Endothelin-1 is involved in stretch-induced early activation of B-type natriuretic peptide gene expression in atrial but not in ventricular myocytes: acute effects of mixed ET(A)/ET(B) and AT1 receptor antagonists in vivo and in vitro.
BACKGROUND
The precise role of paracrine and autocrine factors in mechanical load-induced activation of cardiac gene expression is unknown. Here we report the effects of endothelin-1 (ET-1) and angiotensin II (Ang II) receptor antagonism on acute pressure overload-induced activation of cardiac B-type natriuretic peptide (BNP) gene expression in spontaneously hypertensive rats (SHRs) in vivo and on mechanical stretch-induced increase in atrial BNP gene expression in vitro.


RESULTS
Acute pressure overload produced in conscious SHRs by infusion of arginine8-vasopressin (0.05 microg x kg(-1) x min(-1)) for 2 hours resulted in an increase in BNP mRNA levels in the left ventricle as well as in the atrium. Bolus injections of bosentan (mixed ET(A)/ET(B) receptor antagonist, 10 mg/kg I.V.) but not losartan (AT1 receptor antagonist, 10 mg/kg I.V.) blocked the increase of the BNP mRNA levels produced by pressure overload in the left atria, whereas the elevation of BNP mRNA levels was similar (a 1.9-fold increase) in the left ventricles of vehicle-, losartan-, and bosentan-infused SHRs. In an isolated perfused rat heart preparation, infusion of bosentan (1 micromol/L) for 2 hours inhibited the mechanical stretch-induced increase in BNP mRNA levels in the right atria, whereas an AT1 receptor antagonist, CV-11974 (10 nmol/L), had no effect.


CONCLUSIONS
The findings of the present study demonstrate that Ang II and ET-1 are not obligatorily required for stretch to trigger the increased BNP gene expression in ventricular myocytes in vivo. In contrast, mechanical load on the atrial myocytes did initiate an ET-1-dependent expression of BNP gene showing that endogenous ET-1 production differentially regulates BNP gene expression in atrial and ventricular myocytes.
Magga
J
J
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Vuolteenaho
O
O
Marttila
M
M
Ruskoaho
H
H
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D005786:Gene Expression Regulation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010477:Perfusion; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D013777:Tetrazoles; D020097:Natriuretic Peptide, Brain; D019808:Losartan; D000077300:Bosentan; C081643:candesartan