© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Relationship between the increase in Ca2+ transient and contractile force induced by angiotensin II in aequorin-loaded rabbit ventricular myocardium
Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
* Corresponding author. Tel. +81-236 28 52 32; Fax +81-236 28 52 35.
Objectives: Pieces of evidence have been accumulating that imply a crucial role of angiotensin II (Ang II) in initiation and progress of heart failure, but the signalling processes subsequent to Ang II receptor activation in cardiac myocytes are complex and still controversial. We examined the effects of Ang II on the relationship between the intracellular Ca2+ transient and isometric contraction in mammalian ventricular myocardium. Methods: Isolated rabbit ventricular papillary muscle was loaded with the Ca2+ sensitive bioluminescent protein aequorin and electrically stimulated at a rate of 0.5 Hz at 37°C. Results: Ang II (10–8–10–6 M), in the presence of bupranolol (3x10–7 M) and prazosin (10–7 M), elicited a positive inotropic effect (PIE) in association with an increase in the peak Ca2+ transient. The maximal PIE of Ang II was about 30% of the isoproterenol-induced maximum (ISOmax), while the maximal increase in the peak Ca2+ transient induced by Ang II was only 7% of ISOmax. Ang II tended to prolong the duration of contraction (both time to peak force and relaxation time) but did not produce a discernible change in the duration of Ca2+ transient. The relationship between the amplitude of Ca2+ transient and peak force was shifted to the left by Ang II, as compared with the relationship for elevation of [Ca2+]o (2.5–15.0 mM). The PIE and the increase in the amplitude of Ca2+ transient induced by Ang II were abolished by a selective angiotensin type 1 (AT1) receptor antagonist losartan (10–5 M) but were not affected by a selective AT2 receptor antagonist PD123319 (10–6 M). Conclusions: These results indicate that Ang II elicits a PIE through a dual mechanism via activation of AT1 receptors in rabbit ventricular myocardium: by an increase in the amplitude of Ca2+ transient; and in addition by an increase in the myofilament Ca2+ sensitivity.
KEYWORDS Ang II=angiotensin II; RAS=renin-angiotensin system; PIE=positive inotropic effect; AT1=angiotensin type 1; AT2=angiotensin type 2; ISO=isoproterenol; PI=phosphoinositide; IP3=inositol 1,4,5-trisphosphate; PKC=protein kinase C; [Ca2+]i=intracellular Ca2+ concentration; [Ca2+]o=extracellular Ca2+ concentration; KHS=Krebs-Henseleit solution; EDTA=ethylenediaminetetraacetic acid; HEPES=N-2-hydroxyethylpiperazine-N''-2-ethanesulfonic acid; E-C=excitation-contraction; EIPA=ethylisopropyl amirolide
1 Present address: Department of Internal Medicine I, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
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