title: Endothelin-1 contributes to the Frank-Starling response in hypertrophic rat hearts.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Piuhola
authors.forename: István
authors.initials: I
authors.lastname: Szokodi
authors.forename: Pietari
authors.initials: P
authors.lastname: Kinnunen
authors.forename: Mika
authors.initials: M
authors.lastname: Ilves
authors.forename: Rudolf
authors.initials: R
authors.lastname: deChâtel
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000150:complications; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D012083:Renin / Q000235:genetics; D013314:Stress, Mechanical; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013449:Sulfonamides; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin; D000077300:Bosentan; C081643:candesartan