Abstract
IntroductionThe 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.Methods10 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.ResultsFemale 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.
Highlights
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
The activity of the enzyme was higher in female than in male SHR, NO synthase (NOS) activity increased significantly in both sexes after ANP treatment but the response of cardiac NOS to ANP treatment was more marked in female SHR (Figure 1C). eNOS protein content was higher in female than in male ventricles, and ANP increased eNOS expression in both sexes (Figure 1D)
Examination of TUNEL-stained left ventricle (LV) sections of control rats revealed no differences between males and females in the number of apoptotic cells, but treatment with ANP decreased the number of apoptotic cells in both male and female SHR (Table 3). This is the first experimental in vivo study that shows that chronic treatment with ANP reduces cardiac oxidative stress, fibrosis, apoptosis and hypertrophy in a model of hypertension, increasing NO-system activity
Summary
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. SHR present endothelial dysfunction, an increase in oxidative stress and vasoconstrictor factors, a decrease in the bioavailability and effectiveness of nitric oxide (NO), and elevated plasma levels of atrial natriuretic peptide (ANP) [2,3]. Essential hypertension often leads to hypertrophic cardiomyopathy [5] In this regard, SHR develops left ventricular hypertrophy, showing an increased cardiac fibrosis, in response to elevated ventricular volume or pressure overload [6]
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