Decreased inotropic response to beta-adrenergic stimulation and normal sarcoplasmic reticulum calcium stores in the spontaneously hypertensive rat heart.
Cardiac hypertrophy in the spontaneously hypertensive rat has been shown to be accompanied by a diminished inotropic response to beta-adrenergic stimulation. This diminished response has been attributed to abnormalities in various components of the beta-adrenergic signaling system. There is also evidence that regulation of intracellular Ca2+ cycling may be altered in the hypertrophied heart of the spontaneously hypertensive rat. We proposed that the diminished response to beta-adrenergic stimulation may reflect abnormalities in Ca2+ cycling, specifically alterations in the ability of the sarcoplasmic reticulum to effectively release and resequester Ca2+. We have used the unique combination of functional measurements on isolated, isometrically contracting papillary muscles from hearts of 26-week-old spontaneously hypertensive rats and their Wistar-Kyoto controls, together with electron probe microanalysis measurements of sarcoplasmic reticulum Ca2+ content in the same muscles after rapid freezing, to determine the availability of Ca2+ for activation of contraction, following beta-adrenergic stimulation. We observed a significant decrease in the inotropic response to beta-adrenergic stimulation in papillary muscles from the spontaneously hypertensive rats, as compared with Wistar-Kyoto controls, however in these same muscles, frozen during relaxation, there was no evidence of an accompanying decrease in the size of the sarcoplasmic reticulum Ca2+ store. In an additional group of muscles which were frozen during contraction, the amount of Ca2+ remaining in the sarcoplasmic reticulum after stimulated release was also not different in the two strains. These results indicate that the decreased inotropic response to beta-adrenergic stimulation in hypertrophied hearts of the spontaneously hypertensive rat is unlikely to be due to decreased availability of Ca2+ for activation of contraction. Additionally, to determine whether there is intracellular Ca2+ overload in the cardiac muscle cells of hearts of spontaneously hypertensive rats, we measured the amount of Ca2+ in mitochondrial and at the level of the myofilaments by electron probe microanalysis. These results indicate that intracellular Ca2+ overload does not accompany cardiac hypertrophy in the spontaneously hypertensive rat. This study therefore shows no correlation between altered intracellular Ca2+ cycling and the decreased inotropic response to isoproterenol in the spontaneously hypertensive rat at 26 weeks of age.
Moravec
C S
CS
Department of Molecular Cardiology, Cleveland Clinic Foundation, Ohio 44195, USA.
Keller
E
E
Bond
M
M
D008841:Actin Cytoskeleton / Q000737:chemistry; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002451:Cell Compartmentation; D016616:Cryoultramicrotomy; D004577:Electron Probe Microanalysis; D006973:Hypertension / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000737:chemistry; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000737:chemistry; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D007545:Isoproterenol; D002118:Calcium