Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication,reduced fibrosis and improved impulse propagation in the failing heart

Abstract

Introduction. The influence of chronic administration of losartan on gap junction conductance (gj), conduction velocity and interstitial fibrosis was investigated in the failing heart of 4-month-old cardiomyopathic hamsters (TO-2).After two months of administration of losartan (25 mg/kg/day/po) the number of cell pairs showing very low values of gj (2—8 nS) was significantly reduced whereas the group of cell pairs with larger values of gj (18-45 nS) was significantly increased.The conduction velocity measured with intracellular microelectrodes in the wall of the left ventricle was enhanced from 38+2.3 cm/s (n=25) (control) to 49+2 cm/s (n=24) (p<0.05) after losartan administration. Moreover, the number of ventricular fibres showing non-propagated action potentials was significantly decreased (p<0.05) by losartan.The % area of interstitial fibrosis measured in the wall of the left ventricle was reduced from 22+1.4% (n=18) to 14 1.3% (n=18) (p<0.05) after losartan administration.

Conclusion. Chronic blockade of angiotensin II type 1 receptors increased gj in the failing heart. Moreover,the conduction velocity was enhanced remodelling in part by the increase of gj and in part by the decrease of interstitial fibrosis and structural remodelling.

Keywords

cell communication failing heart chronic angiotensin II AT1 receptor blockade fibrosis impulse conduction

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References

De Mello WC Cardiac arrhythmias; the possible role of the renin angiotensin system . J Mol Med 2001;79:103-08.

De Mello WC Heart failure: how important is cellular sequestration? The role of the renin angiotensin aldosterone system. J Mol Cell Cardiol 2004;37:431-8.

De Mello WC Renin angiotensin system and cell communication in the failing heart . Hypertension 1996; 2:1267-72.

De Mello WC , Cherry R. , Mannivannan S. Electrophysiologicand morphologic abnormalities in the failing heart; effect of enalapril on the electrical properties. J Cardiac Fail 1997;3:53-62.

Powell T. , Twist T. A rapid technique for the isolation and purification of adult cardiac muscle cells having respiratory control and tolerance to calcium. Biochem Biophys Res Commun 1976;72:327-33.

Tanigushi Y. , Kokubun S. , Noma A. , Irisawa. Spontaneously active cells isolated from the sinoatrial and atrioventricular node of the rabbit heart. Jpn J Physiol 1981;31:547-58.

van Rijen HVM , Wilders R. , van Gineken ACC , Jongsma HJ Quantitative analysis of dual whole-cell voltage clamp determination of gap junctional conductance. Pflugers Arch 1998;436:141-51.

Hein L. , Stevens ME , Barsh G. , Pratt RE , Kobilka BK , Dzau VJ Overexpression of angiotensin AT1-receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc Natl Acad Sci USA 1997 ;94:6391-6.

De Mello WC Gap junctional communication in the failing heart. In: Gap Junctions ( C Peracchia , ed.) Academic Press, NY, 2000,pp603-23.

10.

Booz G. , Baker KM Molecular signaling mechanisms controlling growth and function of cardiac fibroblasts. Cardiovasc Res 1995;30:532-43.

11.

Dostal DE Regulation of cardiac collagen:angiotensin and cross-talk with local growth factors. Hypertension 2001; 37:841-4.

12.

Cherry R. , De Mello WC Confocal microscopy and intercellular communication in failing cardiomyopathic heart. FASEB J, April 14th 1996;Abstract 2275.

13.

Kumagai K. , Nakashima H. , Urata H. , Gondo N. , Arakawa K. , Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodelling in atrial fibrillation. J Am Coll Cardiol 2003;41:2197-204.

14.

Ehrlich JR , Hohnloser SH , Nattel S. Role of angiotensin system and effects of its inhibition in atrial fibrillation; clinical and experimental evidence. Eur Heart J 2006;27:512-18.

15.

Crespo M. , De Mello WC Chronic administration of losartan plus hydrochlorothiazide improves vascular status in young cardiomyopathic hamsters. Eur J Pharmacol 2001;42:133-41.

16.

Toyofuku T. , Yabuki M. , Otsu K. , Kuzuyat T. , Tada M. , Hori M. Functional role of c-Src in gap junctions of cardiomyopathic heart. Circ Res 1999;85:672-81.

17.

Haendeler J. , Berk B. Tyrosine phosphorylation is involved in Ang II-mediated signal transduction. Reg Pept 2000;95:1-7. 18. Guo DF , Sun YL , Hamet P. , Inagami T. The angiotensin II type 1 receptor and receptor-associated proteins. Cell Research 2001;11:165-80.

18.

De Mello WC The cardiac syncytium; an overview. In: Heart Cell Coupling and Impulse Propagation in Health and Disease ( De Mello WC , Janse M ,eds) Kluwer Academic Publishers, Boston 2002,pp 1-23.

19.

Severs NJ , Coppen SR , Dupont E. , Yeh HI , Ko YS , Matsushita T. Gap junction alteration in human heart disease. Cardiovasc Res 2004;62:368-77.

20.

Emdad L. , Uzzman H. , Taskagishi Y. et al. Gap junction remodeling in hypertrophied left ventricles of aortic-banded rats; prevention by angiotensin II type 1 receptor blockade . J Mol Cell Cardiol 2001;33:219-31.

21.

Dodge SM , Beardslee MA , Darrow BJ , Green KG , Beyer EC , Saffitz JE Effects of angiotensin II on expression of gap junction channel protein connexin 43 in neonatal rat ventricular myocytes. J Am Coll Cardiol 1998;32:800-07.

22.

Polontchouk L. , Ebelt B. , Jackels M. , Dhein S. Chronic effects of endothelin 1 and angiotensin II on gap junction and inter-cellular communication in cardiac cells. FASEB J 2002;16:87-9.

23.

Saris JJ , van den Eijnden Mmed , Lamers Jmjp et al. Prorenin-induced myocyte proliferation; no role for intracellular angiotensin II. Hypertension 2002;39:573-7.

24.

Kurdi M. , De Mello WC , Booz G. Working outside the system: an update on the unconventional behavior of renin angiotensin system components. Int. J Biochem Cell Biol 2005;37:1357-67.