Sinus node inhibitors reduce the heart rate presumably by blocking the pacemaker current I f in the cardiac conduction system. This pacemaker current is carried by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels. All three substances blocked the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels. There was no subtype-specificity for the steady-state block, with mean IC 50 values of 0.99, 2.25, and 1.96 M for cilobradine, ivabradine, and zatebradine, respectively. Native I f , recorded from mouse sinoatrial node cells, was slightly more efficiently blocked by cilobradine (IC 50 value of 0.62 M) than were the HCN currents. The block of I f in sinoatrial node cells resulted in slower and dysrhythmic spontaneous action potentials. The in vivo action of these blockers was analyzed using telemetric ECG recordings in mice. Each compound reduced the heart rate dose-dependently from 600 to 200 bpm with ED 50 values of 1.2, 4.7, and 1.8 mg/kg for cilobradine, ivabradine, and zatebradine, respectively. ␤-Adrenergic stimulation or forced physical activity only partly reversed this bradycardia. In addition to bradycardia, all three drugs induced increasing arrhythmia at concentrations greater than 5 mg/kg for cilobradine, greater than 10 mg/kg for zatebradine, or greater than 15 mg/kg for ivabradine. This dysrhythmic heart rate is characterized by periodic fluctuations of the duration between the T and P wave, resembling a form of sick sinus syndrome in humans. Hence, all available sinus node inhibitors possess an as-yetunrecognized proarrhythmic potential.

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Conclusions.The findings from recent clinical trials support the use of angiotensin receptor antagonists in patients with nephropathy due to type 2 diabetes, and have shown a significant reduction in the progression towards ESRD (losartan) and proteinuria (losartan, irbesartan), effects that were independent of blood pressure lowering achieved with these agents. Reduction in cardiovascular morbidity and mortality have also been shown in a trial with losartan in diabetics. Collectively, these studies will have worldwide beneficial impact on the treatment of this devastating disease.

i) TS with GH deficiency should be considered as a potential differential diagnosis of hypoglycemia in infants requiring higher doses of GH. ii) While array CGH may be erroneous in quantification of TS mosaicism, it is useful in precisely delineating isochromosomes and identifying genes on them that escape X-inactivation and thus possibly affect the TS phenotype.

1272 Poster Board I-294 About ten percent of infants with Down syndrome (DS) are born with a transient myeloproliferative disorder (DS-TMD), which spontaneously resolves within the first few months of life. However, the basis for this resolution remains unknown. Acquired mutations leading to exclusive production of a short isoform of the transcription factor GATA-1 (GATA-1s) occur in all cases of DS-TMD, and knock-in mice that exclusively produce GATA-1s have hyperproliferation of megakaryocytes during early fetal liver hematopoiesis, but not during later developmental stages. In this study, we found striking upregulation of the interferon-αa (IFN-αa) receptor and multiple IFN-αa responsive genes, including Ifi203, Ifi205, Irf-1, Irf-8, and Ifitm6, in immunophenotypically isolated megakaryocyte progenitor cells (MkPs) from bone marrow versus embryonic day 13.5 (e13.5) fetal liver of wild type mice. These differences were confirmed at the protein level in megakaryocytes by in situ immunohistochemistry. Addition of IFN-αa to GATA-1s containing e13.5 fetal liver MkPs reduces their hyperproliferation in vitro in a dose-dependent manner. Conversely, injection of neutralizing IFN-αa/β antibodies, but not control IgG, into adult GATA-1s mice markedly increases the percentage of bone marrow CD41+ cells and morphologically recognizable megakaryocytes, in contrast to wild type mice. We propose that increases in IFN-αa signaling during megakaryocyte ontogeny may account for the developmental stage-specific effects of GATA-1s on megakaryocyte hyperproliferation, and possibly the spontaneous resolution of DS-TMD. Interestingly, the genes encoding the IFN-αa/β receptor are located on human chromosome 21 and are expressed at 1.6 times that in trisomy versus disomy 21 cells. We speculate that increased interferon alpha signaling during embryogenesis may be the basis for the strong selective pressure for GATA-1s producing mutations in trisomy 21 fetuses in the first place. Disclosures No relevant conflicts of interest to declare.