Angiotensin II subtype-1 receptor blockade during the development of left ventricular hypertrophy in dogs : Effects on ventricular and myocyte function

Inhibition of the angiotensin-converting enzyme (ACE) in developing left ventricular (LV) hypertrophy has been demonstrated to have inhibitory effects on myocardial growth. An important mechanism of action of ACE inhibition is modulation of myocardial AT 1 Ang II-receptor activity. However, whether and to what extent AT 1 Ang II-receptor blockade may influence LV and myocyte function during the hypertrophic process remains unclear. Accordingly, our project examined the relation between changes in LV and myocyte function during the LV hypertrophic process that occurs after recovery from long-term rapid pacing. Dogs were randomly assigned to the following treatment groups: (a) Pace and Recovery, long-term rapid pacing (4 weeks; 216 ± 2 beats/min) followed by a 4-week recovery period (n = 6); (b) Recovery/AT 1 Block, concomitant AT 1 Ang II-receptor blockade [irbesartan (SR 47436; BMS-186295) 30 mg/kg b.i.d.] administered during the 4-week recovery period (n = 5); and (c) Control, sham controls (n = 6). There was no difference in mean arterial pressure in any of the three groups. With pacing and recovery, LV end-diastolic volume and mass were increased by >50% from control values. The significant LV remodeling that occurred with recovery from long-term rapid pacing was associated with a decline in LV ejection fraction (59 ± 3% vs. 68 ± 4%) and myocyte velocity of shortening (43 ± 3 μm/s vs. 63 ± 3, μm/s) when compared with controls (p < 0.05). With recovery from long-term rapid pacing, LV myocyte length (176 ± 6 μm vs. 150 ± 1 μm) and cross-sectional area were increased (292 ± 7 μm 2 vs. 227 ± 6 μm 2 ) compared with controls (p < 0.05). With AT 1 Ang II block during recovery from rapid pacing, LV end-diastolic volume was similar to untreated recovery values, but LV mass was normalized. LV ejection fraction was not different from control values with AT 1 Ang II-receptor block. Steady-state myocyte velocity of shortening with AT 1 Ang II block was similar to control values (55 ± 5 μm/s), but percentage shortening remained reduced from control (3.55 ± 0.37% vs. 4.71 ± 0.12%, respectively, p < 0.05) and was similar to untreated recovery (3.59 ± 0.23%). With AT 1 Ang II block, myocyte length was similar to untreated recovery values, but cross-sectional area was reduced (260 ± 5 μm 2 , p < 0.05). Thus AT 1 Ang II-receptor blockade instituted in this model of developing LV hypertrophy, significantly reduced LV mass but did not reduce the degree of LV dilation. The cellular basis for these effects of AT 1 Ang II-receptor blockade included persistent abnormalities in LV myocyte geometry. AT 1 Ang II-receptor blockade improved certain indices of myocyte contractile function from untreated hypertrophy values. These findings suggest that in this pacing-recovery model, the development of LV hypertrophy and myocyte contractile dysfunction may be caused, at least in part, by AT 1 Ang II-receptor activation.