Atrial natriuretic peptides in Han Wistar, Sprague–Dawley and spontaneously Hypertensive rats

Abstract

The atrial natriuretic peptide (ANP) and its precursor (N-terminal fragment of atrial natriuretic peptide, NT-proANP) are natriuretic peptides released into the circulation as a consequence of an acute atrial stretch. As for the brain natriuretic peptide and its N-terminal fragment, the biological significance of ANP and NT-proANP has been widely studied in humans, but the literature is lacking information about the determination of these biomarkers in veterinary medicine and, in particular, in the toxicological species used in preclinical pharmaceutical drug development. This paper describes the evaluation of ANP and NT-proANP levels in a healthy population of Han Wistar and Sprague-Dawley rats, as well as in a rodent model of hypertension (Spontaneously Hypertensive rats). Both biomarkers were measured by mean of two commercially available enzyme immunoassays and serum levels were correlated with heart weight and histopathological findings in the heart, with the aim of building an integrated assessment of the significance of these biomarkers. Results obtained demonstrated that NT-proANP and ANP can be accurately measured in the different rat strains, with NT-proANP concentrations higher than those of ANP, as expected because of its longer half-life. In addition, both correlated well with cardiac hypertrophy evaluated by means of heart weight and histopathological examination. NT-proANP and ANP represent reliable markers of cardiac hypertrophy in the rat.

Scientific and Regulatory Policy Committee Points to Consider: Integration of Clinical Pathology Data With Anatomic Pathology Data in Nonclinical Toxicology Studies

“…Heart weight increases and changes in in-life parameters (for example, blood pressure and heart rate increases) may be more consistent than histopathologic changes. [85][86][87][88] Associated histopathologic changes in the myocardium might be due to an enlarged ventricular wall crosssection 85 or there may be no histopathologic change. 86 In summary, responses of the cardiovascular system to injury include changes in function and structure.…”

Scientific and Regulatory Policy Committee Points to Consider: Integration of Clinical Pathology Data With Anatomic Pathology Data in Nonclinical Toxicology Studies

“…Heart weight increases and changes in in-life parameters (eg, blood pressure and heart rate increases) may be more consistent than histopathologic changes. [85][86][87][88] Associated histopathologic changes in the myocardium might be due to an enlarged ventricular wall cross section 85 or there may be no histopathologic change. 86 In summary, responses of the cardiovascular system to injury include changes in function and structure.…”

“…As the natriuretic peptides are circulating markers for hemodynamic changes, they may be accompanied by a wide spectrum of associated findings. Heart weight increases and changes in in‐life parameters (eg, blood pressure and heart rate increases) may be more consistent than histopathologic changes 85–88 . Associated histopathologic changes in the myocardium might be due to an enlarged ventricular wall cross section 85 or there may be no histopathologic change 86 …”

Characterization of an Animal Model to Study Risk Factors and New Therapies for the Cardiorenal Syndrome, a Major Health Issue in Our Aging Population

“…The obvious hypertrophy of the heart together with the significant rise in NT-proANP, is indicative of a failing heart function in our animal model. Atrial natriuretic peptide is synthesized by cardiomyocytes in response to increased wall stress [8] and therefore is considered a valid marker for the assessment of heart failure and particularly of left ventricle hypertrophy/systolic dysfunction in humans [9,10] and in rats [11]. Because the active peptide is rapidly degraded upon secretion, the concentrations of the NT-proANP better reflect the total amount of secreted atrial natriuretic peptide, both in humans and rats [12,13].…”