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 le ft ventricular (LV) hypertrophy has been demonstrated to have inhibito ry effects on myocardial growth. An important mechanism of action of A CE inhibition is modulation of myocardial AT(1) Ang II-receptor activi ty. 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 betwee n changes in LV and myocyte function during the LV hypertrophic proces s that occurs after recovery from long-term rapid pacing. Dogs were ra ndomly assigned to the following treatment groups: (a) Pace and Recove ry, long-term rapid pacing (4 weeks; 216 +/- 2 beats/min) followed by a 4-week recovery period (n = 6); (b) Recovery/AT(1) Block, concomitan t AT(1) Ang II-receptor blockade [irbesartan (SR 47436; EMS-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 me an arterial pressure in any of the three groups. With pacing and recov ery, LV end-diastolic volume and mass were increased by >50% from cont rol values. The significant LV remodeling that occurred with recovery from long-term rapid pacing was associated with a decline in LV ejecti on fraction (59 +/- 3% vs. 68 +/- 4%) and myocyte velocity of shorteni ng (43 +/- 3 mu m/s vs. 63 +/- 3, mu m/s) when compared with controls (p < 0.05). With recovery from long-term rapid pacing, LV myocyte leng th (176 +/- 6 mu m vs. 150 +/- 1 mu m) and cross-sectional area were i ncreased (292 +/- 7 mu m(2) vs. 227 +/- 6 mu m(2)) compared with contr ols (p < 0.05). With AT(1) Ang II block during recovery from rapid pac ing, LV end-diastolic volume was similar to untreated recovery values, but LV mass was normalized. LV ejection fraction was not different fr om control Values with AT(1) Ang II-receptor block. Steady-state myocy te velocity of shortening with AT(1) Ang II block was similar to contr ol Values (55 +/- 5 mu m/s), but percentage shortening remained reduce d 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 value s, but cross-sectional area was reduced (260 +/- 5 mu m(2), p < 0.05). Thus AT(1) Ang II-receptor blockade instituted in this model of devel oping 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 m yocyte geometry. AT(1) Ang II-receptor blockade improved certain indic es of myocyte contractile function from untreated hypertrophy values. These findings suggest that in this pacing-recovery model, the develop ment of LV hypertrophy and myocyte contractile dysfunction may be caus ed, at least in part, by AT(1) Ang II-receptor activation.