DECREASED-GS-ALPHA MESSENGER-RNA LEVELS ACCOMPANY THE FALL IN GS AND ADENYLYL CYCLASE ACTIVITIES IN COMPENSATED LEFT-VENTRICULAR HYPERTROPHY - IN HEART-FAILURE, ONLY THE IMPAIRMENT IN ADENYLYL CYCLASE ACTIVATION PROGRESSES

We have previously reported that there is a global reduction in adenylyl cyclase associated with a decrement in G(s) functional activity in cardiac sarcolemma from animals with pressure overload-induced hypertrophy and heart failure. This study was performed to determine whether hypertrophy alone in the absence of heart failure is sufficient to promote these changes and whether the superimposition of heart failure intensified these changes. Basal and stimulated adenylyl cyclase and G(s) activity, as determined in the S49 cyc- reconstitution assay, were measured in sarcolemma from normal (NL), left ventricular hypertrophy (LVH) and heart failure (HF) animals. Simultaneously, we measured the mRNA level encoding for the G(s-alpha) subunit. These studies indicate that G(s) activity and G(s-alpha) mRNA are decreased by approximately 30% both in the failing heart and even in the heart with compensated hypertrophy before heart failure develops (G(s) activity, pmol cyclic AMP/10 min per mu-G, NL 4.2 +/- 0.4, LVH 3.0 +/- 0.2, HF 3.2 +/- 0.3; G(s-alpha) mRNA, pg/10 mu-G RNA, NL 131 +/- 9.0, LVH 104 +/- 7.4, Hf 97.4 +/- 9.1; P < 0.05 as compared with NL for LVh and HF). Accompanying this decrement in G(S) activity is a fall in adenylyl cyclase, both basal and stimulated. However, we also identified a further decrease in adenylyl cyclase without any additional change in G(s) or in its alpha subunit mRNA level. This is seen only in the sarcolemma from animals with heart failure as compared with those with compensated LV hypertrophy (e.g., NaF-stimulated activity, pmol cycle AMP/min per mg, NL 420.2 +/- 17.5, LVH 347.1 +/- 29.6, Hf 244.2 +/- 27.3; P < 0.05 compared with NL for LVH and HF, P < 0.05 compared with LVH for HF). In summary, these studies indicate that both G(s) and adenylyl cyclase activities fall in parallel with the development of LV hypertrophy followed by a further decrement in adenylyl cyclase, independent of G(s), in the setting of heart failure.