Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: absence of AT1 receptor downregulation and 'overdrive' of the endothelin system.
OBJECTIVE
Although isolated diastolic heart failure with preserved left ventricular (LV) systolic function frequently occurs, regulation of local neurohumoral factors in the transition from diastolic dysfunction without signs of heart failure to diastolic failure, a target for therapeutic strategy, remains to be clarified, partly because of a lack of animal models. Our laboratory recently demonstrated that Dahl-Iwai salt-sensitive (Dahl-S) rats fed on a high-salt diet since 7 weeks of age develop hypertension followed by compensated LV hypertrophy at 13 weeks and transition to isolated diastolic heart failure at 19 weeks.


METHODS
Gene expression of the components of the renin-angiotensin system, endothelin (ET) system and natriuretic peptide system in the left ventricle was investigated in the transition to isolated diastolic heart failure in this model.


RESULTS
The compensated ventricular hypertrophy was associated with slight increases in angiotensin-converting enzyme (ACE) and angiotensin II type-1a (AT1a) receptor mRNA levels. Although preproET-1 (ppET-1) and ET-converting enzyme-1 (ECE-1) mRNA levels were not increased, mRNA levels of ET type-A (ETA) and ET type-B (ETB) receptors were increased. Atrial natriuretic peptide (ANP) mRNA level increased, but not brain natriuretic peptide (BNP) mRNA level. At the decompensated failing stage (at 19 weeks), ACE mRNA level further increased without downregulation of ATla receptor mRNA level. The mRNA levels of ppET-1 and ECE-1 increased with persistent upregulation of mRNA levels of ETA and ETB receptors, and immunohistochemical staining for ET-1 was found at endothelial cells and myocytes. BNP mRNA level increased with a further increase in ANP mRNA level.


CONCLUSIONS
The transition to isolated diastolic heart failure in hypertrophied hearts was associated with preserved gene expression of the renin-angiotensin system and 'overdrive' of gene expression of the ET system. BNP gene expression is likely to be activated by the progression of diastolic failure rather than by LV hypertrophy alone.
Osaka University, Graduate School of Medicine, Department of Internal Medicine and Therapeutics, Suita, Japan.
K
K
Yamamoto
T
T
Masuyama
Y
Y
Sakata
R
R
Doi
K
K
Ono
T
T
Mano
H
H
Kondo
T
T
Kuzuya
T
T
Miwa
M
M
Hori
D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D009320:Atrial Natriuretic Factor / Q000235:genetics; D003971:Diastole; D004452:Echocardiography; D019332:Endothelin-1 / Q000032:analysis / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011945:Receptors, Angiotensin / Q000235:genetics; D017466:Receptors, Endothelin / Q000235:genetics; D012084:Renin-Angiotensin System
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes