Sympathetic alpha(2)-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload.
OBJECTIVE
alpha(2)-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of alpha(2)-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of alpha(2A)-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress.


RESULTS
Transgenic mice expressing alpha(2A)-adrenoceptors under control of the dopamine beta-hydroxylase (Dbh) promoter were generated and crossed with mice carrying a constitutive deletion in the alpha(2A)- and alpha(2C)-adrenoceptor genes. alpha(2AC)-deficient mice showed increased norepinephrine plasma levels, cardiac hypertrophy, and fibrosis at baseline. Expression of the Dbh-alpha(2A) transgene in sympathetic neurons prevented these effects. In contrast, Dbh-alpha(2A) receptors mediated only a minor part of the bradycardic and hypotensive effects of the alpha(2)-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, the Dbh-alpha(2A) transgene did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy, or fibrosis. In isolated wild-type atria, alpha(2)-agonist-induced inhibition of [3H]norepinephrine release was significantly desensitized after pressure overload. In primary sympathetic neurons from Dbh-alpha(2A) transgenic mice, norepinephrine and medetomidine induced endocytosis of alpha(2A)-adrenoceptors into neurite processes.


CONCLUSIONS
alpha(2A)-Adrenoceptors expressed in adrenergic cells are essential feedback inhibitors of sympathetic norepinephrine release to prevent cardiac hypertrophy and fibrosis at baseline. However, these receptors are desensitized by chronic pressure overload which in turn may contribute to the pathogenesis of this condition.
Gilsbach
Ralf
R
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, Freiburg 79104, Germany.
Schneider
Johanna
J
Lother
Achim
A
Schickinger
Stefanie
S
Leemhuis
Jost
J
Hein
Lutz
L
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D025461:Feedback, Physiological; D005355:Fibrosis; D020869:Gene Expression Profiling; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020926:Medetomidine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism* / Q000503:physiopathology
C547768:ADRA2A protein, human; C547774:ADRA2C protein, human; C547769:Adra2a protein, mouse; C547775:Adra2c protein, mouse; D000316:Adrenergic alpha-Agonists; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D004299:Dopamine beta-Hydroxylase; D020926:Medetomidine; D009638:Norepinephrine