Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart

Abstract

Heart failure patients are routinely given ␤-adrenoceptor antagonists (␤-blockers), although the mechanism(s) underlying their beneficial effects is not fully resolved. It is not entirely clear how long-term application of negative inotropic compounds improves cardiac performance, slows remodeling processes, and decreases mortality. All ␤-blockers, which produce a beneficial effect in heart failure, have in common a high degree of lipophilicity and, therefore, have the ability to cross the blood-brain barrier. Here, we show that blockade of ␤-adrenoceptors directly in the brain (chronic intracerebroventricular administration of metoprolol) attenuates the progression of left ventricular remodeling in a rat model of myocardial infarction-induced heart failure. These results provide the first direct evidence that the action of certain ␤-blockers in the brain could contribute to their beneficial effect on the failing heart. M ortality associated with heart failure (HF) still remains high, despite considerable achievements in medical therapy, device technology, and cardiac surgery. The use of ␤-adrenoceptor (␤-AR) antagonists (␤-blockers) pioneered in the 1970s for the treatment of arterial hypertension became one of the most important advances in HF therapy. 1,2 The efficacy of 3 ␤-blockers, bisoprolol, carvedilol, and metoprolol, in HF treatment have been demonstrated in large placebo-controlled clinical trials. [3][4][5] These studies have revealed a reduction in the number of deaths from worsening HF in patients treated with carvedilol and metoprolol resulting from an improvement in left ventricular (LV) function and a delayed progression of LV remodeling. 3,4 In contrast, bisoprolol decreased mortality mainly by preventing sudden cardiac death, 5 whereas several ␤-blockers (eg, bisindolol and others) have been found to be insufficiently effective to be used in HF therapy. 2 A number of mechanisms explaining variable effects of ␤-blockers in HF patients have been proposed (including polymorphism in the genes encoding ␤-ARs, modulation of systemic neurohormonal activity, antagonism of the toxic actions of norepinephrine on the myocardium, favorable effects on myocardial energetics, etc). 2,6,7 Interestingly, it appears that the ␤-blockers, which produce a beneficial effect in HF, all have in common a high degree of lipophilicity and, as a result, have the ability to cross the blood-brain barrier. 2,8 Beneficial actions of certain lipophilic ␤-blockers in preventing ventricular fibrillation have already been attributed to their possible action within the brain. 9 We, therefore, suggested that the favorable effects of ␤-blockers in HF may be attributable, at least in part, to their central nervous system (CNS) effects. To test this hypothesis, we infused metoprolol (a ␤ 1 -blocker widely used in HF therapy) directly into the brain and determined the effect of this treatment on the progression of LV remodeling after myocardial infarction (MI) in rats. Materials and MethodsMI in rats was induced using a permanen...

The sympathetic nervous system and blood pressure in humans: implications for hypertension

“…71 However, the actions of metoprolol within the central nervous system appear to exert favourable effects on the failing rat heart, likely due to reductions in cardiac sympathetic outflow. 72 Whether these previously unrecognised pleiotropic effects of b-adrenergic blockade are manifested in human hypertension remains to be determined. Of note, despite lowering blood pressure certain diuretics (for example, chlorthalidone 73 ), dihydropridine calcium channel blockers 74 and combination therapies (for example, AT1-R antagonism plus diuretic 75 ) may actually raise SNA due to baroreceptor unloading.…”

“…98 Following animal studies first conducted over 50 years ago 99,100 and extensive technical development work, 101,102 surgical implantation of a device eliciting chronic carotid baroreflex stimulation (Rheo, CVRx, Minneapolis, MN, USA) has recently been demonstrated to effectively lower blood pressure and muscle SNA in humans. 14,71,72,103,104 This has been based on the recently resurrected idea that arterial baroreceptors control arterial pressure in the long term. 105 In his original study, Thrasher (2002) showed that unloading of baroreceptors at one carotid sinus (with all other arterial baroreceptors denervated) caused a sustained pressor response lasting up to 3 weeks in conscious dogs.…”

The brain as a target for development of new class of drugs for the treatment of somatic diseases

“…Furthermore, it has been demonstrated that intracerebroventricular administration of metoprolol, which induces blockade of central b-adrenergic receptors without peripheral effects, attenuates the progression of left ventricular remodeling in a rat model of heart failure. These data clearly show there is a role of the central action of certain b-blockers in their beneficial effect on the failing heart [18,19].…”

Impact of mitral regurgitation on left ventricular anatomic and molecular remodeling and systolic function: implication for outcome

“…Rat models have been widely used in the study of the pathophysiology of cardiovascular diseases and testing effects of medical therapies (1,9,19). One of important findings of this study is to demonstrate for the first time that a rat model of chronic organic MR expresses a pathophysiology similar to humans.…”