Sepsis is associated with an upregulation of functional beta3 adrenoceptors in the myocardium.
OBJECTIVE
To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression.


RESULTS
beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P<0.05) in hearts from septic patients. The effect of BRL37344, a beta3-AR-preferential agonist, was analyzed by videomicroscopy on the contractility of neonatal mouse ventricular myocytes (NMVM) incubated with conditioned medium from LPS-stimulated cultured macrophages (Mc-LPS+ medium). Stimulation of untreated NMVM with BRL37344 dose-dependently decreased the amplitude of contractile shortening (P<0.05). This response was abolished by L-NAME (NOS inhibitor). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 (P<0.05) as well as of SR58611A (P<0.05) in wild-type myocytes. Importantly, the contractile depression was abrogated in cardiomyocytes from beta3-AR KO mice.


CONCLUSIONS
beta3-AR are upregulated during sepsis in the human myocardium and by cytokines in murine cardiomyocytes, where they mediate an increased negative inotropic response to beta3 agonists. Activation of the beta3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.
Moniotte
S
S
Unit of Pharmacology and Therapeutics, FATH 5349, Université Catholique de Louvain, Brussels, Belgium.
Belge
C
C
Sekkali
B
B
Massion
P B
PB
Rozec
B
B
Dessy
C
C
Balligand
J-L
JL
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013237:Stereoisomerism; D015854:Up-Regulation
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D017077:Culture Media, Conditioned; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; C057368:BRL 37344; D012313:RNA