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G_s and G_i coupling of adrenomedullin in adult rat ventricular myocytes

Department of Physiology, Institute of Cardiovascular Sciences and Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region of China

Submitted 20 April 2005 ; accepted in final form 17 November 2005

Adrenomedullin (ADM) acts as an autocrine or a paracrine factor in the regulation of cardiac function. The intracellular mechanisms involved in the direct effect of ADM on adult rat ventricular myocytes (ARVMs) are still to be elucidated. In ARVMs from normal rats, ADM produced an initial (<30 min) increase in cell shortening and Ca²⁺ transients and a marked decrease in both on prolonged incubation (>1 h). Both effects were sensitive to ADM antagonist ADM-(22–52). Treatment with SQ-22536, an inhibitor of adenylate cyclase, blocked the positive inotropic effect of ADM and potentiated its negative inotropic effect. The negative inotropic effect was sensitive to inhibition by pertussis toxin (PTX), an inhibitor of G_i proteins and KT-5720, an inhibitor of PKA. The observations suggest a switch from G_s-coupled to PTX-sensitive, PKA-dependent G_i coupling by ADM in ARVMs. The ADM-mediated G_i-signaling system involves cAMP-dependent pathways because SQ-22536 further increased the negative inotropic actions of ADM. Also, because ADM is overproduced by ARVMs in our rat model of septic shock, ARVMs from LPS-treated rats were subjected to treatment with ADM-(22–52) and PTX. The decrease in cell shortening and Ca²⁺ transients in LPS-treated ARVMs could be reversed back with ADM-(22–52) and PTX. This indicates that ADM plays a role in mediating the negative inotropic effect in LPS-treated ARVM through the activation of G_i signaling. This study delineates the intracellular pathways involved in ADM-mediated direct inotropic effects on ARVMs and also suggests a role of ADM in sepsis.

cell shortening; calcium transient; pertussis toxin; adenosine 3'5'-cyclic monophosphate-dependent protein kinase inhibitor; septic shock

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