MECHANISMS OF MECHANICAL LOAD-INDUCED ATRIAL-NATRIURETIC-PEPTIDE SECRETION - ROLE OF ENDOTHELIN, NITRIC-OXIDE, AND ANGIOTENSIN-II

There are three members in the natriuretic peptide hormone family, atr ial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, brain natriuretic peptide), and C-type natriuretic peptide (CNP), that are i nvolved in the regulation of blood pressure and fluid homeostasis, CNP is found principally in the central nervous system and vascular endot helial cells while ANP and BNP are cardiac hormones. ANP is synthesize d mainly in the atria of the normal adult heart, while BNP is produced by both the atria and ventricles. The mechanisms controlling ANP rele ase have been the subject of intense research, and are now fairly well understood. The major determinant of ANP secretion is myocyte stretch . Although much less is known about the factors regulating BNP release from the heart, myocyte stretch has also been reported to stimulate B NP release from both atria and ventricles, However, whether wall stret ch acts directly or via factors such as endothelin-1, nitric oxide, or angiotensin II liberated in response to distension has not been estab lished. Recent studies show that by stimulating endothelin type A rece ptors endothelin Flays an important physiological role as a mediator o f acute-volume load-induced ANP secretion from atrial myocytes in cons cious animals, In fact, endogenous paracrine/autocrine factors liberat ed in response to atrial wall stretch rather than direct stretch appea rs to be responsible for activation of ANP secretion in response to vo lume lend, as evidenced by almost complete blockade of ANP secretion d uring combined inhibition of endothelin type A/B and angiotensin II re ceptors. Furthermore, under certain experimental conditions angiotensi n II, and nitric oxide may also exert a significant modulatory effect on stretch-activated ANP secretion. The molecular mechanisms by which endothelin-1, angiotensin II and nitric oxide synergistically regulate stretch-activated ANP release are vet unclear.