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Regulation of ventricular atrial natriuretic peptide release in hypertrophied rat myocardium: effect of phorbol ester
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References Sugrue, M.F. and Viader, M.-P., 1986, Eur. J. Pharmacol. 130, 349. Wilson, W.S., 1988, Br. J. Pharmacol., 94, 346P.
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Regulation of ventricular atrial natriuretic peptide release in hypertrophied rat myocardium: effect of phorbo| ester K i n n u n e n , P.H., Taskinen *, T., Lepp~iluoto *, P.J. and Heikki J. Ruskoaho, Departmem~ of Pharmacology and Toxicology and * Physiology, University of Oulu, Kajaanintie 52 D, SF-90220 Oulu, Finland
Ventricul~r hypertrophy is characterized by augmentation of ventricular synthesis and storage of atrial natriuretic peptide (ANP) Our earlier experiments in vitro using an isolated rat heart preparation indicated that the ventricular source contributes significantly to the circulating level of ANP and the amount released depends on the degree of ventricular hypertrophy (Kinnunen et al., in press) We also reported that in vivo exercise caused release of ANP from the hypertrophied left ventricle (Ruskoaho et al., 1989) Whether ventricular ANP is secreted by constituve or regulatory pathways is, however, not yet clear. Bloch et al. (1986) reported that vent,-icular cells in culture release ANP constitutively and lack secretory granules characteristic of atrial cardiocytes, which store the peptide before secretion. Of note, in cardiac hypertrophy, ANP granules are found within right and left ventricles. Stimulation may thus lead to the formation of secretory granules and to hypersecretion by the alternative pathway like in atria. The aim of this study was to evaluate the cellular mechanisms and relative contribution of atria and ventricles in the release of ANP into the circulation. Atrial and ventricular levels of immunoreactive ANP (IR-ANP) as well as ANP mRNA, and release of ANP from ventricles in the Langendorff preparation in response to a phorbol ester were studied in the 2- and 2i-months old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. A highly significant correlation between ventricular hypertrophy and IR-ANP and ANP mRNA levels was found. The hypertrophic ventricular tissue after atrialectomy secreted more ANP into the perfusate than did the control hearts. The phorbol ester, TPA (0.5 x 107 M), known to activate protein kinase C, caused a marked vasoconstriction in all the groups studied. However, the ANP release increased significantly only from the hypertrophic ventricles of the old SHR rats (from 413 + 30 to tee maximum of 623 + 75 pg/ml, p < 0.05) whereas there was only a minor increase in old WKY rats and no effect at all in the young WKY and SHR rats. In contrast, when intact rat hearts were used, phorbol ester at the same concentration increased the ANP secretion into the perfusate also in young animals. These studi,.s show that the amount of ventriculal ANP release correlates with the degree of hypertrophy of the ventricle and that the secretion of ANP from the hypertrophic ventricular cells probably occurs both by constitutive and regulatory pathways. Further, our results support the consept that the calcium-activated protein kinase C appears to play an important role in the regulation of ANP release. References Kinnunen P., Taskinen T., Lepp~iluoto J.,Ruskoaho H., Br. J. Pharmacol., in press. Ruskoaho H., Kinnunen P., Taskinen T., Vuolteenaho 0., Lepp~iluoto J., Takala T.E.S., 1989, Circulation, 80, 390. Bloch K.D., Seidman J.G., Naftilan J.D., Fallon J.T., 1986, Ceil, 49, 695.
References Sugrue, M.F. and Viader, M.-P., 1986, Eur. J. Pharmacol. 130, 349. Wilson, W.S., 1988, Br. J. Pharmacol., 94, 346P.
I P.fr.ll0 [
Regulation of ventricular atrial natriuretic peptide release in hypertrophied rat myocardium: effect of phorbo| ester K i n n u n e n , P.H., Taskinen *, T., Lepp~iluoto *, P.J. and Heikki J. Ruskoaho, Departmem~ of Pharmacology and Toxicology and * Physiology, University of Oulu, Kajaanintie 52 D, SF-90220 Oulu, Finland
Ventricul~r hypertrophy is characterized by augmentation of ventricular synthesis and storage of atrial natriuretic peptide (ANP) Our earlier experiments in vitro using an isolated rat heart preparation indicated that the ventricular source contributes significantly to the circulating level of ANP and the amount released depends on the degree of ventricular hypertrophy (Kinnunen et al., in press) We also reported that in vivo exercise caused release of ANP from the hypertrophied left ventricle (Ruskoaho et al., 1989) Whether ventricular ANP is secreted by constituve or regulatory pathways is, however, not yet clear. Bloch et al. (1986) reported that vent,-icular cells in culture release ANP constitutively and lack secretory granules characteristic of atrial cardiocytes, which store the peptide before secretion. Of note, in cardiac hypertrophy, ANP granules are found within right and left ventricles. Stimulation may thus lead to the formation of secretory granules and to hypersecretion by the alternative pathway like in atria. The aim of this study was to evaluate the cellular mechanisms and relative contribution of atria and ventricles in the release of ANP into the circulation. Atrial and ventricular levels of immunoreactive ANP (IR-ANP) as well as ANP mRNA, and release of ANP from ventricles in the Langendorff preparation in response to a phorbol ester were studied in the 2- and 2i-months old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. A highly significant correlation between ventricular hypertrophy and IR-ANP and ANP mRNA levels was found. The hypertrophic ventricular tissue after atrialectomy secreted more ANP into the perfusate than did the control hearts. The phorbol ester, TPA (0.5 x 107 M), known to activate protein kinase C, caused a marked vasoconstriction in all the groups studied. However, the ANP release increased significantly only from the hypertrophic ventricles of the old SHR rats (from 413 + 30 to tee maximum of 623 + 75 pg/ml, p < 0.05) whereas there was only a minor increase in old WKY rats and no effect at all in the young WKY and SHR rats. In contrast, when intact rat hearts were used, phorbol ester at the same concentration increased the ANP secretion into the perfusate also in young animals. These studi,.s show that the amount of ventriculal ANP release correlates with the degree of hypertrophy of the ventricle and that the secretion of ANP from the hypertrophic ventricular cells probably occurs both by constitutive and regulatory pathways. Further, our results support the consept that the calcium-activated protein kinase C appears to play an important role in the regulation of ANP release. References Kinnunen P., Taskinen T., Lepp~iluoto J.,Ruskoaho H., Br. J. Pharmacol., in press. Ruskoaho H., Kinnunen P., Taskinen T., Vuolteenaho 0., Lepp~iluoto J., Takala T.E.S., 1989, Circulation, 80, 390. Bloch K.D., Seidman J.G., Naftilan J.D., Fallon J.T., 1986, Ceil, 49, 695.