Sex differences in the beneficial cardiac effects of chronic treatment with atrial natriuretic Peptide in spontaneously hypertensive rats.
BACKGROUND
The aim of this study was to investigate both the effects of chronic treatment with atrial natriuretic peptide (ANP) on systolic blood pressure (SBP), cardiac nitric oxide (NO) system, oxidative stress, hypertrophy, fibrosis and apoptosis in spontaneously hypertensive rats (SHR), and sex-related differences in the response to the treatment.


METHODS
10 week-old male and female SHR were infused with ANP (100 ng/hr/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). SBP was recorded and nitrites and nitrates excretion (NOx) were determined. After treatment, NO synthase (NOS) activity, eNOS expression, thiobarbituric acid-reactive substances (TBARS) and glutathione concentration were determined in left ventricle, as well as the activity of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD). Morphological studies in left ventricle were performed in slices stained with hematoxylin-eosin or Sirius red to identify collagen as a fibrosis indicator; immunohistochemistry was employed for identification of transforming growth factor beta; and apoptosis was evaluated by Tunel assay.


RESULTS
Female SHR showed lower SBP, higher NO-system activity and less oxidative stress, fibrosis and hypertrophy in left ventricle, as well as higher cardiac NOS activity, eNOS protein content and NOx excretion than male SHR. Although ANP treatment lowered blood pressure and increased NOS activity and eNOS expression in both sexes, cardiac NOS response to ANP was more marked in females. In left ventricle, ANP reduced TBARS and increased glutathione concentration and activity of CAT and SOD enzymes in both sexes, as well as GPx activity in males. ANP decreased fibrosis and apoptosis in hearts from male and female SHR but females showed less end-organ damage in heart. Chronic ANP treatment would ameliorate hypertension and end-organ damage in heart by reducing oxidative stress, increasing NO-system activity, and diminishing fibrosis and hypertrophy.
Cátedra De Fisiología, Facultad De Farmacia Y Bioquímica, Universidad De Buenos Aires, Instituto De Química Y Metabolismo Del Fármaco, Consejo Nacional De Investigaciones Científicas Y Técnicas, Buenos Aires, Argentina.
Mariana
M
Romero
Carolina
C
Caniffi
Gonzalo
G
Bouchet
Rosana
R
Elesgaray
Myriam Mac
MM
Laughlin
Analía
A
Tomat
Cristina
C
Arranz
Maria A
MA
Costa
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D011918:Rats, Inbred SHR; D012737:Sex Factors; D013482:Superoxide Dismutase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000959:Antihypertensive Agents; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D005978:Glutathione