We studied target organ-protective effects of aracepril, an angiotensin-converting enzyme inhibitor, and the expression of endothelin-1 (ET-1) and nitric oxide synthase (NOS) mRNA. Aracepril (30 mg/kg) was administered orally to Izumo strain of stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) for 8 weeks from 4 weeks of age and for 4 weeks from 8 weeks of age. The expression of ET-1 and endothelial NOS (eNOS) mRNA in the heart, aorta, kidneys, and brain cortex, and the expression of neuronal NOS (bNOS) mRNA in brain cortex, were analyzed by RT-PCR/Southern blotting or RNase protection analysis. Administration of aracepril markedly lowered blood pressure and decreased left ventricular weight in SHR-SP/Izm. Expression of ET-1 mRNA in the heart, kidneys, and brain was significantly enhanced in SHR/SP/Izm compared with that in WKY/Izm. Aracepril significantly decreased the expression of ET-1 mRNA, whereas there was no significant change of that in the aorta. Although expression of eNOS mRNA in the heart, aorta, and kidneys did not show any significant difference between the two strains of rats, administration of aracepril for 8 weeks significantly decreased the expression of eNOS and bNOS mRNA in brain tissue. These results suggested that aracepril may protect major target organs by modifying the expression of ET-1 and NOS mRNA, in addition to its hypotensive effect.
Previously we found intragranular colocalization of immunoreactive endothelin-1 and neurohypophysial hormones in the axon terminals of the rat neural lobe. To investigate the function of endothelin-1 in the rat neural lobe, immunoreactive endothelin-1 in plasma and the neural lobe was measured by enzyme immunoassay in rats subjected to hemorrhage and in other rats who were deprived of water for 2 days to induce dehydration. Changes in plasma arginine vasopressin were determined by radioimmunoassay. In addition, morphometric analysis was performed in the neural lobe of rats exposed to these stresses. Plasma concentrations of immunoreactive endothelin-1 were unchanged following hemorrhage or dehydration, whereas those of immunoreactive vasopressin were remarkably increased. In the neural lobe, immunoreactive endothelin-1 content and the number of neurosecretory granules decreased significantly after dehydration. However, immunoreactive endothelin-1 in tissue increased nearly three-fold in hemorrhaged rats, whereas the endothelin-1-immunolabeling in the axon terminals was unchanged. These results suggest that endothelin-1 in the hypothalamo-hypophysial system may be involved in the local modulation of vasopressin secretion when an animal is exposed to hypovolemic and/or osmotic stress.
To elucidate the intracellular localization of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human cardiac myocytes, an immunocytochemical study was carried out by a double immunogold technique using antisera highly specific for ANP and BNP. Surgical and autoptic tissue specimens of human heart were studied. In the atrial myocytes, ANP was localized in almost all of the secretory granules, whereas BNP was colocalized with ANP in some of the granules. Although very few secretory granules were observed in ventricular myocytes, colocalization of ANP and BNP was basically the same as in atrial myocytes. No immunoreactive products were found in the control studies. These results suggest that secretion of BNP is under a regulatory mechanism similar to that of ANP.
BACKGROUND Atrial natriuretic factor (ANF) is produced by myocardial tissue, and the plasma ANF concentration is known to be elevated in congestive heart failure (CHF). Data from animal models indicate that myocardial concentrations of ANF are depleted in CHF, and this has given rise to the hypothesis that CHF is characterized by depletion of stored ANF. To date, the molecular forms of ANF and their concentrations in atrial and ventricular myocardium remain poorly characterized in the normal and the failing human heart. METHODS AND RESULTS We measured ANF concentrations in fresh tissue from failing human hearts explanted at the time of cardiac transplantation and from organ donors whose normal hearts could not be used for transplantation. We determined total ANF and alpha, beta, and gamma ANF concentrations in the right and left atrial appendages, atrial free walls, and ventricles. In normal hearts, ANF concentration in the atrial appendages was 40-fold higher than ANF in the rest of the atrial free wall and in the ventricles. In the failing hearts, atrial appendage ANF concentrations increased 5- to 10-fold, and atrial free wall ANF concentrations increased 200-fold. Analysis of molecular forms of ANF demonstrated significant increases in the gamma and beta forms in the left atrial appendage of failing hearts. alpha, beta, and gamma ANF forms were also significantly increased in right and left atrial free wall tissue from failing hearts. In addition, failing hearts were characterized by absolute and relative increases in the precursor form gamma ANF. CONCLUSIONS These data from fresh tissues suggest that cardiac ANF stores are not decreased in severe CHF in humans; rather, chronic CHF is characterized by marked increases in atrial ANF tissue concentrations, particularly the beta and gamma ANF forms. These findings are consistent with intracellular accumulation of precursor ANF forms in severe chronic human CHF.
The presence and distribution of human atrial natriuretic polypeptide (ANP) were investigated immunohistochemically in the ventricles of hearts of 14 cases with endocardial fibroelastosis and 15 cases with noncardiac disease in children. Paraffin sections of autopsied hearts with endocardial fibroelastosis were stained with polyclonal antibodies against human alpha-ANP. Immunoreactive myocytes were clearly demonstrated in the ventricles of 10 hearts with endocardial fibroelastosis. The distribution of ANP-positive cells was most frequent in the inner one-third of the left ventricle. No ANP immunoreactivity was detected in any heart in cases with noncardiac disease. The left ventricular volume index of hearts with ANP-positive cells was larger than that with ANP-negative cells. The mean diameter of ANP-positive myocytes was greater than that of ANP-negative myocytes. These results suggest that ANP expression in ventricular myocytes is related to severe dilatation of the ventricular cavity and to development of myocardial hypertrophy in endocardial fibroelastosis.
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