacin. Although changes in renin release following volume expansion were not statistically significant, the direction of change for both forms of renin was similar. Following logarithmic conversion of the rate of release, the plot of active vs. inactive renin formed a straight line. Values for active renin as a percentage of the total renin in simultaneously drawn arterial and renal venous plasma samples were not different. Thus, under the conditions of these experiments, release of active and inactive renin appears to be controlled by similar mechanisms. Both stimulation and suppression of renin release result in parallel changes in release of the two forms. Data on relative amounts of active renin in arterial and renal venous plasma suggest that there is no systemic conversion of the two forms. Circ Res 44: 32-37, 1979