Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla

Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla. Studies were performed to examine the regulation of atrial natriuretic peptide-(ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10-7 M ANP increased cGMP formation to 31.2 ± 1.8 compared to the basal production of 2.1 ± 0.6 fm/µg protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10-7 M ANP, and saponized cells exposed to 10 µM GTPγS did not enhance the response to ANP (77.3 ± 5.9 vs. 86.7 ± 6.3 g/µg). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 µM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 ± 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 ± 2.5) altered the response to 10-7 M ANP (32.2 ± 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10-8 and 10-7 M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein. The response is highly sensitive to elevations in tonicity, with Na+ as the mediator of this effect

Role of vasopressin in impaired water excretion in conscious rats with experimental cirrhosis

Role of vasopressin in impaired water excretion in conscious rats with experimental cirrhosis. The present study was undertaken to study the mechanism of impaired water excretion in experimental cirrhosis in the rat. Conscious rats in whom histologically proven cirrhosis was induced with carbon tetrachloride and phenobarbital were compared with control rats given phenobarbital alone. Impaired water excretion in experimental cirrhosis was verified by a basal hyponatremia (138 vs. 147 mEq/liter, P < 0.005) and an impaired excretion of water load (minimal urinary osmolality, 262 vs. 100 mOsm/kg; 58 vs. 102% of water load excreted, P < 0.001). To clarify the mechanism of this impaired water excretion, we measured glomerular filtration rate (GFR), renal blood flow (RBF), and vasopressin (VP) levels. In cirrhosis, GFR was normal but RBF was decreased (4.5 vs 6.8 ml/min/g, P < 0.01). VP levels were found to be higher in cirrhotic rats (1.61 vs. 0.71 pg/ml, P < 0.025). The significance of the impaired renal hemodynamics and the increase in VP was assessed by inducing cirrhosis in VP-free Brattle-boro (diabetes insipidus; DI) rats. Despite histologic, biochemical, and renal hemodynamic changes that were comparable to cirrhotic rats with an intact neurohypophysis, cirrhotic DI rats had no impairment in water excretion. To determine the cause of increased VP in experimental cirrhosis, we determined blood volume and systemic hemodynamics. Although plasma volume was greater in experimental cirrhosis (4.3 vs. 3.0 ml/100 g, P < 0.05), cirrhotic rats had a significantly lower peripheral resistance (0.37 vs. 0.42mm Hg/ml/min/kg, P < 0.05) and mean arterial pressure (104 vs. 120mm Hg, P < 0.001) than did control rats. These results document that experimental cirrhosis in the rat is associated with impaired renal water excretion in association with both abnormal renal hemodynamics and increased VP levels. The impaired water excretion, however, is solely VP mediated. The nonosmolar stimulus for VP release may be due to abnormal systemic hemodynamics.Rôle de la vasopressine dans l'altération de l'excrétion de l'eau par le rat conscient atteint de cirrhose expérimentale. Cette étude a été entreprise pour élucider le mécanisme de l'altération de l'excrétion de l'eau au cours de la cirrhose du rat. Des rats conscients chez lesquels une cirrhose prouvée histologiquement a été induite par le tétrachlorure et le phénobarbital ont été comparés à des rats contrôles recevant seulement le phénobarbital. L'altération de l'excrétion de l'eau dans la cirrhose expérimentale a été vérifiée par l'hyponatrémie basale (138 vs. 147 mEq/litre, P < 0,005) et le défaut d'excrétion d'une charge en eau (osmolalité urinaire minimale 262 vs. 100 mOsm/kg; 58 vs. 102% de la charge d'eau sont excrétés, P < 0,001). Pour élucider le mécanisme de cette altération de l'excrétion de l'eau le débit de filtration glomérulaire (GFR), le débit sanguin rénal (RBF) et les concentrations de vasopressine (VP) ont été mesurés. Dans la cirrhose GFR est normal alors que RBF est diminué (4,5 vs. 6,8 ml/min/gm, P < 0,01). VP est plus élevée chez les rats cirrhotiques (1,61 vs. 0,71 pg/ml, P < 0,025). La signification des modifications de l'hémodynamique rénale et de l'augmentation de VP a été évaluée en créant des cirrhoses chez des rats sans VP de la souche Brattleboro (DI). Malgré des modifications histologiques, biochimiques et hémodynamiques rénales qui sont comparables à celles des rats dont la neurohypophyse est intacte, les rats DI cirrhotiques n'ont pas d'altération de l'excrétion de l'eau. Pour connaître la cause de l'augmentation de VP dans la cirrhose expérimentale le volume sanguin et l'hémodynamique systémique ont été étudiés. Quoique le volume plasmatique soit augmenté dans la cirrhose expérimentale (4,3 vs. 3,0 ml/100 g, P < 0,05) les rats cirrhotiques ont des résistances périphériques inférieures (0,37 vs. 0,42mm Hg/ml/min/kg, P < 0,05) et une pression artérielle moyenne inférieure (104 vs. 120mm Hg, P < 0,001) à celles des rats contrôles. Ces résultats indiquent que la cirrhose expérimentale du rat comporte une altération de l'excrétion de l'eau associée à une hémodynamique rénale anormale et à des concentrations de VP augmentées. L'altération de l'excrétion de l'eau, cependant, a la vasopressione comme seul médiateur. Le stimulus non osmolaire de la libération de VP pourrait être l'anomalie de l'hémodynamique systémique

Impact of Achieved Blood Pressure on Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial

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Treatment Guidelines for Hyponatremia Stay the Course

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.</p

Renoprotective effect of the angiotensin-receptro antagonist ibersartan in patients with nephropathy due to type 2 diabetes

Background: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. Methods: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. Results: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. Conclusions: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes

Cardio-renal syndromes: report from the consensus conference of the Acute Dialysis Quality Initiative

A consensus conference on cardio-renal syndromes (CRS) was held in Venice Italy, in September 2008 under the auspices of the Acute Dialysis Quality Initiative (ADQI). The following topics were matter of discussion after a systematic literature review and the appraisal of the best available evidence: definition/classification system; epidemiology; diagnostic criteria and biomarkers; prevention/protection strategies; management and therapy. The umbrella term CRS was used to identify a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. Different syndromes were identified and classified into five subtypes. Acute CRS (type 1): acute worsening of heart function (AHF–ACS) leading to kidney injury and/or dysfunction. Chronic cardio-renal syndrome (type 2): chronic abnormalities in heart function (CHF-CHD) leading to kidney injury and/or dysfunction. Acute reno-cardiac syndrome (type 3): acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. Chronic reno-cardiac syndrome (type 4): chronic kidney disease leading to heart injury, disease, and/or dysfunction. Secondary CRS (type 5): systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. Consensus statements concerning epidemiology, diagnosis, prevention, and management strategies are discussed in the paper for each of the syndromes

Cellular calcium uptake in the action of prostaglandins on renal water excretion

Cellular calcium uptake in the action of prostaglandins on renal water excretion. The role of cellular calcium uptake in the antidiuretic response to vasopressin was studied in anesthetized dogs undergoing water diuresis. In prostaglandin (PG) intact animals, an intrarenal infusion of verapamil caused only a modest blunting of the response to antidiuretic hormone (ADH), because the urinary osmolality (UOsm) achieved in the contralateral control kidney was 338 ± 40 mOsm/kg H2O but was only 270 ± 23 mOsm/kg H2O in the verapamil-infused kidney. The possibility was then studied that PG inhibit the action of ADH by impairing cellular calcium uptake. If so, verapamil would be expected to abolish the effect of PG inhibition to enhance the action of ADH. In eight PG-inhibited dogs, the control kidney's UOsm increased to a mean of 650 ± 103 mOsm/kg H2O but only to 280 ± 22 mOsm/kg H2O in the infused side. Thus, verapamil abolished the effect of PG inhibition to enhance the action of ADH. Likewise, in five dogs a second chemically dissimilar inhibitor of calcium transport, proadifen, also abolished the effect of PG inhibitors as UOsm rose to 590 ± 78 mOsm/kg H2O in the control kidney but only to 278 ± 11 mOsm/kg H2O in the proadifen-infused kidney. Neither prior vasodilatation nor an increased solute excretion with mannitol of a degree observed with verapamil mimicked the effect of the calcium uptake blockers to inhibit the action of ADH. The present in vivo studies therefore demonstrate that the effect of PG inhibitors to enhance the hydroosmotic effect of vasopressin involve cellular calcium transport.La captation cellulaire de calcium dans l'action des prostaglandines sur l'excrétion rénale d'eau. Le rôle de la captation cellulaire de potassium sur la réponse antidiurétique à la vasopressine a été étudiée chez les chiens anesthésiés et soumis à une diurèse aqueuse. Une perfusion intrarénale de vérapamil détermine une atténuation discrète de la réponse à d'hormone antidiurétique (ADH) puisque l'osmolalité urinaire (UOsm) obtenue dans le rein controlatéral est de 338 ± 40 mOsm/kg H2O mais seulement de 270 ± 23 mOsm/kg H2O (P < 0,05) du côté perfusé avec du vérapamil. La possibilité que les prostaglandines (PG) inhibent l'action de l'ADH en empêchant la captation cellulaire du calcium a été étudiée. Si cela était le cas, on devrait s'attendre à ce que le vérapamil abolisse l'effet de l'inhibition de PG qui augmente l'action de l'ADH. Chez huit chiens dont PG était inhibé UOsm des reins contrôles a augmenté jusqu'à une valeur de 650 ± 103 mOsm/kg H2O, mais seulement à 280 ± 22 mOsm/kg H2O du côté perfusé. Ainsi le vérapamil abolit l'effet de l'inhibition de PG. De la même façon, chez cinq chiens, un autre inhibiteur du transport du calcium chimiquement différent, le proadifen (0,375 mg/kg/min), abolit aussi l'effet des inhibiteurs de PG puisque UOsm augmente à 590 ± 78 mOsm/kg H2O dans les reins contrôles, mais seulement à 278 ± 11 mOsm/kg H2O dans les reins perfuses avec le proadifen. Ni la vasodilatation préalable, ni l'augmentation de l'excrétion de substances dissoutes par le mannitol à un niveau comparable à celui observé avec le vérapamil ne reproduisent l'effet des inhibiteurs de la captation de calcium. Les résultats obtenus in vivo démontrent donc que l'effet des inhibiteurs de PG, l'augmentation de l'effet hydroosmotique de la vasopressine, implique le transport cellulaire du calcium