Intracrine action of angiotensin II in the intact ventricle of the failing heart: angiotensin II changes cardiac excitability from within

Abstract

The influence of intracellular injection of angiotensin II (Ang II) on electrical properties of single right ventricular fibers from the failing heart of cardiomyopathic hamsters (TO2) was investigated in the intact ventricle of 8-month-old animals. Intracellular injection was performed using pressure pulses (40-70 psi) for short periods of time (20 ms) while recoding the action potential simultaneously from the same fiber. The results indicated that intracellular Ang II caused a hyperpolarization of 7.7 mV ± 4.3 mV (n = 39) (4 animals) (P < 0.05) followed by a small fall in membrane potential. The action potential duration was significantly increased at 50% and at 90% repolarization, and the refractoriness was significantly enhanced. The effect of intracellular Ang II on action potential duration was related to the inhibition of potassium conductance through PKC activation because Bis-1 (360 nM), a selective PKC inhibitor, abolished the effect of the peptide. Injections performed in different fibers of the same ventricle showed a variable effect of Ang II on action potential duration and generated spontaneous rhythmicity. The effect of intracellular Ang II on action potential duration and cardiac refractoriness remains for more than 1 h after interruption of the intracellular injection of the peptide.

Fig. 1

Top, Left—influence of intracellular Ang II injection on transmembrane action potential duration recorded from a single fiber of the right ventricle. A—control B—after 4 min of intracellular Ang II administration (for 20 s); C—spontaneous rhythmicity recorded after the performance of intracellular injections in different areas of the right ventricle. Vertical calibration in A 34 mV. Horizontal calibration in A, B, and C 50 ms. In C, the sweep velocity was smaller. Right—each bar shows the effect of intracellular injection of Ang II on action potential duration recorded from 40 right ventricular fibers (4 animals). The effect of Bis-1 (360 nM), a selective PKC inhibitor, on the effect of Ang II is also shown. Each bar for this experiment is the average from 15 fibers (3 animals). Vertical line at each bar SEM. P < 0.05. Bottom—influence of intracellular Ang II injection on the resting potential. Each point is the average from 39 fibers (4 animals). Vertical line at each point SEM

Fig. 2

Long-lasting effect of intracellular Ang II injection on action potential duration. Each bar is the average from 32 fibers (4 animals). Vertical line at each bar SEM. P < 0.05

Fig. 3

Lack of action of intracellular administration of Ang II in single ventricular fiber of the right ventricle from a cardiomyopathic hamster. A—control; B—recorded after 5 min of intracellular Ang II injection (45 psi, for 20 s). Vertical calibration in A 40 mV. Horizontal calibration in A and B 50 ms

Fig. 4

Influence of intracellular administration of losartan on the effect of intracellular Ang II on action potential duration in the intact ventricle. Each bar is the average from 35 fibers (4 animals). Vertical tine at each bar SEM. P > 0.05

Fig. 5

Current/voltage relationship recorded from myocytes isolated from the ventricle of 8-month-old cardiomyopathic hamsters (TO2) showing the effect of intracellular injection of Ang II on potassium current. Each point is the average from 20 cardiomyomyocytes (3 animals). Vertical line at each point SEM. P < 0.05

Fig. 6

Effect of intracellular Ang II injection on cardiac refractoriness. Each bar is the average from 35 fibers (4 animals). Vertical line at each bar SEM

Fig. 7

Influence of intracellular injection of Ang II on action potential duration recorded from the right ventricle of F1B control hamsters. Each bar is the average from 20 fibers (3 animals). Vertical tine at each bar SEM