Keith M. McDonald

In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin.

In a previous study we demonstrated that indomethacin potentiated the hydro-osmotic action of vasopressin in vivo. It was hypothesized that this action of indomethacin was due to its ability to suppress renal medullary prostaglandin synthesis, since in vitro studies have suggested that prostaglandins interfere with the ability of vasopressin to stimulate production of its intracellular mediator, cyclic AMP. In the present study this hypothesis was tested in vivo. Anesthetized rats undergoing a water diuresis were studied. In a control group, bolus injections of 200 muU of vasopressin caused a rise in urinary osmolality (Uosm) from 124 +/- 6 to 253 +/- 20 mosmol/kg H2O (P less than 0.005). In a group treated with 2 mg/kg of indomethacin the same dose of vasopressin caused a significantly greater (P less than 0.001) rise in Uosm from 124 +/- 7 to 428 +/- 19 mosmol/kg H2O. Medullary tissue cyclic AMP rose from 9.4 +/- 0.9 to 13.4 +/- 1.7 (P less than 0.05) pmol/mg tissue protein after vasopressin administration in animals receiving no indomethacin, while in indomethacin-treated animals there was a significantly greater rise (P less than 0.001) in medullary cyclic AMP from 10.4 +/- 0.9 to 21.6 +/- 2.1 pmol/mg tissue protein in response to the vasopressin injections. In neither control animals nor indomethacin-treated animals were there significant changes in renal hemodynamics, as measured by clearance techniques. Indomethacin, when given alone, had no effect on Uosm or medullary tissue cyclic AMP. Indomethacin did, however, reduce medullary prostaglandin E content from 84.7 +/- 15.0 to 15.6 +/- 4.3 pg/mg tissue. This study has shown that indomethacin, in a dose which suppresses medullary prostaglandin content, potentiates the ability of vasopressin to increase the tissue content of its intracellular mediator, cyclic AMP. Indomethacin caused no demonstrable inhibition of cyclic AMP phosphodiesterase. Therefore, it seems likely that indomethacin enhanced the ability of vasopressin to increase medullary cyclic AMP levels by causing an increased production rather than decreased destruction of the nucleotide. We conclude that this action of indomethacin contributes to its ability to potentiate the hydro-osmotic action of vasopressin in vivo. A corollary to this conclusion is that endogenous medullary prostaglandin Es may be significant physiological modulators of the renal response to vasopressin.

The Role of Renal Nerves and Prostaglandins in Control of Renal Hemodynamics and Plasma Renin Activity during Hypotensive Hemorrhage in the Dog

The effects of hypotensive hemorrhage (HH) on renal hemodynamics and plasma renin activity (PRA) during prostaglandin (PG) synthesis inhibition were examined in three groups of dogs. In each group of animals arterial blood pressure was lowered by a 30% decrement. In the first group of eight control animals, HH was not associated with a significant change in glomerular filtration rate (GFR, 42-36 ml/min, NS); renal blood flow (RBF) declined significantly, from 234 to 171 ml/min, P < 0.05. In the second group of eight animals, pretreated with RO 20-5720 (RO, 2 mg/kg), a competitive inhibitor of PG synthesis, HH was associated with a significant fall in GFR (43-17 ml/min, P < 0.001) and RBF (195-89 ml/min, P < 0.001). In the third group of eight animals, pretreatment with indomethacin (IN, 10 mg/kg), a chemically dissimilar PG inhibitor, HH was also associated with a significant fall in GFR (38-8 ml/min, P < 0.001) and RBF (150-30 ml/min, P < 0.001). Renal denervation attenuated this renal ischemic effect of HH in the presence of PG inhibition. In the RO group, GFR (34 vs. 17 ml/min, P < 0.005) and RBF (145 vs. 89 ml/min, P < 0.025) were significantly greater in denervated vs. innervated kidneys during HH. Similarly, in animals treated with IN, a significantly higher GFR (28 vs. 8 ml/min, P < 0.005) and RBF (101 vs. 30 ml/min, P < 0.005) occurred in denervated as compared to innervated kidneys during HH. With HH, the increase in PRA in the control group (3.34-11.68 ng/ml per h, P < 0.005) was no different than that observed in the RO group (4.96-18.9 ng/ml per h, P < 0.001) or IN group (4.71-17.8 ng/ml per h, P < 0.001). In summary, the present results indicate that renal PG significantly attenuate the effect of HH to decrease GFR and RBF. Furthermore, renal denervation exerts a protective effect against the enhanced renal ischemic effects which occur in the presence of PG inhibition during HH. Finally, PG inhibition does not alter the effect of HH to cause an increase in PRA.

Mechanism of Effect of Hypoxia on Renal Water Excretion

The effect of lowering the pressure of oxygen from 80 to 34 mm Hg was examined in anesthetized dogs that were undergoing a water diuresis. This degree of hypoxia was associated with an antidiuresis as urine osmolality (Uosm) increased from 107 to 316 mosmol/kg H(2)O (P < 0.001) and plasma arginine vasopressin increased from 0.06 to 7.5 muU/ml, (P < 0.05). However, hypoxia was not associated with significant changes in cardiac output (CO, from 4.2 to 4.7 liters/ min), mean arterial pressure (MAP, from 143 to 149 mm Hg), glomerular filtration rate (GFR, from 46 to 42 ml/min), solute excretion rate (SV, from 302 to 297 mosmol/min), or filtration fraction (from 0.26 to 0.27, NS). Hypoxia was associated with an increase in renal vascular resistance (from 0.49 to 0.58 mm Hg/ml per min, P < 0.01). The magnitude of hypoxia-induced antidiuresis was the same in innervated kidneys and denervated kidneys. To further examine the role of vasopressin in this antidiuresis, hypoxia was induced in hypophysectomized animals. The effect of hypoxia on CO, MAP, GFR, SV, and renal blood flow in hypophysectomized animals was the same as in intact animals. In contrast to intact animals, however, hypoxia did not induce a significant antidiuresis in hypophysectomized animals (Uosm from 72 to 82 mosmol/kg H(2)O). To delineate the afferent pathway for hypoxia-stimulated vasopressin release, hypoxia was induced in dogs with either chemo- or baroreceptor denervation. The effect of hypoxia on CO, MAP, GFR, SV, and renal blood flow in the denervated animals was the same as in nondenervated animals. Hypoxia resulted in an antidiuresis in chemoreceptor (Uosm from 113 to 357 mosmol/kg H(2)O, P < 0.001) but not in baroreceptor (Uosm from 116 to 138 mosmol/kg H(2)O, NS) denervated animals. To determine if hypoxia alters renal response to vasopressin, exogenous vasopressin was administered to normoxic and hypoxic groups of dogs. The antidiuretic effect of vasopressin was no different in these two groups. These results demonstrate that hypoxia induces an antidiuresis which is independent of alterations in CO, MAP, SV, filtration fraction, renal nerves, or renal response to vasopressin and occurs through baroreceptor-mediated vasopressin release. The nature of the baroreceptor stimulation remains to be elucidated.

Mechanism of effect of thoracic inferior vena cava constriction on renal water excretion.

Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (U(osm)) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (C(H2o)) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on U(osm) (87-104 mosmols/kg) and C(H2o) (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on U(osm) was not significant (65-79 mosmols/kg) although C(H2o) decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in C(H2o) and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither U(osm) nor C(H2o) when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on U(osm) is primarily vasopressin mediated while the effect on C(H2o) is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.

Role of the renin-angiotensin system in post-transplantation hypertension in patients with multiple kidneys.

To define the role of the renin-angiotensin system in post-transplantation hypertension we studied 12 hypertensive recipients of renal transplants. The patients received saralasin acetate, an angiotensin II antagonist, while on a normal sodium diet and again after seven days of sodium restriction. In six patients with only one kidney, saralasin did not lower blood pressure on either diet; salt depletion did not lower systolic or diastolic blood pressures. In six patients with more than one kidney, salt depletion also did not lower blood pressure; however, salt depletion plus saralasin lowered their systolic pressures from a mean (+/- S.E.M.) of 146 +/- 9 to 128 +/- 8 mm Hg, and mean diastolic pressures fell from 103 +/- 5 to 89 +/- 5 (P less than 0.001). In four of five patients renal-vein renin activity was greater in one or more host kidneys than in the transplant kidney (or kidneys). Although pre-transplant blood pressure was the same in both groups, post-transplantation hypertension is more likely to be angiotensin II-dependent in patients with more than one kidney.

Effect of Central Catecholamine Depletion on the Osmotic and Nonosmotic Stimulation of Vasopressin (Antidiuretic Hormone) in the Rat

The central nervous system (CNS) mechanism(s) for the release of antidiuretic hormone (ADH) by various stimuli is unknown. In this study, the role of CNS catecholamines in effecting ADH release was examined in conscious rats 10-14 d after the cerebroventricular injection of 6-hydroxydopamine (6-OHDA). This dose of 6-OHDA caused a 67% depletion of brain tissue norepinephrine and only 3% depletion of heart norepinephrine, as compared with controls, which were injected with the vehicle buffer alone. Either intravenous 3% saline (osmotic stimulus) or intraperitoneal hyperoncotic dextran (nonosmotic stimulus) was administered to water-diuresing rats through indwelling catheters. Neither of these maneuvers changed arterial pressure, pulse, or inulin clearance in control or 6-OHDA rats. The 3% saline caused similar increases in plasma osmolality (15 mosmol/kg H(2)O) in control and 6-OHDA rats. The control rats, however, increased urinary osmolality (Uosm) to 586 mosmol/kg H(2)O, whereas 6-OHDA rats increased Uosm only to 335 mosmol/kg H(2)O (P < 0.005). These changes in Uosm were accompanied by an increase in plasma ADH to 7.6 muIU/ml in control animals vs. 2.9 muIU/ml in 6-OHDA rats (P < 0.005). All waterdiuresing animals had undetectable plasma ADH levels. Dextran-induced hypovolemia caused similar decrements (- 10%) in blood volume in both control and 6-OHDA animals, neither of which had significant changes in plasma osmolality. This nonosmotic hypovolemic stimulus caused an increase in Uosm to 753 mosmol/kg H(2)O in control rats, whereas Uosm in 6-OHDA rats increased to only 358 mosmol/kg H(2)O (P < 0.001). At the same time, ADH levels also were significantly greater in Cont rats (2.4 muIU/ml) than in the 6-OHDA animals (0.69 muIU/ml; P < 0.05). These results therefore suggest that CNS catecholamines may play an important role in mediating ADH release in response to both osmotic and nonosmotic (hypovolemic) stimuli.

Central, renal and adrenal effects of lithium in man

Abstract The effect of lithium on thirst and plasma vasopressin concentration was tested in seven subjects with affective psychiatric disorders. Mean ad libitum fluid intake was liberal but no different before (3,293 ml/day) and three to four weeks after treatment with lithium (3,443 ml/day). After fluid deprivation, plasma vasopressin was 1.5 ± 0.39 pg/ml before and 3.72 ± 0.55 pg/ml after treatment with lithium (p 3 − , HPO 4 = , glucose, amino acid and uric acid excretion). A lower titratable acid excretion (21 ± 5 versus 32 ± 4 μeq/min, p 4 Cl ingestion during lithium therapy as compared to control. In conclusion, three to four weeks of lithium therapy neither stimulates thirst nor suppresses vasopressin release; some of the polyuria in patients with affective disorders may be due to their liberal fluid intakes. Lithium does not alter base line or standing PRA, aldosterone or proximal tubular function. Lithium does, however, induce an incomplete renal tubular acidosis.

Catecholamines and Renal Water Excretion

The in vivo mechanisms whereby systemic alpha- and beta-adrenergic stimulation exert opposing effects on renal water excretion are reviewed. An extrarenal mechanism is suggested since the effect of intravenous infusion of norepinephrine or isoproterenol on water excretion cannot be mimicked by the intrarenal administration of these agents. A ROLE OF VASOPRESSIN IS IMPLICATED SINCE NEITHER MAN NOR DOG WITHOUT A PITUITARY SOURCE OF VASOPRESSIN DEMONSTRATE THE SAME EFFECT OF CATECHOLAMINES ON WATER EXCRETION AS OBSERVED IN INTACT MAN AND DOG. Evidence also is presented that systemic alpha- and beta-adrenergic stimulation affect vasopressin release primarily by altering baroreceptor tone. The potential role of the autonomic nervous system in mediating other nonosmotic stimuli for vasopressin is discussed.

The Role of the Adrenergic Nervous System in the Renal Response To Acute Extracellular Fluid Volume Expansion.

Summary The role of the adrenergic nervous system in the renal response to acute extracellular fluid (ECF) volume expansion was examined in the same dogs before and after catecholamine depletion with reserpine. In the control experiments before reserpine, acute ECF volume expansion produced marked increases in glomerular filtration rate (GFR). pamino-hippurate clearance (CPAH), mean arterial pressure (MAP), urine flow (V), sodium excretion (UNaV) and osmolar clearance (Cosm). One week later the same animals were studied under the same experimental conditions except for generalized impairment of the adrenergic nervous system secondary to catecholamine depletion with reserpine. The ECF volume expansion produced very similar increases in GFR, CPAH and filtered loads of sodium (FNa) before and after reserpine; however, the MAP, and thus renal perfusion pressures, were significantly lower after reserpine. Diminished urine flows (V), sodium excretion rates (UNaV) and osmolar clearances (Cosm) occurred after reserpine and correlated closely with the level of MAP. Since the FNa were comparable before and after reserpine, the effect of the lower MAP after reserpine on UNaV appeared to be related to a relatively greater tubular reabsorption of sodium. This study indicates, therefore, that the role of adrenergic nervous system in the renal pressure-flow relationships is an important factor in the natriuretic response to acute ECF volume expansion in dogs.

Unilateral ureteric obstruction

Abstract Two patients were found to have unusual forms of unilateral mid or distal ureteral obstruction associated with systemic hypertension. Assay of differential renal vein renin activity showed a significantly increased level on the affected side. After surgical correction of the ureteral obstruction, by nephrectomy in one case and the ureteroneocystostomy in the other, the systemic blood pressure returned to normal levels in both patients as did the renal vein renin activity in the one case restudied. The importance of early relief of obstruction, if feasible, and the contribution of renal vein renin activity measurements to patient management are stressed.