Background. We have shown previously that norepinephrine (NE) uptake activity is reduced in the failing right ventricle of animals with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary constriction. However, it is unknown whether this defect in neuronal NE uptake is related to reduction of noradrenergic nerve terminals or whether these changes also occur in animals with left heart failure (LHIF). It is also unknown whether increased NE release in heart failure contributes to the noradrenergic nerve abnormalities.Methods and Results. We measured myocardial NE content, NE uptake function, and noradrenergic nerve profiles in dogs with either RHF or LHF induced by rapid ventricular pacing. NE uptake activity was

. Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion. Am J Physiol Heart Circ Physiol 284: H1729-H1736, 2003. First published January 23, 2003 10.1152/ajpheart. 00853.2002We reported recently that inhibition of neuronal reuptake of norepinephrine (NE) by desipramine prevented the reduction of sympathetic neurotransmitters in the failing right ventricle of right heart failure animals. In this study, we studied whether desipramine also reduced the sympathetic neurotransmitter loss in animals with left heart failure induced by rapid ventricular pacing (225 beats/min) or after chronic NE infusion (0.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Desipramine was given to the animals for 8 wk beginning with rapid ventricular pacing or NE infusion. Animals receiving no desipramine were studied as controls. We measured myocardial NE content, NE uptake activity, and sympathetic NE, tyrosine hydroxylase, and neuropeptide Y profiles by histofluorescence and immunocytochemical techniques. Effects of desipramine on NE uptake inhibition were evidenced by potentiation of the pressor response to exogenous NE and reduction of myocardial NE uptake activity. Desipramine treatment had no effect in sham or saline control animals but attenuated the reduction of sympathetic neurotransmitter profiles in the left ventricles of animals with rapid cardiac pacing and NE infusion. In contrast, the panneuronal marker protein gene product 9.5 profile was not affected by either rapid pacing or NE infusion, nor was it changed by desipramine treatment in the heart failure animals. The study confirms that excess NE contributes to the reduction of cardiac sympathetic neurotransmitters in heart failure. In addition, it shows that the anatomic integrity of the sympathetic nerves is relatively intact and that the neuronal damaging effect of NE involves the uptake of NE or its metabolites into the sympathetic nerves. neuronal uptake activity; histofluorescence; tyrosine hydroxylase; neuropeptide Y; protein gene product 9.5 EARLIER STUDIES FROM OUR LABORATORY have shown that right heart failure produced by progressive pulmonary constriction and tricuspid valve avulsion is associated with a selective reduction of norepinephrine (NE) reuptake and downregulation of myocardial ␤-adrenoceptor density in the failing right ventricle (33). The sympathetic nerve terminal profiles, as measured by catecholaminergic histofluorescence, and tyrosine hydroxylase and neuropeptide Y immunocytochemistry are also reduced only in the failing right ventricle (27). These findings suggest that the reductions of myocardial ␤-adrenoceptors and sympathetic nerve neurotransmitters in congestive heart failure (CHF) are caused by local mechanisms occurring only in the failing myocardium; the correspondent left ventricle is relatively unaffected despite exposure to the same systemic elevation of plasma catecholamines (33). A similar chamber specific reduction of myocardial ␤-adrenoceptors was reported in humans with right heart fail...

We have shown previously that right heart failure (RHF) in dogs is associated with activated endogenous opiate systems, and that administration of the opioid receptor antagonist, naloxone, increases arterial pressure, cardiac contractile function and organ blood flows. To study whether the cardiovascular effects of naloxone are mediated via the mu- or delta-opioid receptors, we administered ICI-154,129, a delta-receptor antagonist, and naloxonazine, a mu-receptor antagonist, to 10 conscious dogs with RHF on 2 separate days. Like naloxone, ICI-154,129 increased mean aortic pressure, cardiac output, peak positive first derivative of left ventricular pressure, and blood flows to the myocardium, kidneys, splanchnic beds, and skeletal muscle. These changes were associated with increases in plasma epinephrine and norepinephrine. In contrast, naloxonazine had no effects on systemic hemodynamics, regional blood flow distribution, and plasma catecholamines in RHF. These findings suggest that the increased endogenous opioids during heart failure act on the delta-opioid receptors to decrease myocardial mechanical performance and alter regional blood flow distribution. Opioid receptor-blocking agents may exert beneficial cardiovascular effects in heart failure.

Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, ␤-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre-and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [ 3 H]NE, ␤-receptor density by [125 I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial ␤-adrenoceptor density and ␤-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial ␤-adrenoceptor density and ␤-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.congestive heart failure; neuronal norepinephrine uptake; tyrosine hydroxylase; neuropeptide Y MYOCARDIAL ␤-adrenoceptors are reduced in number in the failing right ventricles of both animals subjected to tricuspid avulsion and pulmonary artery constriction (19) and patients with primary pulmonary hypertension (8). The correspondent left ventricle showed no changes in myocardial ␤-adrenoceptor density despite exposure to the same elevation of circulating norepinephrine (NE) as the right ventricle. Other studies (2, 56) have also shown that myocardial ␤-adrenoceptor downregulation occurs only in the ventricles with elevated filling pressures, such as in selective left heart failure produced by aortic regurgitation. In contrast, when biventricular heart failure is produced by doxorubicin (56) or rapid ventricular pacing (15), myocardial ␤-adrenoceptor density is reduced in both ventricles. These findings suggest myocardial ␤-receptor changes are caused by local rather than systemic mechanisms in heart failure. Furthermore, because myocardial ␤-receptor density correlates inversely with cardiac interstitial NE concentration (15), we speculate that ␤-receptor downregulation occurs in the failing ventricle where interstitial NE is increased by either an increase in NE release, a decrease in tissue clearance of NE, or both.Increased cardiac NE spillover in heart failure has been well established (18,38). In addition, work from our laboratories (21, 25, 31...

In order to assess the responses of coronary stenosis to an elevation of myocardial metabolic demand, the effects of pacing induced tachycardia on systemic and coronary haemodynamics were examined during four grades of compliant coronary stenosis which preserved stenosis vasomotility in eight open chest dogs. Grades of the coronary stenosis were defined as trifling, mild, moderate, and severe by pressure gradients of 12(0.5), 19(1.0), 28(1.4) and 37(1.6) mm Hg (mean [SEM]), respectively. Stepwise increases in heart rate (+30, +60 and +90 beats.min-1) decreased the resistance caused by trifling and mild coronary stenosis by 47(11.9) and 26(8.8)%, respectively, with an increase in coronary blood flow and a decrease in pressure gradient across the stenosis. By contrast, the resistance caused by moderate and severe stenosis increased by 96(24.2) and 148(63.2)%, respectively, with a decrease in coronary blood flow and an increase in pressure gradient. During lower grades of coronary stenosis, flow-dependent dilatation of large epicardial coronary arteries reduced the stenosis severity, whereas during higher grades of stenosis, passive narrowing of the stenosed arterial segment due to arteriolar vasodilatation outstripped the flow-dependent stenosis dilator effects and resulted in an intensification of the stenosis.