The influence of diabetes on cardiac β-adrenoceptor subtypes

Department of Pharmacology, Faculty of Pharmacy, University of Ankara, Tandogan, Ankara, 06100, Turkey.
Heart Failure Reviews (Impact Factor: 3.79). 04/2007; 12(1):58-65. DOI: 10.1007/s10741-007-9005-6
Source: PubMed


Despite the significant developments in the treatment of diabetes mellitus, diabetic patients still continue to suffer from cardiac complications. The increase of cardiac adrenergic drive may ultimately contribute to the development and progression of diabetic cardiomyopathy. beta-Adrenoceptors play an important role in the regulation of heart function. However, responsiveness of diabetic heart to beta-adrenoceptor agonist stimulation is diminished. The chronotropic responses mediated by beta(1)-subtype, which is mainly responsible for cardiac effects of catecholamines are decreased in the atria of diabetic rats. The expression of cardiac beta(1)-subtype is significantly decreased in diabetic rats as well. beta(2)-Adrenoceptors also increase cardiac function. Although the expression of this subtype is slightly decreased in diabetic rat hearts, beta(2)-mediated chronotropic responses are preserved. On the other hand, functional beta(3)-adrenoceptor subtype was characterized in human heart. Interestingly, stimulation of cardiac beta(3)-adrenoceptors, on the contrary of beta(1)- and beta(2)-subtypes, mediates negative inotropic effect in human ventricular muscle. Cardiac beta(3)-adrenoceptors are upregulated in experimental diabetes as well as in human heart failure. These findings suggest that each beta-adrenoceptor subtype may play an important role in the pathophysiology of diabetes-induced heart disease. However, it is still not known whether the changes in the expression and/or responsiveness of beta-adrenoceptors are adaptive or maladaptive. Therefore, this review outlines the potential roles of these receptor subtypes in cardiac pathologies of diabetes.

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    • "Many neurotransmitters and neurohormones also exert regulatory effects on the biochemical and physiological processes in the CNS and in the periphery via ACSS. It was shown by us and the other authors that the changes in ACSS activity in diabetic tissues correlate positively with severity and duration of DM2 [30] [31] [32] [33] [34] [35] [36]. Therefore, the study of ACSS is one of the most promising approaches to be used in the case of DM2 for identification of functional abnormalities in the CNS and the periphery as well as for monitoring dysfunctions in the nervous, cardiovascular, and other systems and for evaluation of the effectiveness of antidiabetic therapy [13] [31] [32] [37]. "
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    ABSTRACT: In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 g/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation by β-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.
    Full-text · Article · Jun 2015 · International Journal of Endocrinology
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    • "Although contractile function at rest was not altered by diabetes, the relaxation of the right atrial diabetic muscles was impaired over the entire range of myocardial stretch, and both the inotropic and lusitropic responses to β-adrenergic stimulation were completely absent in cardiac muscles from DM patients. A reduced but still responsive myocardium to β-adrenergic stimulation has been observed in many diabetic animal models [33,34] and has been related to reduced expression levels of β1-adrenoreceptors [35]. Surprisingly, cardiac muscles from our cohort of diabetic patients failed to respond to the β-adrenergic stimulation, even at very high (10-5 M) concentrations, which would indicate a lack of contractile reserve even in these patients with normal resting contractile function. "
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    ABSTRACT: Diastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, however the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function. Right atrial appendages from patients with type 2 diabetes mellitus (DM, n = 20) and non-diabetic patients (non-DM, n = 36), all with preserved ejection fraction and undergoing coronary artery bypass grafting (CABG), were collected. From appendages, small cardiac muscles, trabeculae, were isolated to measure basal and beta-adrenergic stimulated myocardial function. Expression levels of calcium-handling proteins, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban (PLB), and of beta1-adrenoreceptors were determined in tissue samples by Western blot. Collagen deposition was determined by picro-sirius red staining. In trabeculae from diabetic samples, contractile function was preserved, but relaxation was prolonged (Tau: 74 +/- 13 ms vs. 93 +/- 16 ms, non-DM vs. DM, p = 0.03). The expression of SERCA2a was increased in diabetic myocardial tissue (0.75 +/- 0.09 vs. 1.23 +/- 0.15, non-DM vs. DM, p = 0.007), whereas its endogenous inhibitor PLB was reduced (2.21 +/- 0.45 vs. 0.42 +/- 0.11, non-DM vs. DM, p = 0.01). Collagen deposition was increased in diabetic samples. Moreover, trabeculae from diabetic patients were unresponsive to beta-adrenergic stimulation, despite no change in beta1-adrenoreceptor expression levels. Human type 2 diabetic atrial myocardium showed increased fibrosis without systolic dysfunction but with impaired relaxation, especially during beta-adrenergic challenge. Interestingly, changes in calcium-handling protein expression suggests accelerated active calcium re-uptake, thus improved relaxation, indicating a compensatory calcium-handling mechanism in diabetes in an attempt to maintain diastolic function at rest despite impaired relaxation in the diabetic fibrotic atrial myocardium. Our study addresses important aspects of the underlying mechanisms of diabetes-associated diastolic dysfunction, which is crucial to developing new therapeutic treatments.
    Full-text · Article · Apr 2014 · Cardiovascular Diabetology
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    • "Plasma epinephrine and norepinephrine are also elevated in IUGR fetal sheep where placental insufficiency is the known etiology [26] [27] [28]. Catecholamines act via the G-protein coupled receptors, Adrα and Adrβ [29] [30], which express multiple subtypes (α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, and β3) with distinct physiological and pharmacological properties [31]. Receptor expression patterns determine how tissues respond to catecholamines, and skeletal muscle predominantly expresses Adrβ1 and Adrβ2 subtypes, but Adrβ3 and Adrα subtypes are also present. "
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    ABSTRACT: Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR), skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization.
    Full-text · Article · Jul 2012 · Journal of pregnancy
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