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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H2888    most recent 00312.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, X.-H. Articles by Bourreau, J.-P. Search for Related Content PubMed PubMed Citation Articles by Zhang, X.-H. Articles by Bourreau, J.-P.

The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway

¹Department of Physiology and Institute of Cardiovascular Sciences and Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China, ²Department of Pharmacy, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

Submitted 13 March 2007 ; accepted in final form 27 August 2007

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I_Ca,L) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 ± 2 ms; control, 257 ± 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 ± 2 ms; control, 305 ± 2 ms, P < 0.05). I_Ca,L density was significantly reduced in myocytes from the LPS group (–3.2 ± 0.8 pA/pF) compared with that of control myocytes (–6.7 ± 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I_Ca,L in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I_Ca,L density. This effect was reversed by ADM-(22-52). The G_i protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I_Ca,L. The results suggest a COX-2-involved PKA-dependent switch from G_s coupled to PTX-sensitive G_i coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I_Ca,L in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.

pertussis toxin; protein kinase A inhibitor

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