Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.

Kiuchi, Kaname; Shannon, Richard P.; Komamura, Kazuo; Cohen, David J.; Bianchi, Clementina; Homcy, Charles J.; Vatner, Stephen F.; Vatner, Dorothy E.

doi:10.1172/jci116312

Cited by 165 publications

(85 citation statements)

References 48 publications

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“…From these data, in contrast to ␤ 1 -ARs, one would not expect a decrease in the expression of cardiac ␤ 2 -ARs in diabetic rats. As a matter of fact, in paced pigs and dogs, ␤ 2 -AR protein and mRNA levels were found to be unchanged despite the reduced number of ␤ 1 -ARs and mRNA content (34,35). Therefore, the decrease that we observed in ␤ 2 -AR protein levels in diabetic rat hearts is somewhat surprising.…”

Section: Discussionmentioning

confidence: 61%

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

et al. 2001

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Diabetic hearts exhibit decreased responsiveness to stimulation by ␤-adrenoreceptor (␤-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of ␤-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to ␤ 1 -AR agonist stimulation, but not to ␤ 2 -AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac ␤ 1 -, ␤ 2 -, and ␤ 3 -ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that ␤ 1 -AR mRNA and protein levels decreased by 34.9 ± 5.8 and 44.4 ± 5.8%, respectively, in 14 week-STZtreated diabetic rat hearts when compared with agematched controls. On the other hand, mRNA levels encoding ␤ 2 -and ␤ 3 -ARs increased by 72.5 ± 16.6 and 97.3 ± 26.1%, respectively. Although the latter translated into a proportional increase in ␤ 3 -AR protein levels (100.0 ± 17.0%), ␤ 2 -AR protein levels decreased to 82.6 ± 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored ␤ 1 -AR mRNA and protein levels to 60.1 ± 8.4 and 83.2 ± 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding ␤ 2 -and ␤ 3 -ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of ␤-AR agonists may be due to a decrease in ␤ 1 -AR and an increase ␤ 3 -AR expression. Diabetes 50: [455][456][457][458][459][460][461] 2001

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Section: Discussionmentioning

confidence: 61%

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

et al. 2001

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“…This may limit increases in ventricular contractility (10). Furthermore, a decreased density of ␤ 1 -receptors has been shown previously in canine pacing-induced failing hearts, which in turn can lead to subsensitivity of ␤-adrenergic pathways and reductions in ␤-agonist-stimulated muscle contractions (4,19,51). Thus the sympathetic pathways the MMR uses in normal conditions are altered in HF, in addition to intrinsic alteration in the myocardial cells and interstitial tissue (myocardial cell death, hypertrophy) (13).…”

Section: Discussionmentioning

confidence: 83%

“…After completion of the control experiments, congestive heart failure was induced via rapid ventricular pacing. This technique has been widely accepted to create chronic model of LV failure and has been utilized by others and us previously (11,12,19,37). Briefly, the right ventricular pacing electrodes were connected to a pacemaker set at 240 beats/min for ϳ30 days, and the experiments were repeated.…”

Section: Methodsmentioning

confidence: 99%

Heart failure attenuates muscle metaboreflex control of ventricular contractility during dynamic exercise

Sala‐Mercado¹,

Hammond²,

Kim³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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DS. Heart failure attenuates muscle metaboreflex control of ventricular contractility during dynamic exercise. Am J Physiol Heart Circ Physiol 292: H2159 -H2166, 2007. First published December 22, 2006; doi:10.1152/ajpheart.01240.2006.-Underperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex (MMR). In normal dogs during mild exercise, MMR activation causes large increases in cardiac output (CO) and mean arterial pressure (MAP); however, in heart failure (HF) although MAP increases, the rise in CO is virtually abolished, which may be due to an impaired ability to increase left ventricular contractility (LVC). The objective of the present study was to determine whether the increases in LVC seen with MMR activation during dynamic exercise in normal animals are abolished in HF. Conscious dogs were chronically instrumented to measure CO, MAP, and left ventricular (LV) pressure and volume. LVC was calculated from pressure-volume loop analysis [LV maximal elastance (E max) and preload-recruitable stroke work (PRSW)] at rest and during mild and moderate exercise under free-flow conditions and with MMR activation (via partial occlusion of hindlimb blood flow) before and after rapid ventricular pacing-induced HF. In control experiments, MMR activation at both workloads [mild exercise (3.2 km/h) and moderate exercise (6.4 km/h at 10% grade)] significantly increased CO, E max, and PRSW. In contrast, after HF was induced, CO, Emax, and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, E max and PRSW did not change. In addition, MMR activation caused no significant change in CO, E max, or PRSW at either workload. We conclude that MMR causes large increases in LVC in normal animals but that this ability is abolished in HF. pressor response; elastance; preload recruitable stroke work WHEN EXERCISING SKELETAL MUSCLE does not receive sufficient blood flow to meet the ongoing metabolic demands, by-products of metabolism such as lactic acid, H ϩ , adenosine, potassium, diprotonated phosphate, and arachidonic acid products, among others, accumulate within the muscle and stimulate group III and IV afferent neurons, which evokes a reflex response known as the muscle metaboreflex (MMR). This reflex response consists of increases in efferent sympathetic nerve activity (SNA) and mean arterial pressure (MAP) (1, 3, 11, 17, 18, 24, 31-35, 39, 40, 43, 46, 47, 52, 53). In addition, MMR activation causes increases in cardiac output (CO), heart rate (HR), and plasma levels of vasoactive hormones and produces vasoconstriction in the renal and the nonischemic active skeletal muscle vasculature to partially restore arterial O 2 delivery and blood flow to the hypoperfused muscles (25,33,36). The rise in CO likely results from increases in ventricular performance, HR, and central blood volume mobilization (32,42,43). By this means the MMR-induced increases in ventricular performance act to slightly increase or sustain stroke volume (SV) despite decreas...

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“…[2][3][4][5] As a consequence, depletion of cardiac NE stores and chronic overstimulation of adrenergic receptors leads to worsening of heart failure and sudden death, as well as to profound alterations of postreceptor signal coupling and cardiac remodeling. 6,7 Whereas some studies reported that an impaired NE reuptake was the result of a reduced NET density on cardiac sympathetic nerve endings, 5 other studies demonstrated a loss of sympathetic nerve endings, which occurred mainly in advanced stages of experimental CHF. 8 Likewise, it has been implied that an impaired NE reuptake precedes a loss of sympathetic nerves.…”

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confidence: 99%

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

et al. 2006

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Abstract-An impairment of cardiac norepinephrine reuptake through the neuronal norepinephrine transporter promotes depletion of cardiac norepinephrine stores and local cardiac sympathetic activation in heart failure. Nerve growth factor regulates differentiation and survival of adult sympathetic cells and is decreased in failing hearts. We hypothesized that injection of nerve growth factor into stellate ganglia normalizes cardiac norepinephrine homeostasis in experimental heart failure. Rats with transverse aortic constriction characterized by heart failure, depleted cardiac norepinephrine stores, and impaired cardiac norepinephrine reuptake were used as an experimental model. Nerve growth factor (20 g) or saline was directly injected into left stellate ganglia 4 weeks after transverse aortic constriction. Thirty-two hours after injection, determinants of cardiac norepinephrine homeostasis were measured. As compared with saline, nerve growth factor refilled depleted cardiac norepinephrine stores and improved cardiac [ 3 H]-norepinephrine uptake into isolated perfused hearts of transverse aortic constricted rats. In addition, pharmacological blockade of the norepinephrine transporter led to a higher increase in the overflow of endogenous norepinephrine from hearts of nerve growth factor-injected than saline-injected transverse aortic constricted rats. Norepinephrine transporter mRNA levels and the density of cardiac sympathetic nerves were not changed. Thirty-two hours after nerve growth factor injection, echocardiography revealed an increase in fractional shortening as compared with 2 days before injection. In conclusion, nerve growth factor attenuates local cardiac sympathetic overdrive of hypertrophic hearts by improving cardiac norepinephrine reuptake and might represent a novel therapeutic principle in the treatment of heart failure.

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Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.

Cited by 165 publications

References 48 publications

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

Heart failure attenuates muscle metaboreflex control of ventricular contractility during dynamic exercise

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

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