Dexamethasone-induced hypertrophy in rat neonatal cardiac myocytes involves an elevated L-type Ca(2+)current.

The mechanism responsible for dexamethasone-induced hypertrophy in infants has not been defined. In this study, we have investigated the role of L-type Ca(2+)currents in the development of dexamethasone-induced hypertrophy in rat neonatal cardiac myocytes. Using cytoplasmic membrane capacitance measurements, we have shown that the size of the cells treated with dexamethasone were larger than those of the control cells. In addition, treating the cells with 1 microM dexamethasone for 48 h increased L-type Ca(2+)current density significantly, without affecting the voltage-dependent activation and steady state inactivation of the current. The increase in current density was associated with an elevation of the mRNA transcript encoding the L-type Ca(2+)channel subunit alpha(1)C. Dexamethasone treatment also resulted in an increase in the peak amplitude of the intracellular Ca(2+)transient measured by fura-2/epifluorescence. Finally, we have demonstrated that the hypertrophic effect of dexamethasone, characterized by the ratio of protein content per cell, was blocked by the L-type specific antagonist, nifedipine. In conclusion, an elevation of L-type Ca(2+)current is involved in the process of dexamethasone-induced cardiac myocyte hypertrophy in neonatal rats.

Influence of group B streptococci on piglet pulmonary artery response to bradykinin.

To study whether a sepsis-induced increase in des-Arg9-bradykinin (des-Arg9-BK) and bradykinin (BK) B1-receptor activity participates in the observed increase in pulmonary vascular resistance in neonatal group B streptococcal sepsis (GBS), isometric force bioassays of pulmonary artery (PA) rings were studied, after 4-h exposure to either Krebs or GBS, by using the following protocols: 1) BK dose-response curve, 2) vascular response to BK with NG-nitro-L-arginine methyl ester (L-NAME), and 3) response to des-Arg9-BK (BK metabolite and B1 agonist). PA rings exposed to BK resulted in contraction in the GBS group and a decrease in resting tension in the Control group (P = 0.034) at a concentration of 10(-5) M. GBS-treated PA rings contracted more to des-Arg9-BK than did Controls (P < 0.001). BK (10(-6) M) relaxed preconstricted PA rings incubated in GBS less than BK relaxed Controls (P < 0.001), and preincubation with L-NAME decreased relaxation in both. These results suggest that GBS decreased endothelium-dependent BK relaxation and increased contractile response to des-Arg9-BK. We speculate that this occurs secondary to upregulation of B1 receptors reflected by B1-agonist-mediated PA contraction.

T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting beta-cell line, INS-1.

The present study addresses the function of T-type voltage-gated calcium channels in insulin-secreting cells. We used whole-cell voltage and current recordings, capacitance measurements, and RIA techniques to determine the contribution of T-type calcium channels in modulation of electrical activity and in stimulus-secretion coupling in a rat insulin secreting cell line, INS-1. By employing a double pulse protocol in the current-clamp mode, we found that activation of T-type calcium channels provided a low threshold depolarizing potential that decreased the latency of onset of action potentials and furthermore increased the frequency of action potentials, both of which are abolished by administration of nickel chloride (NiCl2), a selective T-type calcium channel blocker. Moreover application of high frequency stimulation, as compared with low frequency stimulation, caused a greater change in membrane capacitance (deltaCm), suggesting higher insulin secretion. We demonstrated that glucose stimulated insulin secretion in INS-1 is reduced dose dependently by NiCl2. We conclude that T-type calcium channels facilitate insulin secretion by enhancing the general excitability of these cells. In light of the pathological effects of both hypo and hyperinsulinemia, the T-type calcium channel may be a therapeutic target.

Cyclosporine-associated renal arteriopathy resulting in loss of allograft function.

Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

Glycosylated serum protein levels in diabetic and nondiabetic pregnant patients: an indicator of short-term glycemic control in the diabetic patient.

Measurement of the level of nonenzymatic glycosylation of blood proteins with more rapid turnover times than hemoglobin has been suggested as an indicator of time-averaged glucose control in nonpregnant diabetic patients. Using affinity chromatography, we have measured the levels of glycosylated serum proteins during pregnancy in 14 normal volunteers and 15 insulin-dependent diabetic patients. No relationship was noted between the percentage of glycosylated serum proteins in serum from normal patients and the gestational age at the time of sampling in the second and third trimesters of pregnancy. When the relative frequency distribution of glycosylated serum protein levels in normal patients was compared with that in diabetic patients, a significant difference was noted between the two groups, with a higher percentage of glycosylated serum protein levels in diabetic patients being at elevated values compared to those in normal patients. Normal patients had measured glycosylated serum protein levels of 12.5% +/- 2.2% whereas diabetic patients had glycosylated serum protein levels of 14.0% +/- 3.6%. When peak fasting serum glucose and high Chemstrip glucose levels were compared with glycosylated serum proteins in the diabetic population, a significant correlation for each was noted. The best correlation resulted from a comparison of an average Chemstrip glucose level (mean of 49 glucose values during the previous week) and the glycosylated serum protein value obtained at the end of that week. This inexpensive assay can be adapted to any clinical laboratory and should provide an objective means to evaluate short-term glycemic control, complementing the evaluation provided by self-glucose monitoring (immediate control) and intermittent assay of glycosylated hemoglobin (long-term control).