β₁-Adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog

Abstract

Mitral regurgitation (MR) is associated with increased neuronal release of norepinephrine (NE) and epinephrine (EP) into myocardial interstitial fluid (ISF) that may be necessary in sustaining left ventricular (LV) function via activation of cardiomyocyte beta-adrenergic receptors (ARs). However, activation of neuronal beta-ARs on cardiac neurons may lead to further catecholamine release, with an attendant risk of functional deterioration. We hypothesize that a beneficial effect of beta-AR blockade may therefore mitigate excessive catecholamine release from cardiac adrenergic neurons in dogs with MR. We measured the effects of chronic beta-receptor blockade (beta-RB) on ISF NE and EP release using in vivo microdialysis in open-chest anesthetized dogs after 4 wk of MR with or without extended release of metoprolol succinate (100 mg/day) as well as in control dogs. Fractional shortening increased by 30% in both MR and MR + beta-RB dogs after 4 wk of MR. In MR + beta-RB dogs, stellate-stimulated heart rate change was attenuated compared with control and MR dogs, whereas peak change of LV pressure over time (+dP/dt) increased equally in all groups. Stellate-stimulated ISF NE increased fivefold over baseline in MR versus twofold in control dogs (< 0.05), but the NE release was significantly attenuated in MR + beta-RB dogs. In contrast, stellate-stimulated increases in ISF EP did not differ in control, MR, and MR + beta-RB dogs. This study demonstrates that beta-RB attenuates ISF NE release from cardiac neurons and that the LV functional response to MR is not dependent on an excess increase in ISF NE. Thus beta1-RB may exert a beneficial effect by attenuating untoward effects of excessive sympathetic efferent neural NE release while sustaining early LV functional adaptation to MR.

Sympathetic Activation Causes Focal Adhesion Signaling Alteration in Early Compensated Volume Overload Attributable to Isolated Mitral Regurgitation in the Dog

“…1,2 In addition to these structural changes, there is development of cardiac hypertrophy and subsequent LV dysfunction in MR that are improved by ␤-adrenergic receptor blockade (␤-RB) 3 but not by angiotensin-converting enzyme inhibition or angiotensin type 1 receptor blockade, 4,5 suggesting that the adrenergic system is more central to the pathophysiology of VO of isolated MR. Moreover, studies in humans and dogs have demonstrated an increase in adrenergic drive even in a mild compensated state of isolated MR, 6,7 most likely attributable to the early achievement of preload reserve.…”

Dissociation between cardiomyocyte function and remodeling with β-adrenergic receptor blockade in isolated canine mitral regurgitation

“…There is a strong impetus for the use of ␤-receptor blockers in the treatment of MR (15) given that there is increased sympathetic drive in both the human (8) and dog (4,9,17). Although initial sympathetic drive is a necessary compensatory mechanism in MR, long-term activation may have a cytotoxic effect on cardiomyocytes.…”

“…Increased sympathetic drive follows the initial recruitment of preload reserve in the early phase of MR in the human (8) and dog (4,9,17). Using the microdialysis technique in healthy open-chest canines, we have shown that there is compartmentalized norepinephrine and epinephrine release into the LV interstitial fluid space during electrical stimulation of the stellate ganglion (4,17).…”

“…Increased sympathetic drive follows the initial recruitment of preload reserve in the early phase of MR in the human (8) and dog (4,9,17). Using the microdialysis technique in healthy open-chest canines, we have shown that there is compartmentalized norepinephrine and epinephrine release into the LV interstitial fluid space during electrical stimulation of the stellate ganglion (4,17). We have reported that catecholamine release into the cardiac interstitial fluid in response to ANG II and stellate ganglion stimulation is enhanced in 4-wk MR compared with normals and, moreover, that the interstitial fluid catecholamine release was normalized after chronic treatment with extended release metoprolol succinate (4), a relatively selective ␤ 1 -adrenergic receptor blocker (␤ 1 -RB) (17).…”

Pilot Study to Assess the Influence of β-Blockade on Mitral Regurgitant Volume and Left Ventricular Work in Degenerative Mitral Valve Disease

“…The sympathetic nervous system is activated in severe mitral regurgitation, 24 and in a dog model of mitral regurgitation, ␤ 1 -receptor blockade decreases the adverse effects of excess norepinephrine release on myocardial function. 25 In large clinical trials, ␤-blockers decreased the risk of sudden death, 4,5 an occasional catastrophic event that is known to occur in asymptomatic patients with mitral regurgitation. 26 …”