Endothelin Stimulates Basal and Stretch-Induced Atrial Natriuretic Peptide Secretion from the Perfused Rat Heart*

To examine the role of intracellular signals in the regulation of atrial natriuretic peptide (ANP) release, the effects of endothelin (ET), a putative endogenous agonist for voltage-dependent Ca2+ channels on basal and atrial stretch-stimulated ANP release as well as on hemodynamic parameters (perfusion pressure, heart rate, contractile force) in isolated perfused rat hearts were studied. Infusion of ET (0.9 x 10(-9)-2.3 x 10(-9) M) alone for 30 min caused a dose-dependent sustained increase in the perfusate immunoreactive ANP (IR-ANP) concentration and coronary vasoconstriction. An initial inotropic response with a later decrease in the contractile force in response to ET was observed, while heart rate remained unchanged. A phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to stimulate protein kinase-C activity, at a dose of 4.6 x 10(-8) M caused a gradual, slowly progressive increase in perfusate IR-ANP levels and a more rapid increase in perfusion pressure. ET, when infused in combination with TPA, enhanced IR-ANP secretion induced by the phorbol ester. When hearts from spontaneously hypertensive rats (SHR) were examined, the vasoconstrictor response to infusion of ET was greater than that in the normotensive Wistar-Kyoto (WKY) rats. Infusion of eguipressor doses of ET increased the release of IR-ANP in WKY rats, but had no effect on perfusate IR-ANP levels in SHR. To examine effects of ET on stretch-stimulated ANP release, the modified perfused rat heart preparation that enabled the stepwise distension of the right atrium was used. The increase in right atrial pressure (2.65 +/- 0.13 mm Hg) was accompanied by an increase in the perfusate IR-ANP concentration (from 8.3 +/- 1.1 to 13.9 +/- 2.0 ng/5 min; P less than 0.05; n = 15). The increase in right atrial pressure during the ET infusions resulted in a significantly greater increase in the perfusate IR-ANP concentration than vehicle alone. The calculated ANP increase corresponding to the 2-mm Hg increase in the right atrial pressure was 1.52-fold in the control group and 1.74-fold when 1.9 x 10(-9) M ET was infused (P less than 0.05). This study shows that ET stimulates both basal and atrial stretch-stimulated ANP secretion from the isolated perfused heart and suggests that ET is involved in the regulation of stretch-induced ANP release. The results further confirm the potent vasoconstrictor and cardiac effects of ET.