Chronic treatment with C-type natriuretic peptide impacts differently in the aorta of normotensive and hypertensive rats.

The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 µg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.

Respuesta cardiovascular a la administración crónica de péptido natriurético tipo C en ratas espontáneamente hipertensas / Cardiovascular Response to Chronic Administration of C-type Natriuretic Peptide in Spontaneously Hypertensive Rats

Introducción: El péptido natriurético tipo C (CNP) ha cobrado relevancia por sus efectos sobre la regulación de la función y la morfología del corazón y los vasos sanguíneos. Previamente demostramos in vitro que el CNP incrementa la actividad del sistema del óxido nítrico (NO) en ratas espontáneamente hipertensas (SHR). Objetivo: Estudiar el efecto del tratamiento crónico con CNP sobre la presión arterial sistólica (PAS), la función cardíaca y vascular y el sistema del NO en ratas espontáneamente hipertensas y normotensas. Material y métodos: Se emplearon ratas Wistar macho de 12 semanas de edad normotensas y espontáneamente hipertensas. Los animales recibieron infusión crónica de solución salina o CNP (0,75 mg/hora/rata) durante 14 días mediante la implantación de bombas osmóticas subcutáneas. Se midió la PAS y se realizaron un electrocardiograma y un ecocardiograma. Se extrajeron el ventrículo izquierdo y la arteria aorta torácica y se determinó la actividad, con L-[U14C]-arginina, de la óxido nítrico sintasa (NOS) y se realizaron estudios de reactividad vascular. Resultados: La administración crónica de CNP disminuyó la PAS en las SHR. Se observó menor volumen minuto en las SHR y el CNP incrementó dicho volumen, en tanto que no indujo cambios en las ratas normotensas. En las SHR se observó un desequilibrio en las respuestas vasodilatadora y vasoconstrictora en la arteria aorta y el tratamiento con CNP mejoró la función vascular respecto de las ratas normotensas. En ambos tejidos, la actividad de la NOS fue mayor en las SHR y se incrementó con la infusión durante 14 días de CNP. Sin embargo, dicho incremento fue menor en las SHR. Conclusión: El CNP induce cambios a nivel cardiovascular y en el sistema del NO que podrían resultar beneficiosos en este modelo de hipertensión arterial.

Background: C-type natriuretic peptide (CNP) plays an important role in the regulation of cardiovascular function and morphology. We have previously demonstrated that CNP increases nitric oxide (NO) system activity in vivo in spontaneously hypertensive rats (SHR). Objective: The goal of this study is to evaluate the effect of chronic CNP administration on systolic blood pressure (SBP), cardiovascular function and the NO system in spontaneously hypertensive and normotensive rats. Methods: Twelve-week-old normotensive male Wistar rats and SHR were used. They received chronic infusion of saline or CNP (0.75 mg/h/rat) for 14 days via subcutaneously implanted osmotic pumps. Systolic blood pressure was measured and an electrocardiogram and echocardiogram were performed. The left ventricle and the thoracic aorta were resected; nitric oxide synthase (NOS) activity was determined using L-[U14C]-arginine and vascular reactivity was assessed. Results: Chronic administration of CNP decreased SBP in SHR. Cardiac output was lower in SHR and increased with CNP; however, CNP had no effect in normotensive rats. Spontaneously hypertensive rats had unbalanced aortic vasodilation and vasoconstriction responses, and CNP improved the vascular function. Nitric oxide synthase activity was greater in SHR and increased with the 14-day CNP infusion, but this increase was lower than in normotensive rats. Conclusion: C-type natriuretic peptide induces cardiovascular and NO system changes which may be beneficial in this model of hypertension.

Chronic treatment with atrial natriuretic peptide in spontaneously hypertensive rats: beneficial renal effects and sex differences.

OBJECTIVE: The aim of this study was to investigate the effects of chronic treatment with atrial natriuretic peptide (ANP) on renal function, nitric oxide (NO) system, oxidative stress, collagen content and apoptosis in kidneys of spontaneously hypertensive rats (SHR), as well as sex-related differences in the response to the treatment. METHODS: 10 week-old male and female SHR were infused with ANP (100 ng/h/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). Systolic blood pressure (SBP) was recorded and diuresis and natriuresis were determined. After treatment, renal NO synthase (NOS) activity and eNOS expression were evaluated. Thiobarbituric acid-reactive substances (TBARS), glutathione concentration and glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in the kidney. Collagen was identified in renal slices by Sirius red staining and apoptosis by Tunel assay. RESULTS: Female SHR showed lower SBP, oxidative stress, collagen content and apoptosis in kidney, and higher renal NOS activity and eNOS protein content, than males. ANP lowered SBP, increased diuresis, natriuresis, renal NOS activity and eNOS expression in both sexes. Renal response to ANP was more marked in females than in males. In kidney, ANP reduced TBARS, renal collagen content and apoptosis, and increased glutathione concentration and activity of GPx and SOD enzymes in both sexes. CONCLUSIONS: Female SHR exhibited less organ damage than males. Chronic ANP treatment would ameliorate hypertension and end-organ damage in the kidney by reducing oxidative stress, increasing NO-system activity, and diminishing collagen content and apoptosis, in both sexes.

Sex differences in the beneficial cardiac effects of chronic treatment with atrial natriuretic Peptide in spontaneously hypertensive rats.

INTRODUCTION: 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.