Propranolol therapy in experimental heart failure in rabbits improves cardiac response to catecholamines without beta‐adrenoceptor up‐regulation

Abstract

Beta-blockade has been shown to improve cardiac response to catecholamines in heart failure but cellular mechanisms of the improvement are unknown. The effect on left ventricular function of a 14 day propranolol treatment was studied in seven treated and eight non-treated rabbits with experimental heart failure. All animals were subjected to a volume (aortic insufficiency) plus pressure (aortic constriction) overload and were instrumented with a left ventricular catheter and ultrasonic crystals measuring anteroposterior left ventricular diameter. Beta-adrenoceptors were measured using 125I-Cyanopindolol in crude membranes. With isoproterenol, the heart rate was slower in treated rabbits than in non-treated rabbits (p < 0.005) and isoproterenol increased more systolic diameter shortening in treated than in non-treated rabbits (p < 0.05). With norepinephrine, for matched pressures, % delta D increased in the treated group but it did not change in the non-treated group. This improvement of ventricular function was due, in a large part, to an increased diastolic response to norepinephrine: end-diastolic diameter increased in the treated group but not in the non-treated group. In contrast with the improved ventricular response to catecholamines, beta-adrenergic receptor density in the treated group was identical to that of the non-treated group (27.8 fmoles/mg/proteins) and was significantly lower than that of normal rabbits (58.2 fmoles/mg, p < 0.01). The improvement of ventricular response to catecholamines appears to be due to a myocardial protection by propranolol against the toxic effect of catecholamines in heart failure and not, at least in this model, to an up-regulation of beta-adrenoceptors.

Benefits of long-term β-blockade in experimental chronic aortic regurgitation

“…The role of ␤-blockade in the management of AR has been explored by other investigators in animal models (1,19,21,(23)(24)(25)(26)(27) (Table 4). These studies have suggested that adrenergic blockade may be beneficial in animal models of acute AR, although none of them evaluated the long-term effects in a chronic AR model.…”

“…␤-Blockers may have acted in the same way in our animals with severe chronic AR but preserved LV ejection fraction. Indeed, we observed that Met improved the ratio of gene expression of the ␤ 1 -and ␤ 2 -adrenergic receptors, which (19) Rat AR (chronic) Met (25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 6 mo Improvement of LVEF, decrease in LVH, increase in ␤1-AR expression Suzuki et al (21) Rabbit AR (acute) Intravenous propranolol for 7 days Prevention of ␤-AR downregulation Wright et al (23) Rabbit AR (8 wk) Bradycardial pacing Improvement of myocardial capillary density and cardiac work per minute in AR Xiong et al (24) Rabbit AR (acute, 14 days) Propranolol Improvement of fractional shortening; no effect on ␤-AR; possible protection against toxic effects of catecholamines Yamazaki et al (25) Rat AR (8 wk) No treatment Increase in synthesis of ␤-AR from week 1 to week 4 and return to baseline by week 8 Yoshikawa et al (26) Rabbit AR (acute, 7 days) Alacepril (ACEI) for 7 days Prevention of acute decrease in myocardial ␤-AR density and NE content LVEF, LV ejection fraction; LVH, LV hypertrophy; ACEI, angiotensin-converting enzyme inhibitor; ␤-AR, ␤-adrenergic receptor; NE, norepinephrine. …”

Effectiveness of β-Blockade in Experimental Chronic Aortic Regurgitation

“…20 Significant abnormalities of the adrenergic system have also been identified in humans and animals submitted to chronic volume overload. [2][3][4][5][6][7][8][9][10][11][12]21,22 Others have reported significant decreases in ␤-adrenoreceptor density in the LV of patients with chronic volume overload compared with pressure-overload and normal controls. 23 In subjects with clinical heart failure from severe AR, intense adrenergic activity is present, as in other causes of heart failure.…”

“…1 Significant alterations of the adrenergic system and adrenergic receptors have been reported in animal models of chronic volume overload. [3][4][5][6][7][8][9][10][11][12] Despite these interesting findings, the hypothesis that ␤-adrenergic blocking agents might be effective to protect the volume-overloaded LV has not been adequately tested. A few studies have suggested that a short-term treatment with ␤-blockers might be beneficial in volume overload.…”

“…A few studies have suggested that a short-term treatment with ␤-blockers might be beneficial in volume overload. 3,11,13,14 However, the long-term effectiveness of this type of drugs in chronic AR has never been adequately evaluated. In the present study, we assessed the effects of a 6-month treatment with the ␤-blocker metoprolol on the LV function and remodeling of rats with severe chronic AR.…”