The effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, and losartan, an angiotensin II receptor type I antagonist, were investigated on alterations in myofibrillar ATPase activity as well as myosin heavy chain (MHC) content and gene expression in failing hearts following myocardial infarction (MI). Three weeks after ligation of the left coronary artery, rats were treated with or without enalapril (10 mg/kg/day), and/or losartan (20 mg/kg/day) for 5 weeks. The infarcted animals exhibited an increase in left ventricle (LV) end diastolic pressure and depressed rates of LV pressure development as well as pressure decay. LV myofibrillar Ca2+ -stimulated ATPase activity was decreased in the infarcted hearts compared with controls, MHC alpha-isoform content was significantly decreased whereas that of MHC beta-isoform was markedly increased. The level of MHC alpha-isoform mRNA was decreased whereas that of MHC beta-isoform was increased in the viable infarcted LV. Treatment of animal with enalapril, losartan, or combination of enalapril and losartan partially prevented the MI induced changes in LV function, myofibrillar Ca2+ -stimulated ATPase activity, MHC protein expression and MHC gene expression. The results suggest that the beneficial effects of the renin-angiotensin system blockade in heart failure are associated with partial prevention of myofibrillar remodeling.

To examine whether cardiac hypertrophy is associated with changes in beta-adrenoceptor signal transduction mechanisms, pressure overload (PO) was induced by occlusion of the abdominal aorta and volume overload (VO) by creation of an aortocaval shunt for 4 and 24 wk in rats. After hemodynamic assessment of the animals, the left ventricular (LV) particulate fraction was isolated for measurement of beta(1)-adrenoceptors and adenylyl cyclase activity, and cardiomyocytes were isolated for monitoring of the intracellular Ca(2+) concentration. Although PO and VO produced cardiac hypertrophy and increased LV end-diastolic pressure at 4 wk, cardiac function was increased in animals subjected to PO but remained unaltered in animals subjected to VO. Cardiac hypertrophy and increased LV end-diastolic pressure were associated with depressed cardiac function at 24 wk of PO or VO, but clinical signs of congestive heart failure were evident only in animals subjected to VO. Isoproterenol-induced increases in cardiac function, activation of adenylyl cyclase activity, and increase in intracellular Ca(2+) concentration, as well as beta(1)-adrenoceptor density, were unaltered by PO at 4 wk, augmented by VO at 4 wk, and attenuated by PO and VO at 24 wk. These results suggest that alterations in beta(1)-adrenoceptor signal transduction are dependent on the type and stage of cardiac hypertrophy.

Ventricular remodeling subsequent to myocardial infarction (MI) is a complex process and is considered to be a major determinant of the clinical course of congestive heart failure (CHF). Emerging evidence suggests that activation of the renin-angiotensin system (RAS) plays an important role in post-MI ventricular remodeling; however, it is becoming clear that this is one of several neurohumoral systems that are activated in CHF. Blockade of RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists attenuates the ventricular dysfunction, but the effects of individual drugs in reducing the morbidity and mortality in CHF patients are variable. Furthermore, there is a difference of opinion as to the time of initiation of therapy with RAS blockers after the onset of MI. Since blockade of RAS partially improves cardiac function, it is suggested that a combination therapy involving RAS blockers (angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists) and agents that affect other neurohumoral systems may prove useful for improved treatment of CHF. Although activation of RAS has been shown to promote oxidative stress in experimental studies, the use of antioxidant therapy in CHF patients is controversial. Recent experimental studies have shown that ventricular remodeling in CHF is associated with remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, myofibrils and extracellular matrix in terms of their molecular structure and composition. Since attenuation of remodeling in one and/or more subcellular organelles by different agents may prevent the progression of CHF, it is a challenge to develop specific drugs affecting molecular mechanisms associated with subcellular remodeling for the improved therapy of CHF.

Post‐myocardial infarction (MI) remodeling of cardiac myocytes and the myocardial interstitium results in alteration of gross ventricular geometry and ventricular dysfunction. To investigate the mechanisms of the remodeling process of the heart after large MI, the expression of various genes in viable left ventricle and infarct scar tissue were examined at 16 weeks post‐MI. Steady‐state expression of Na+‐K+ATPase α‐1 and −2, phospholamban (PLB), α‐myosin heavy chain (α‐MHC), ryanodine receptor (Rya) and Ca2+ ATPase (Serca2) mRNAs were decreased in the infarct scar vs noninfarcted sham‐operated controls (P < 0.05). On the other hand, Giα2 and β‐MHC mRNAs were upregulated (P < 0.05, respectively) in the infarct scar whereas Na+‐K+ ATPase‐β, Na+‐Ca2+ exchanger and Gs mRNAs were not altered vs control values. In viable left ventricle, the a‐1 subunit of Na+‐K+ATPase, α‐3, β‐isoforms, Rya, β‐MHC, Giα2, Gs and Na+‐Ca2+ exchanger were significantly elevated while expression of the a‐2 subunit of Na+‐K+ ATPase, PLB and Serca2 were significantly decreased compared to controls. Expression of CK2α mRNA was elevated in noninfarcted heart (145 ± 15%) and diminished in the infarct scar (66 ± 13%) vs controls. Expression of β‐MHC mRNA was elevated in both viable and infarct scar tissues of experimental hearts (140 ± 31% and 183 ± 30% vs. controls, respectively). These results suggest that cardiac genes in the infarcted tissue and viable left ventricle following MI are differentially regulated.

Although activation of the renin-angiotensin system (RAS) is known to produce ventricular remodeling and congestive heart failure (CHF), its role in inducing changes in the sarcoplasmic reticulum (SR) protein and gene expression in CHF is not fully understood. In this study, CHF was induced in rats by ligation of the left coronary artery for 3 weeks and then the animals were treated orally with or without an angiotensin converting enzyme inhibitor, enalapril (10 mg/kg/day) or an angiotensin II receptor antagonist, losartan (20 mg/kg/day) for 4 weeks. Sham-operated animals were used as control. The animals were hemodynamically assessed and protein content as well as gene expression of SR Ca(2+)-release channel (ryanodine receptor, RYR), Ca(2+)-pump ATPase (SERCA2), phospholamban (PLB) and calsequestrin (CQS) were determined in the left ventricle (LV). The infarcted animals showed cardiac hypertrophy, lung congestion, depression in LV +dP/dt and -dP/dt, as well as increase in LV end diastolic pressure. Both protein content and mRNA levels for RYR, SERCA2 and PLB were decreased without any changes in CQS in the failing heart. These alterations in LV function as well as SR protein and gene expression in CHF were partially prevented by treatment with enalapril or losartan. The results suggest that partial improvement in LV function by enalapril and losartan treatments may be due to partial prevention of changes in SR protein and gene expression in CHF and that these effects may be due to blockade of the RAS.

No abstract

To investigate the mechanisms underlying the depressed sarcolemmal (SL) Na(+)-K(+)-ATPase activity in congestive heart failure (CHF), different isoforms and gene expression of Na(+)-K(+)-ATPase were examined in the failing left ventricle (LV) at 8 weeks after myocardial infarction (MI). In view of the increased activity of renin-angiotensin system (RAS) in CHF, these parameters were also studied after 5 weeks of treatment with enalapril (10 mg x kg-1 x day-1), an angiotensin-converting enzyme inhibitor, and losartan (20 mg.kg-1.day-1), an angiotensin II type 1 receptor antagonist, starting at 3 weeks after the coronary ligation in rats. The infarcted animals showed LV dysfunction and depressed SL Na(+)-K(+)-ATPase activity. Protein content and mRNA levels for Na(+)-K(+)-ATPase alpha2 isoform were decreased whereas those for Na(+)-K(+)-ATPase alpha3 isoform were increased in the failing LV. On the other hand, no significant changes were observed in protein content or mRNA levels for Na(+)-K(+)-ATPase alpha1 and beta1 isoforms. The treatment of infarcted animals with enalapril or losartan improved LV function and attenuated the depression in Na(+)-K(+)-ATPase alpha2 isoform as well as the increase in alpha3 isoform, at both the protein and mRNA levels; however, combination therapy with enalapril and losartan did not produce any additive effects. These results provide further evidence that CHF due to MI is associated with remodeling of SL membrane and suggest that the blockade of RAS plays an important role in preventing these alterations in the failing heart.

No abstract