Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

Abstract

The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonistinduced homologous desensitization. However, recent evidence suggests that excessive adrenergic stimulation may not produce myocardial beta-receptor downregulation unless there is an additional defect in the local norepinephrine (NE) uptake mechanism. To investigate the association between betaadrenoceptor regulation and NE uptake activity, we carried out studies in 30 dogs with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary artery constriction and 23 sham-operated control dogs. We determined NE uptake activity by measuring accumulation of IHINE in tissue slices, NE uptake-i carrier density by V3Hlmazindol binding and beta-adrenoceptor density by VHJdihydroalprenolol binding. Compared with sham-operated dogs, RHF dogs showed a 26% decrease in beta-adrenoceptor density, a 51% reduction in NE uptake activity, and a 57% decrease in NE uptake-i carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-i carrier density. In contrast, neither NE uptake activity nor beta-receptor density in the left ventricle and renal cortex was affected by RHF. Thus, the failing myocardium is associated with an organ-and chamber-specific subnormal neuronal NE uptake. This chamber-specific loss of NE uptake-i carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

Chamber‐specific alterations of noradrenaline uptake (uptake1) in right ventricles of monocrotaline‐treated rats

“…Liang et al (1989) showed similar changes in noradrenaline uptake 1 activity and carrier density in right ventricles of dogs with right heart failure produced by tricuspid avulsion and progressive pulmonary artery constriction. Himura et al (1993) observed under the same conditions a chamber-speci®c loss of noradrenergic nerve terminals, as evidenced by a reduction in catecholaminergic histo¯uorescence-and tyrosine hydroxylase-immunoreactive pro®les.…”

“…[ 3 H]-noradrenaline uptake 1 activity was assessed as described by Liang et al (1989) with minor modi®cations. Right and left ventricular tissue taken from saline-and MCT-treated rats was chopped in modi®ed Krebs-Henseleit solution (mM: NaCl 118, KCl 4.7, CaCl 2 2.5, MgCl 2 0.54, NaHCO 3 25, NaH 2 PO 4 1, glucose 11, EDTA 0.094, ascorbic acid 1.14, nialamide 0.067) into 2506250 mm slices with a McIllwain tissue chopper (Bachhofer, Reutlingen, Germany).…”

“…In patients with primary pulmonary hypertension, who exhibit isolated right ventricular failure, catecholamine stores were depleted only in the failing right ventricle but not in the nonfailing left ventricle . Similarly, chamber-speci®c depletion of myocardial stores were found in rabbits (Yoshikawa et al, 1994), dogs (Liang et al, 1989) and transgenic rats (BoÈ hm et al, 1998).…”

“…In fact, elevated circulating catecholamines (Thomas & Marks, 1978;Cohn et al, 1984), reduced myocardial catecholamine stores (Chidsey & Braunwald, 1966;Anderson et al, 1992), decreased neuronal uptake 1 (Petch & Nayler, 1979) and a reduction in density of noradrenaline carrier sites (BoÈ hm et al, 1995) have been described in the failing human heart. However, in animal models of right-sided and of left-sided heart failure a chamber-speci®c decrease in right or left ventricular neuronal uptake 1 was observed (Liang et al, 1989;Himura et al, 1993;Yoshikawa et al, 1994) indicating that local rather than systemic e ects might be responsible for these changes. In patients with primary pulmonary hypertension, who exhibit isolated right ventricular failure, catecholamine stores were depleted only in the failing right ventricle but not in the nonfailing left ventricle .…”

Heart Rate Modulation by Sympathetic Nerves in Dogs with Heart Failure.

“…Rose et al [40] reported that the neuronal release of NA in the failing heart is actually decreased, and that this decrease is obscured by a concomitant decrease in NA reuptake. This reduction in the efficiency of cardiac NA uptake in heart failure has now been confirmed by numerous other studies [19,28], and might explain many of the abnormalities of the failing heart, such as increased adrenergic drive, desensitization of β-receptors, and depletion of NA stores [8,12]. In turn, depletion of NA stores has been proposed to contribute to decreased cardiac neuronal release of NA and insufficient inotropic support of the failing myocardium [18,23,39].…”