Studies of the elevated extracellular concentration of cyclic AMP in uremic man.

Abstract

A B S T R A C T This study was designed to elucidate the mechanism of elevation of plasma cyclic AMP in uremic man. Plasma cyclic AMP was measured in 15 normal subjects and in 18 patients with severe renal failure. In some members from both groups the kinetic parameters of the metabolism of extracellular cyclic AMP were measured.Plasma cyclic AMP was elevated from 23 nM in control subjects to 59 nM in uremic patients, regardless of the presence or absence of the kidneys or parathyroid glands. A single pass of uremic blood through a Kiil hemodialyzer decreased plasma cyclic AMP from 58 to 30 nM. The clearance of cyclic AMP by the dialyzer correlated directly with the blood flow passing through the machine. Hemodialysis for 6 h decreased plasma cyclic AMP levels in the systemic circulation by only 12%. Studies with tritiated cyclic AMP revealed a plasma clearance rate of 624 ml/min in normal subjects and of 344 ml/min in patients with uremia. Such a large decrease in plasma clearance rate cannot be explained by a failure of urinary excretion of cyclic AMP and suggests impairment of "metabolic clearance." In addition, the "plasma production rate" of cyclic AMP was 65% higher in patients with renal failure than in normal subjects.It is concluded that the elevation of plasma cyclic AMP in uremic man is due to a combination of: (a) lack of urinary excretion, (b) decreased metabolic clearance, and (c) increased production of plasma cyclic AMP.

Zeptomole per milliliter detection and quantification of edema factor in plasma by LC-MS/MS yields insights into toxemia and the progression of inhalation anthrax

“…The capture step avoids possible false positives from naturally occurring cAMP in a sample. This is even more relevant because cAMP has been found to be abnormally elevated in certain stages of pregnancy [28], hyperthyroidism [29], renal failure [30,31], and eczema [32] among others. For methods with potential clinical application, the specificity for the source of cAMP is essential.…”

Immune Abnormalities in Renal Failure and Hemodialysis

“…HD can reduce the level of mid dle molecules with improvement in lympho cyte function [30]. A long list of factors capa ble of interfering with lymphocyte function include: nutritional status [70], plasma cyclic AMP levels [71], thymosin deficiency [72], a reversible vitamin B6 coenzyme deficiency [73] and a variety of circulatory cytotoxic antibodies [74], Thus, it is not surprising that several studies have found the suppressive effect nondialyzable [54,[56][57][58] and others have found improvement after dialysis [54][55][56],…”

Adenylate Cyclase and Alpha-2-Adrenoceptors in Thrombocytes of Chronic Uremic Patients

“…Occupancy of the thrombocyte alpha-2-adrenoccptor leads to an inhibition of adenylate cyclase activity [for review see 17], mediated by an inhibi tory G protein [for review see 7] and causes or facilitates platelet aggregation [4,17], Stimulation of adenylate cyclase activity, leading to elevated cAMP levels, reverses the thrombin-induced increases in thrombocytefree calcium concentrations and exerts thus an antiaggregatory response [21]. A dimin ished platelet adhesiveness, which seems to be closely linked to serum urea nitrogen lev els, is believed to be a cause of uremic bleed ing disorders [6], Additionally, an increase in plasma and thrombocyte cAMP content and of thrombocyte adenylate cyclase activ ity has been observed in uremia [8,19], A possible explanation for this alteration was presented by Brodde et al [1,2], who found a diminished number of thrombocyte alpha-2-adrenoceptors and a shift of the doseresponse curve of (-)-adrenaline, inhibiting adenylate cyclase activity, towards higher concentrations. It was speculated that the decrease in the alpha-2-adrenoceptor num ber was due to elevated catecholamine lev els, possibly because of an impaired neu ronal uptake mechanism in uremia [9], How ever, arguments against a pathophysiological relevance of these findings are furnished by studies of MacFarlane and Stump [12], showing that only about 50% of the throm bocyte alpha-2-adrenoceptors have to be oc cupied to reach maximal inhibition of ade nylate cyclase activity, whereas the decrease in receptor number, observed by Brodde et al [1,2], was only about 20%.…”