Atrial and pulmonary endothelin mRNA is increased in a canine model of chronic low cardiac output

Chronic thoracic inferior vena caval constriction (TIVCC) is a model of low-cardiac output congestive heart failure (CHF), in which pulmonary and atrial as well as circulating endothelin (ET) are increased. ET is a potent vasoconstrictor and mitogenic peptide whose circulating concentrations are increased in severe human and experimental CHF. To date, an increase in ET production at key sites in CHF remains controversial. Therefore, the current study was designed to determine cardiac and pulmonary ET-1 mRNA in an experimental model of CHF produced by TIVCC in which avid sodium retention, intense vasoconstriction, and elevation of circulating ET-1 occur as in human CHF. Experiments were conducted in normal dogs and dogs with 7 days of TIVCC. Cardiac and pulmonary ET-1 mRNA were measured by quantified densitometry of Northern blots. Plasma and tissue (cardiac and pulmonary) ET-1 immunoreactivity were determined by radioimmunoassay. Cardiac and pulmonary tissue localization of ET-1 were determined by immunohistochemical staining. Plasma ET-1 was significantly increased in TIVCC compared with normal dogs. ET-1 mRNA was detectable in normal canine atria, ventricle, and lung. ET-1 mRNA was significantly increased in TIVCC compared with normal dogs in both atrial and pulmonary tissues without alternations in ventricular ET mRNA. Atrial and pulmonary tissue concentrations of ET-1 also were markedly elevated in TIVCC compared with normal dogs. Immunohistochemical staining of atrial and pulmonary tissues for ET-1 demonstrated that the increased ET immunoreactivity was localized to atrial myocytes and pulmonary epithelial cells. These studies support a role for the heart and lung in the increased production of ET-1 in CHF. The current studies also suggest that ET-1 may have important autocrine and paracrine actions in cardiopulmonary regulation in experimental CHF.