Abstract-Altered expression and functional responses to cardiac ␤ 3 -adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte ␤ 3 -AR mRNA and protein levels and myocyte contractile, [Ca 2ϩ ] i transient, and Ca 2ϩ current (I Ca,L ) responses to BRL-37344 (BRL, 10 Ϫ8 mol/L), a selective ␤ 3 -AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription-polymerase chain reaction, we detected ␤ 3 -AR mRNA from myocyte total RNA in each animal. Using a cloned canine ␤ 3 -AR cDNA probe and myocyte poly A ϩ RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. ␤ 3 -AR protein was detected by Western blot. ␤ 3 -AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced ␤ 3 -AR-mediated negative modulation on myocyte contractile response and [Ca 2ϩ ] i regulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca 2ϩ ] i transient and I Ca,L . These responses were not modified by pretreating myocytes with metoprolol (a ␤ 1 -AR antagonist) or nadolol (a ␤ 1 -and ␤ 2 -AR antagonist), but were nearly prevented by bupranolol or L-748,337 (␤ 3 -AR antagonists). We conclude that in dogs with pacing-induced CHF, ␤ 3 -AR gene expression and protein levels are upregulated, and the functional response to ␤ 3 -AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.

With slowed relaxation during the development of HF, E(M) is reduced and delayed so that it occurs after early, rapid filling. Thus, with slowed relaxation, E(M) does not respond to the early diastolic LA to LV pressure gradient, because it occurs when LV pressure is greater than or equal to LA pressure.

The objective of the present study was to test the hypothesis that endogenous beta(3)-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the beta(3)-AR inhibits cardiac contraction. In the failing myocardium, beta(3)-ARs are upregulated, suggesting that stimulation of beta(3)-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous beta(3)-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific beta(3)-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (E(es)) of the LV pressure-volume relation (18%, 6.2 +/- 0.9 vs. 7.3 +/- 1.2 mmHg/ml, P < 0.05) and the improved LV relaxation time constant (tau; 28.4 +/- 1.9 vs. 26.8 +/- 1.0 ms, P < 0.05). After CHF, the plasma norepinephrine concentration increased eightfold, and L-748,337 produced a larger increase in E(es) (34%, 3.8 +/- 0.7 vs. 5.1 +/- 0.8 mmHg/ml, P < 0.05) and a greater decrease in tau (46.4 +/- 4.2 vs. 41.0 +/- 3.9 ms, P < 0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8 +/- 0.9 vs. 6.8 +/- 0.9%, P < 0.05) and relengthening (33.5 +/- 4.2 vs. 39.7 +/- 4.0 microm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca(2+) concentration regulation. In CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function. Stimulation of beta(3)-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.

␤ 3 -adrenergic receptors (AR) have recently been identified in mammalian hearts and shown to be up-regulated in heart failure (HF). ␤ 3 -AR stimulation reduces inotropic response associated with an inhibition of L-type Ca 2ϩ channels in normal hearts; however, the effects of ␤ 3 -AR activation on Ca 2ϩ channel in HF remain unknown. We compared the effects of ␤ 3 -AR activation on L-type Ca 2ϩ current (I Ca,L ) in isolated left ventricular myocytes obtained from normal and age-matched rats with isoproterenol (ISO)-induced HF (4 months after 340 mg/kg s.c.

Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.

The new myofilament Ca 2ϩ sensitizer levosimendan (LSM) is a positive inotropic and vasodilatory agent. Its beneficial effects have been demonstrated at rest in congestive heart failure (CHF). However, its effect during exercise (Ex) in CHF is unknown. We assessed the effects of LSM on left ventricular (LV) dynamics at rest and during Ex in eight conscious, instrumented dogs with pacing-induced CHF. After CHF, with dogs at rest, LSM decreased arterial elastance (E a) and increased LV contractile performance as assessed by the slope of LV pressure-volume (P-V) relation. LSM caused a Ͼ60% increase in the peak rate of mitral flow (dV/dtmax) due to decreases in minimal LV pressure and the time constant of LV relaxation (). LV arterial coupling, quantified as the ratio of end-systolic elastance (E es) to Ea, was increased from 0.47 to 0.85%. LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, was improved from 0.54 Ϯ 0.09 to 0.61 Ϯ 0.07. These beneficial effects persisted during Ex after CHF. Compared with CHF Ex dogs, treatment with LSM prevented Ex-induced abnormal increases in mean left atrial pressure and end-diastolic pressure and decreased E es/Ea. With LSM treatment during CHF Ex, the early diastolic portion of the LV P-V loop was shifted downward with decreased minimal LV pressure and values and a further augmented dV/dtmax. Ees/Ea improved, and mechanical efficiency further increased from 0.61 Ϯ 0.07 to 0.67 Ϯ 0.07, which was close to the value reached during normal Ex. After CHF, LSM produced arterial vasodilatation; improved LV relaxation and diastolic filling; increased contractility, LV arterial coupling, and mechanical efficiency; and normalized the response to Ex.congestive heart failure; left ventricular dynamics; filling; contractility; mechanical efficiency IMPORTANT GOALS IN THE TREATMENT of patients with congestive heart failure (CHF) are to prolong survival and improve the patient's quality of life. The major symptom and cause of disability in CHF patients is exercise (Ex) intolerance (5,32,45). Observational work in the general healthy population has shown that Ex capacity is a more powerful prognostic indicator than traditional risk factors for cardiovascular disease (36, 44). However, despite enormous advances in the understanding and treatment of CHF that have taken place during the last 50 years, CHF remains a serious and, in fact, growing health problem. Present treatment of Ex intolerance is unsatisfactory in CHF patients (45,63). The ␤-adrenergic agonist dobutamine and phosphodiesterase inhibitor milrinone were associated with worse survival and clinical outcomes and did not improve quality of life for severe CHF patients (42, 48). Angiotensinconverting enzyme inhibitor therapy and ␤-blockade treatment improve survival in patients with CHF but do not always enhance Ex tolerance (37). Recently myofilament Ca 2ϩ sensitizers, which are a new class of nonglycosidic, nonadrenergic, positive inotropic agents, have been studied in patients with CHF. Because impair...

The diastolic dysfunction present at rest in congestive heart failure (CHF) is exacerbated during exercise (Ex). Increases in circulating ANG II and endothelin-1 (ET-1) during Ex may contribute to this response. We assessed the effect of Ex on circulating plasma levels of ANG II and ET-1 and left ventricular (LV) dynamics before and after pacing-induced CHF at rest and during Ex in nine conscious, instrumented dogs. Before CHF, there were modest increases in circulating levels of ANG II (but not ET-1) during Ex. LV diastolic performance was enhanced during Ex with decreases in the time constant of LV relaxation (tau), LV end-systolic volume (V(ES)), and LV minimum pressure with a downward shift of the LV early diastolic portion of the pressure-volume (P-V) loop. This produced an increase in peak LV filling rate without an increase in mean left atrial (LA) pressure. After CHF, the resting values of ANG II and ET-1 were elevated and increased to very high levels during Ex. After CHF, mean LA pressure, tau, and LV minimum pressure were elevated at rest and increased further during Ex. Treatment with L-754,142, a potent ET-1 antagonist, or losartan, an ANG II AT(1)-receptor blocker, decreased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.

Background-Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT 1 ) blockade on the development of alcoholic cardiomyopathy. Methods and Results-We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg · kg Ϫ1 · d Ϫ1 PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT 1 receptor expression. The RAS activation was followed by a progressive fall in LV contractility (E ES , alcohol-fed dogs 3.9Ϯ0.