Intracellular Calcium Signalling and Vascular Reactivity in Bartter’s Syndrome

Abstract

We investigated patients affected by Bartter’s syndrome in the attempt to localize the intracellular defect mediating the reduced intracellular Ca²⁺ mobilization that may be responsible for the decreased vascular reactivity characteristic of Bartter’s syndrome. Using the formylmethionyl-leucyl-phenylalanine (fMLP) receptor system, which causes intracellular calcium release, we investigated fMLP-stimulated intracellular inositol 1,4,5-trisphosphate (IP3) production as well as the number and affinity of fMLP receptors in neutrophils from Bartter’s syndrome patients and healthy controls. Scatchard plot analysis of radioactive fMLP binding to neutrophils indicated that there were no differences in either cell receptor number and affinity for ligand between healthy controls (n = 5) and patients with Bartter’s syndrome (n = 5): 6,151 ± 1,431 vs. 7,112 ± 2,566 receptors/cell; K_D: 0.446 ± 0.14 vs. 0.454 ± 0.09 pM of fMLP. 5- and 10-second fMLP-stimulated intracellular IP₃ production was instead reduced in patients affected by Bartter’s syndrome: 2.479 ± 1.07 vs. 4.073 ± 1.04nmol/l0⁷ cells at 5 s(n = 8;p < 0.01);1.673 ± 0.741 vs. 3.766 ± 1.348 nmol/l0⁷ cells at 10 s (n – 8; p < 0.005). The results of this study indicate that the anomaly of intracellular calcium mobilization in patients with Bartter’s syndrome arises from a defect at the postreceptor level. The anomalous calcium signalling that takes place in Bartter’s syndrome may provide a mechanism for the hyporesponsiveness to pressor stimuli characteristic of these patients.

Hypomagnesemia and Chondrocalcinosis in Bartter’s and Gitelman’s Syndrome: Review of the Pathogenetic Mechanisms

“…We showed, in fact, in Bartter's and Gitelman's patients [15] an anomaly in the intracellular Ca 2+ and IP 3 signaling system [16,17], a reduced protein kinase C activity [17,18] and upregulation of the nitric oxide system [19,20]. We have also studied aspects of these diseases connected with electrolyte abnormalities [21] and, more recently, with magnesium handling and chondrocalcinosis [22].…”

Evidence of Myocardial Dysfunction in Bartter&rsquo;s Syndrome

“…Furthermore, although in this study no calcium measure ments have been presented, in all the patients included in this study we previously reported not only a reduced intracellular calcium release [5], but we also recently showed a reduced inositol 1,4,5-triphosphate (IP3) pro duction [6] that, along the calcium-dependent signal transduction sequence, causes calcium release and pro tein kinase C activation [14], Therefore, the reduced intracellular IP3 production and calcium release found in our patients together with the results of the present study, strongly point toward a relationship, in Bartter's syn drome, between the defective myocardial contractile re cruitment and the altered intracellular calcium handling.…”

“…In fact, in addi- tion to defects in vascular smooth muscle calcium-dependent processes (reduced the response to AT II and norepi nephrine) [ 1 ], a number of defects in physiologic activities related to decreased response to Ca2+ mobilizing stimuli (anomalies in shape changes and aggregation) have been demonstrated also in platelets of patients affected by Ban ter's syndrome [4]. Furthermore, we have reported that patients affected by Bartter's syndrome exhibit a smaller than normal increment of neutrophil intracellular Ca2+ release [5] and we have recently shown where in the intra cellular signal transduction system the basic anomaly responsible for the decreased mobilization of intracellular Ca2+ is located [6], This anomaly in intracellular calcium handling could cause the hyporesponsiveness of Bartter's syndrome's vascular smooth muscle [6] as it is well known that the contractile response of vascular smooth muscle is strongly dependent on cytosolic Ca2+ levels [7], This anomalous intracellular calcium homeostasis could also be due an anomaly of myocardial contractile reserve recruitment since inotropic activation depends on the ability to adequately increase intracellular calcium [8].…”

Perioperative endocrinological findings in a patient with Bartter's syndrome and living-related renal transplantation

“…Recently, however, down-regulation in response to the chronic high levels of renin and aldosterone has been considered to be the cause [7][8][9][10]. In Bartter's syndrome, the increase in intracellular calcium ions is suppressed at the second messenger level, and therefore vascular and myocardial reactivity is decreased [11][12][13][14][15].…”