Published Online
on December 2, 2002

A more recent version of this article appeared on January 1, 2003

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Submitted on April 9, 2002
Revised on May 2, 2002

Endothelin-1 Contributes to the Frank-Starling Response in Hypertrophic Rat Hearts

Jarkko Piuhola; István Szokodi; Pietari Kinnunen; Mika Ilves; Rudolf deChâtel; Olli Vuolteenaho; and Heikki Ruskoaho^*

From the Department of Pharmacology and Toxicology (J.P., I.Sz., P.K., H.R.) and the Department of Physiology (M.I., O.V.), Biocenter Oulu, University of Oulu, Oulu, Finland; the Heart Institute, Faculty of Medicine, University of Pécs (I.Sz.), Pécs, Hungary; and the First Department of Medicine, Semmelweis University, and Molecular Genetic Research Group of the Hungarian Academy of Science (R.d.C.), Budapest, Hungary.

^* To whom correspondence should be addressed. E-mail: heikki.ruskoaho{at}oulu.fi.

Abstract—Endothelin-1 is involved in mechanical load-induced cardiac growth processes; it also has effects on contractility. The interaction of endothelin-1 and the Frank-Starling response is unknown. The present study aimed to characterize the role of endothelin-1 in the regulation of the Frank-Starling response, one of the major mechanisms regulating cardiac contractile force, in both normal and hypertrophied hearts. Nontransgenic rat hearts and hypertrophic hearts of hypertensive double transgenic rats harboring human angiotensinogen and renin genes were studied in a Langendorff isolated heart setup with a liquid-filled balloon inside the left ventricle used to measure contractile parameters. The rats were studied at compensated phase, before showing any signs of heart failure. Compensated hypertrophy in double transgenic rat hearts resulted in improved contractility at a given level of preload when compared with nontransgenic rat hearts. Hearts of both rat lines showed preserved Frank-Starling responses, that is, increased contractile function in response to increased end-diastolic pressure. The mixed endothelin A/B receptor antagonist bosentan attenuated the Frank-Starling response by 53% (P<0.01) in the double transgenic hearts but not in nontransgenic hearts. The diastolic parameters remained unaffected. The left ventricles of the double transgenic rat hearts showed an 82% higher level of endothelin type A receptor mRNA and a 25% higher level of immunoreactive endothelin-1 compared with nontransgenic rat hearts. The type 1 angiotensin II receptor antagonist CV-11974 had no significant effect on contractile function in response to load in either strain. These results show that endogenous endothelin-1 contributes to the Frank-Starling response in hypertrophied rat hearts by affecting systolic performance.

Key words: angiotensin II • endothelin • hypertrophy • rats, transgenic • stress, mechanical

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