Renal Site Of Action Research Articles

EFFECTS OF OPIATES ON SODIUM EXCRETION IN THE ISOLATED PERFUSED RAT KIDNEY

1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates.

Muzolimine: Renal site of action and interaction with probenecid in humans

Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hours after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% +/- 0.59% versus 9.07% +/- 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% +/- 2% to 31% +/- 1%; p less than 0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% +/- 1% to 67% +/- 1% (p less than 0.001) of the delivered load. The fractional reabsorption of free water during hydropenia decreased after muzolimine (5.63% +/- 0.26% to 2.00% +/- 0.81%; p less than 0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 +/- 25 mmol/24 hr for muzolimine alone 161 +/- 24 mmol/24 hr for muzolimine and probenecid; p less than 0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug.

Anabolic steroids in polytrauma patients. Influence on renal nitrogen and amino acid losses: a double‐blind study

Severe trauma leads to considerable losses of nitrogen in the first days after the accident. As nutritional efforts cannot reduce these losses sufficiently, an adjunctive therapy using the anabolic steroid nandrolone decanoate (Nd) was applied. In a double-blind study 10 male multiple-traumatized patients each received 50 mg of Nd on day 3 and 25 mg of Nd on day 6 after the trauma, an additional 10 patients received placebo only. Both groups had identical nutritional support. Nitrogen balance, total nitrogen excretion as well as plasma amino acid concentration, and urine amino acid excretion were measured daily. The anabolic agent improved the nitrogen balance mainly by reducing nitrogen excretion. 3-Methylhistidine excretion and renal amino acid losses were decreased. Nandrolone decanoate increased the concentration of total plasma amino acids. The underlying principle seems to be an amino acid-saving mechanism with a renal site of action. It is shown that in the early posttraumatic period nandrolone decanoate improves nitrogen metabolism. Further studies are required to determine whether this offers a clinical benefit to trauma patients.

The effect of angiotensin II and vasopressinonrenal haemodynamics

A comparison was made of the vascular actions of two hormones having a renal site of action, angiotensin II and vasopressin, using laser Doppler flowmetry to measure perfusion of the cortical and papillary regions of the kidney. Angiotensin II infusion caused dose-related increases in blood pressure and reductions in cortical perfusion, the latter responses being potentiated in the presence of the converting enzyme inhibitor, cilazapril. However, angiotensin II had no effect on papillary perfusion either before or following cilazapril. The reasons for this differing vasoconstrictor ability of angiotensin II at the cortex and papilla are unclear, but it could be due to medullary generation of prostaglandin or bradykinin. Administration of equipressor doses of vasopressin caused graded reductions in both cortical and papillary perfusions, and subsequent cilazapril significantly enhanced the papillary responses. This study demonstrates that the regulation of blood flow through the different regions of the kidney can be differentially regulated by the peptide hormones angiotensin II and vasopressin.

Renal effect of atrial natriuretic polypeptide: Comparison with standard saluretics

The effects of synthetic α-human atrial natriuretic polypeptide (α-hANP) on renal hemodynamics and urine production were examined and compared with those of furosemide and trichlormethiazide (TCM) in anesthetized rats. The diuretic effect of α-hANP was brief but more powerful. Also, α-hANP produced a rapid and acute decrease in blood pressure (BP) accompanied by an increase in renal blood flow (RBF), while furosemide and TCM had no effect on either BP or RBF. Both the free water reabsorption rate (T H 2O C) and free water production (C H 2O ) increased with administration of α-hANP but the linear relationship between C H 2O and osmolar clearance (C osm) and that between T H 2O C and C osm were not affected. Furosemide, on the other hand, affected the relationship between T H 2O C and C osm T H 2O C and C osm were not affected. Furosemide, on the other hand, affected. Furosemide, on the other hand, affected the relationship between T H 2O C and C osm and between C H 2O . TCM affected only the relationship between C H 2O and C osm. These results suggest that the renal site of action and the mechanism of action of α-hANP differ from those of furosemide and TCM.

The pathogenesis of idiopathic hypercalciuria: An alternative hypothesis

Currently, four hypotheses attempt to explain the pathogenesis of idiopathic hypercalciuria. Proposed theories include hypersecretion of parathyroid hormone, hyperabsorption of calcium by the gastrointestinal tract, hyperreabsorption of calcium by the kidney, and hyperexcretion of phosphate by the kidney. These hypotheses are more descriptive than explanatory. A new hypothesis is suggested which encompasses the divergent findings. Idiopathic hypercalciuria may result from hypersecretion of parathyroid hormone which is active at the gastrointestinal and bone target site but is partially defective at its renal site of action.

Ochratoxin A and penicillic acid interaction in mice.

Penicillic Acid (PA) and Ochratoxin A (OA) are toxic fungal metabolites that are synergistic in combination. This interaction was investigated using mice which were doses orally as follows: control, none; solvent control, 0.2 ml bicarbonate buffer; PA, 40 mg/kg; OA, 10 mg/kg and combination, 40 mg/kg PA + 10 mg/kg OA. The only significant histopathologic change observed was an acute multifocal toxic tubular nephrosis which appeared most severe in the combination-treated mice killed on day 10. While the combination group had a death rate of 20% (5/25), no deaths occurred in the other treatment groups. The increased death rate and the extensive nephrotoxic findings in the combination group indicate a toxic interaction between OA and PA at sublethal dose levels and is consistent with a renal site of action.

Comparison of effects of standard diuretics and indanone in isolated toad cornea and bladder.

Short-circuit current (SCC) techniques were used to monitor effects of various diuretic agents on Na+ transport in toad bladder and Cl- transport in toad cornea. In bladder, various agents from different "classes" of diuretics inhibited SCC whereas in cornea only "loop diuretics," i.e., those with a primary site of action in the ascending limb of the loop of Henle, inhibited SCC. Classification of the diuretics based on sensitivity in cornea and bladder revealed that diuretics with a common renal site of action gravitated into common classification groups. Thus, our studies suggested that cornea may be a suitable model of the thick ascending limb of the loop of Henle and that cornea and bladder, studied jointly, may serve as an in vitro system for predicting potential renal sites of action of new diuretics. This system, when used to characterize the new diuretic indanone, revealed that this agent, in all respects, displayed the characteristics of a loop diuretic.

Diuretic and Diet Treatment of Hypertension

Diuretic drugs and low-sodium diets are effective in control of hypertension. They seem to have a similar mechanism of action that is dependent on their ability initially to produce a negative salt and water balance and, during long-term treatment, to prevent sodium retention. This effect on body sodium and water stores produces both short-term and long-term hemodynamic adjustments that account for the arterial blood pressure reduction. There is a wide variety of diuretic drugs available with differing potencies and renal sites of action. All, however, have similar antihypertensive potential when given in equal diuretic dosages. Dietary sodium restriction is equally effective in lowering arterial blood pressure, but its usefulness is sharply limited by cultural dietary habits.

Localization of the site of action of mercurial diuretics by stop flow analysis.

Experiments utilizing the new technique of ‘stop flow’ analysis have been performed to localize the renal site of action of mercurial diuretics. Control ureteral occlusions were done on dogs after stabilization of mannitol osmotic diuresis. After release of occlusion and collection of samples, either thiomerin or meralluride (4–8 mg Hg/kg) was administered and a second occlusion performed forty minutes later. The mercurials caused at least a 50% reduction in the mass of water and sodium reabsorbed by the proximal tubule during the brief period of occlusion. These reductions were equivalent so that the sodium concentration of the proximal reabsorbate always remained plasma-like. The mercurials did not interfere with the ability of the distal tubule to lower urinary sodium concentration during the period of ureteral occlusion.