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. 1998 Feb 15;101(4):812–818. doi: 10.1172/JCI119883

Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts.

A Calderone 1, C M Thaik 1, N Takahashi 1, D L Chang 1, W S Colucci 1
PMCID: PMC508629  PMID: 9466976

Abstract

This study tested the hypothesis that nitric oxide (NO) and atrial natriuretic peptide (ANP) can attenuate the effects of adrenergic agonists on the growth of cardiac myocytes and fibroblasts. In ventricular cells cultured from neonatal rat heart, ANP and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) caused concentration-dependent decreases in the norepinephrine (NE)-stimulated incorporation of [3H]leucine in myocytes and [3H]thymidine in fibroblasts. In myocytes, the NO synthase inhibitor NG-monomethyl-L-arginine potentiated NE-stimulated [3H]leucine incorporation. In both cell types, ANP and SNAP increased intracellular cGMP levels, and their growth-suppressing effects were mimicked by the cGMP analogue 8-bromo-cGMP. Furthermore, in myocytes, 8-bromo-cGMP attenuated the alpha1-adrenergic receptor-stimulated increases in c-fos. Likewise, ANP and 8-bromo-cGMP attenuated the alpha1-adrenergic receptor- stimulated increase in prepro-ANP mRNA and the alpha1-adrenergic receptor-stimulated decrease in sarcoplasmic reticulum calcium ATPase mRNA. The L-type Ca2+ channel blockers verapamil and nifedipine inhibited NE-stimulated incorporation of [3H]leucine in myocytes and [3H]thymidine in fibroblasts, and these effects were not additive with those of ANP, SNAP, or 8-bromo-cGMP. In myocytes, the Ca2+ channel agonist BAY K8644 caused an increase in [3H]leucine incorporation which was inhibited by ANP. These findings indicate that NO and ANP can attenuate the effects of NE on the growth of cardiac myocytes and fibroblasts, most likely by a cGMP-mediated inhibition of NE-stimulated Ca2+ influx.

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Selected References

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  1. Balligand J. L., Kelly R. A., Marsden P. A., Smith T. W., Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):347–351. doi: 10.1073/pnas.90.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bhambi B., Eghbali M. Effect of norepinephrine on myocardial collagen gene expression and response of cardiac fibroblasts after norepinephrine treatment. Am J Pathol. 1991 Nov;139(5):1131–1142. [PMC free article] [PubMed] [Google Scholar]
  3. Bishopric N. H., Kedes L. Adrenergic regulation of the skeletal alpha-actin gene promoter during myocardial cell hypertrophy. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2132–2136. doi: 10.1073/pnas.88.6.2132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Booz G. W., Dostal D. E., Singer H. A., Baker K. M. Involvement of protein kianse C and Ca2+ in angiotensin II-induced mitogenesis of cardiac fibroblasts. Am J Physiol. 1994 Nov;267(5 Pt 1):C1308–C1318. doi: 10.1152/ajpcell.1994.267.5.C1308. [DOI] [PubMed] [Google Scholar]
  5. Brady A. J., Warren J. B., Poole-Wilson P. A., Williams T. J., Harding S. E. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol. 1993 Jul;265(1 Pt 2):H176–H182. doi: 10.1152/ajpheart.1993.265.1.H176. [DOI] [PubMed] [Google Scholar]
  6. Cahill P. A., Hassid A. Clearance receptor-binding atrial natriuretic peptides inhibit mitogenesis and proliferation of rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1606–1613. doi: 10.1016/0006-291x(91)91758-5. [DOI] [PubMed] [Google Scholar]
  7. Calderone A., Takahashi N., Izzo N. J., Jr, Thaik C. M., Colucci W. S. Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circulation. 1995 Nov 1;92(9):2385–2390. doi: 10.1161/01.cir.92.9.2385. [DOI] [PubMed] [Google Scholar]
  8. Cao L., Gardner D. G. Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. Hypertension. 1995 Feb;25(2):227–234. doi: 10.1161/01.hyp.25.2.227. [DOI] [PubMed] [Google Scholar]
  9. Evans H. G., Shah A. M., Lewis M. J. Cyclic GMP inhibits the inotropic response to alpha 1-adrenoceptors in the papillary muscle of the ferret. Cardioscience. 1992 Dec;3(4):257–264. [PubMed] [Google Scholar]
  10. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Harding P., Carretero O. A., LaPointe M. C. Effects of interleukin-1 beta and nitric oxide on cardiac myocytes. Hypertension. 1995 Mar;25(3):421–430. doi: 10.1161/01.hyp.25.3.421. [DOI] [PubMed] [Google Scholar]
  12. Haywood G. A., Tsao P. S., von der Leyen H. E., Mann M. J., Keeling P. J., Trindade P. T., Lewis N. P., Byrne C. D., Rickenbacher P. R., Bishopric N. H. Expression of inducible nitric oxide synthase in human heart failure. Circulation. 1996 Mar 15;93(6):1087–1094. doi: 10.1161/01.cir.93.6.1087. [DOI] [PubMed] [Google Scholar]
  13. Iizuka K., Sano H., Kawaguchi H., Kitabatake A. Transforming growth factor beta-1 modulates the number of beta-adrenergic receptors in cardiac fibroblasts. J Mol Cell Cardiol. 1994 Apr;26(4):435–440. doi: 10.1006/jmcc.1994.1054. [DOI] [PubMed] [Google Scholar]
  14. Izzo N. J., Jr, Seidman C. E., Collins S., Colucci W. S. Alpha 1-adrenergic receptor mRNA level is regulated by norepinephrine in rabbit aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6268–6271. doi: 10.1073/pnas.87.16.6268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Knowlton K. U., Michel M. C., Itani M., Shubeita H. E., Ishihara K., Brown J. H., Chien K. R. The alpha 1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J Biol Chem. 1993 Jul 25;268(21):15374–15380. [PubMed] [Google Scholar]
  16. Knowlton K. U., Rockman H. A., Itani M., Vovan A., Seidman C. E., Chien K. R. Divergent pathways mediate the induction of ANF transgenes in neonatal and hypertrophic ventricular myocardium. J Clin Invest. 1995 Sep;96(3):1311–1318. doi: 10.1172/JCI118166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kohno M., Ikeda M., Johchi M., Horio T., Yasunari K., Kurihara N., Takeda T. Interaction of PDGF and natriuretic peptides on mesangial cell proliferation and endothelin secretion. Am J Physiol. 1993 Nov;265(5 Pt 1):E673–E679. doi: 10.1152/ajpendo.1993.265.5.E673. [DOI] [PubMed] [Google Scholar]
  18. Kolpakov V., Gordon D., Kulik T. J. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res. 1995 Feb;76(2):305–309. doi: 10.1161/01.res.76.2.305. [DOI] [PubMed] [Google Scholar]
  19. Levin E. R., Frank H. J. Natriuretic peptides inhibit rat astroglial proliferation: mediation by C receptor. Am J Physiol. 1991 Aug;261(2 Pt 2):R453–R457. doi: 10.1152/ajpregu.1991.261.2.R453. [DOI] [PubMed] [Google Scholar]
  20. Lin X., Hänze J., Heese F., Sodmann R., Lang R. E. Gene expression of natriuretic peptide receptors in myocardial cells. Circ Res. 1995 Oct;77(4):750–758. doi: 10.1161/01.res.77.4.750. [DOI] [PubMed] [Google Scholar]
  21. Liu Q. Y., Karpinski E., Pang P. K. The L-type calcium channel current is increased by alpha-1 adrenoceptor activation in neonatal rat ventricular cells. J Pharmacol Exp Ther. 1994 Nov;271(2):935–943. [PubMed] [Google Scholar]
  22. Long C. S., Hartogensis W. E., Simpson P. C. Beta-adrenergic stimulation of cardiac non-myocytes augments the growth-promoting activity of non-myocyte conditioned medium. J Mol Cell Cardiol. 1993 Aug;25(8):915–925. doi: 10.1006/jmcc.1993.1104. [DOI] [PubMed] [Google Scholar]
  23. Matsuoka H., Nakata M., Kohno K., Koga Y., Nomura G., Toshima H., Imaizumi T. Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats. Hypertension. 1996 Jan;27(1):14–18. doi: 10.1161/01.hyp.27.1.14. [DOI] [PubMed] [Google Scholar]
  24. McCall D., Fried T. A. Effect of atriopeptin II on Ca influx, contractile behavior and cyclic nucleotide content of cultured neonatal rat myocardial cells. J Mol Cell Cardiol. 1990 Feb;22(2):201–212. doi: 10.1016/0022-2828(90)91116-o. [DOI] [PubMed] [Google Scholar]
  25. Morishita R., Gibbons G. H., Pratt R. E., Tomita N., Kaneda Y., Ogihara T., Dzau V. J. Autocrine and paracrine effects of atrial natriuretic peptide gene transfer on vascular smooth muscle and endothelial cellular growth. J Clin Invest. 1994 Aug;94(2):824–829. doi: 10.1172/JCI117402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Méry P. F., Lohmann S. M., Walter U., Fischmeister R. Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1197–1201. doi: 10.1073/pnas.88.4.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nunez D. J., Dickson M. C., Brown M. J. Natriuretic peptide receptor mRNAs in the rat and human heart. J Clin Invest. 1992 Nov;90(5):1966–1971. doi: 10.1172/JCI116075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Qi M., Ojamaa K., Eleftheriades E. G., Klein I., Samarel A. M. Regulation of rat ventricular myosin heavy chain expression by serum and contractile activity. Am J Physiol. 1994 Aug;267(2 Pt 1):C520–C528. doi: 10.1152/ajpcell.1994.267.2.C520. [DOI] [PubMed] [Google Scholar]
  29. Sadoshima J., Izumo S. Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993 Sep;73(3):413–423. doi: 10.1161/01.res.73.3.413. [DOI] [PubMed] [Google Scholar]
  30. Schorb W., Booz G. W., Dostal D. E., Conrad K. M., Chang K. C., Baker K. M. Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res. 1993 Jun;72(6):1245–1254. doi: 10.1161/01.res.72.6.1245. [DOI] [PubMed] [Google Scholar]
  31. Schulz R., Nava E., Moncada S. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992 Mar;105(3):575–580. doi: 10.1111/j.1476-5381.1992.tb09021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sei C. A., Irons C. E., Sprenkle A. B., McDonough P. M., Brown J. H., Glembotski C. C. The alpha-adrenergic stimulation of atrial natriuretic factor expression in cardiac myocytes requires calcium influx, protein kinase C, and calmodulin-regulated pathways. J Biol Chem. 1991 Aug 25;266(24):15910–15916. [PubMed] [Google Scholar]
  33. Simpson P. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha 1 adrenergic response. J Clin Invest. 1983 Aug;72(2):732–738. doi: 10.1172/JCI111023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stewart A. F., Rokosh D. G., Bailey B. A., Karns L. R., Chang K. C., Long C. S., Kariya K., Simpson P. C. Cloning of the rat alpha 1C-adrenergic receptor from cardiac myocytes. alpha 1C, alpha 1B, and alpha 1D mRNAs are present in cardiac myocytes but not in cardiac fibroblasts. Circ Res. 1994 Oct;75(4):796–802. doi: 10.1161/01.res.75.4.796. [DOI] [PubMed] [Google Scholar]
  35. Takahashi N., Calderone A., Izzo N. J., Jr, Mäki T. M., Marsh J. D., Colucci W. S. Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes. J Clin Invest. 1994 Oct;94(4):1470–1476. doi: 10.1172/JCI117485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Thaik C. M., Calderone A., Takahashi N., Colucci W. S. Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest. 1995 Aug;96(2):1093–1099. doi: 10.1172/JCI118095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tohse N., Nakaya H., Takeda Y., Kanno M. Cyclic GMP-mediated inhibition of L-type Ca2+ channel activity by human natriuretic peptide in rabbit heart cells. Br J Pharmacol. 1995 Mar;114(5):1076–1082. doi: 10.1111/j.1476-5381.1995.tb13316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wahler G. M., Dollinger S. J. Nitric oxide donor SIN-1 inhibits mammalian cardiac calcium current through cGMP-dependent protein kinase. Am J Physiol. 1995 Jan;268(1 Pt 1):C45–C54. doi: 10.1152/ajpcell.1995.268.1.C45. [DOI] [PubMed] [Google Scholar]
  39. Wu C. F., Bishopric N. H., Pratt R. E. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem. 1997 Jun 6;272(23):14860–14866. doi: 10.1074/jbc.272.23.14860. [DOI] [PubMed] [Google Scholar]
  40. Yu S. M., Hung L. M., Lin C. C. cGMP-elevating agents suppress proliferation of vascular smooth muscle cells by inhibiting the activation of epidermal growth factor signaling pathway. Circulation. 1997 Mar 4;95(5):1269–1277. doi: 10.1161/01.cir.95.5.1269. [DOI] [PubMed] [Google Scholar]
  41. Zheng J. S., Boluyt M. O., Long X., O'Neill L., Lakatta E. G., Crow M. T. Extracellular ATP inhibits adrenergic agonist-induced hypertrophy of neonatal cardiac myocytes. Circ Res. 1996 Apr;78(4):525–535. doi: 10.1161/01.res.78.4.525. [DOI] [PubMed] [Google Scholar]

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