Vasodilator therapy with hydralazine induces angiotensin AT receptor-mediated cardiomyocyte growth in mice lacking guanylyl cyclase-A.
OBJECTIVE
Recent clinical guidelines advocate the use of the isosorbide dinitrate/hydralazine combination in treatment for heart failure. However, clinical and laboratory evidence suggest that some vasodilators may induce cardiac hypertrophy under uncertain conditions. This study investigated the effects and underlying mechanism of action of the vasodilator hydralazine on cardiac growth.


METHODS
Wild-type mice and animals deficient in guanylyl cyclase-A (GCA) and/or angiotensin receptors (AT(1) and AT(2) subtypes) were treated with hydralazine ( approximately 24 mg.kg(-1).day(-1) in drinking water) for 5 weeks. Cardiac mass and/or cardiomyocyte cross-sectional area, fibrosis (van Giessen-staining) and cardiac gene expression (real-time RT-PCR) were measured.


RESULTS
Hydralazine lowered blood pressure in mice of all genotypes. However, this treatment increased the heart and left ventricular to body weight ratios, as well as cardiomyocyte cross-sectional area, and cardiac expression of atrial natriuretic peptide mRNA in mice lacking GCA. Hydralazine did not affect cardiac hypertrophy in wild-type mice and mice lacking either AT(1) or AT(2) receptors alone. However, the pro-hypertrophic effect of hydralazine was prevented in mice lacking both GCA and AT(2), but not GCA and AT(1) receptors. However, hydralazine did decrease cardiac collagen deposition and collagen I mRNA (signs of cardiac fibrosis) in mice that were deficient in GCA, or both GCA and AT(2) receptors.


CONCLUSIONS
The vasodilator hydralazine induced AT(2) receptor-mediated cardiomyocyte growth under conditions of GCA deficiency. However, attenuation of cardiac fibrosis by hydralazine could be beneficial in the management of cardiac diseases.
Li
Y
Y
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan. yuhao@kuhp.kyoto-u.ac.jp
Saito
Y
Y
Kuwahara
K
K
Rong
X
X
Kishimoto
I
I
Harada
M
M
Horiuchi
M
M
Murray
M
M
Nakao
K
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology; D005355:Fibrosis; D015870:Gene Expression; D006830:Hydralazine / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology*
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014665:Vasodilator Agents; D006830:Hydralazine; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A