Relationship between the increase in Ca2+ transient and contractile force induced by angiotensin II in aequorin-loaded rabbit ventricular myocardium

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 degrees C. RESULTS: Ang II (10(-8)-10(-6) M), in the presence of bupranolol (3 x 10(-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.