β_3肾上腺素受体对前蛋白转化酶枯草溶菌素9和低密度脂蛋白受体表达的影响

目的观察激动β3肾上腺素受体(β3-AR)对载脂蛋白E基因敲除(apoE-/-)老年高脂小鼠血脂、肝脏前蛋白转化酶枯草溶菌素9(PCSK9)和LDL受体(LDLR)表达水平的影响。方法选择10周龄雄性C57BL/6小鼠10只(A组)。apoE-/-小鼠40只给予高脂饲料饲养至36周龄,随机分为4组,分别为高脂模型组(B组)、阿托伐他汀阳性药物对照组(C组)、β3-AR激动剂小剂量组(D组)、β3-AR激动剂大剂量组(E组),每组10只,共干预12周。采用Beckman CX7全自动生化分析仪,检测血清TC、TG、VLDL/LDL-C、HDL-C水平,采用Western blot测定肝脏PCSK9和LDLR表达水平。结果与B组比较,C组、D组和E组TC、VLDL/LDL-C明显下降,C组、B组、D组LDLR水平明显上调,C组PCSK9水平明显上调(P<0.05,P<0.01);与C组比较,D组和E组TG、PCSK9水平明显下降,D组LDLR水平明显下降,HDL-C水平明显升高,差异有统计学意义(P<0.05,P<0.01)。结论β3-AR调脂、升高LDLR、降低PCSK9表达水平是其抗动脉粥样硬化的多重作用机制之一。     

激动β_3肾上腺素受体对载脂蛋白E基因敲除小鼠肺脏血管紧张素受体表达的影响

目的探讨激动β3肾上腺素受体(β3-AR)对载脂蛋白E基因敲除(apoE-/-)老年高脂小鼠肺脏血管紧张素受体(ATR)表达的影响。方法野生型C57BL/6J小鼠10只作为对照组,apoE-/-老年高脂小鼠40只随机分为高脂模型组、β3-AR激动剂小剂量组(小剂量组)、β3-AR激动剂大剂量组(大剂量组)和β3-AR拮抗剂组(拮抗剂组),每组10只。给予高脂饮食饲养至36周龄后分别给予药物干预12周。采用全自动生化分析仪检测TC和VLDL/LDL-C水平,实时定量PCR或Western blot测定肺组织β3-AR、AT1R和AT2R的mRNA及蛋白表达水平。结果与高脂模型组比较,小剂量组、大剂量组TC和VLDL/LDL-C水平明显降低[(18.27±1.30)mmol/L,(17.06±1.50)mmol/L vs(22.20±1.29)mmol/L和(14.31±0.31)mmol/L,(12.78±0.55)mmol/L vs(19.41±0.40)mmol/L,P<0.01]。与对照组比较,高脂模型组和拮抗剂组AT1R mRNA和AT1R蛋白水平明显升高,AT2R mRNA、β3-AR蛋白水平明显降低(P<0.05)。与高脂模型组比较,小剂量组和大剂量组AT1R表达下调,AT2R和β3-AR表达上调(P<0.05,P<0.01)。结论β3-AR激动剂在改善apoE-/-老年高脂小鼠血脂代谢紊乱的同时,影响了肺组织β3-AR和ATR各亚型表达,这种受体间交互作用可能与维持高脂血症条件下肺脏的正常功能有关。     

Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes

Anabolic and catabolic signaling oppose one another in adipose tissue to maintain cellular and organismal homeostasis, but these pathways are often dysregulated in metabolic disorders. Although it has long been established that stimulation of the β-adrenergic receptor inhibits insulin-stimulated glucose uptake in adipocytes, the mechanism has remained unclear. Here we report that β-adrenergic–mediated inhibition of glucose uptake requires lipolysis. We also show that lipolysis suppresses glucose uptake by inhibiting the mammalian target of rapamycin (mTOR) complexes 1 and 2 through complex dissociation. In addition, we show that products of lipolysis inhibit mTOR through complex dissociation in vitro. These findings reveal a previously unrecognized intracellular signaling mechanism whereby lipolysis blocks the phosphoinositide 3-kinase–Akt–mTOR pathway, resulting in decreased glucose uptake. This previously unidentified mechanism of mTOR regulation likely contributes to the development of insulin resistance.Adipose tissue plays an essential role in maintaining whole-body energy homeostasis by storing or releasing nutrients. This balance is controlled by opposing signaling pathways where anabolic processes are activated by insulin (INS) and catabolic actions are activated by catecholamines. An important unanswered question in adipose biology is how catecholamine-induced β-adrenergic signaling opposes insulin-stimulated glucose uptake (1–6). Surprisingly, the underlying mechanism for this well-established physiological response in adipocytes is still unknown.When nutrients are plentiful, insulin is released by the pancreas and stimulates the absorption of glucose and fatty acids in adipose tissue, where they are packaged and stored as triacylglycerol (TAG) in cellular lipid droplets. Insulin signaling in adipocytes is mediated by the phosphoinositide 3-kinase (PI3K)–Akt–mTOR pathway. mTOR is a highly conserved serine/threonine protein kinase that functions in either of two distinct multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is defined primarily by the association of mTOR with raptor, whereas mTORC2 includes mTOR with rictor (7). Importantly, mTORC2 phosphorylation of Akt at S473 is required for Akt activity on AS160, which is necessary for glucose uptake in response to insulin (8–11). Of note, for both mTORC1 and mTORC2, the integrity of these protein complexes is essential for kinase substrate specificity and proper signaling (12, 13).During periods of fasting or stress, catecholamines are released by the sympathetic nervous system to activate lipolysis. Stimulation of the β-adrenergic receptor on adipocytes activates adenylyl cyclase (AC), leading to elevated cAMP and protein kinase A (PKA) activity. PKA initiates lipolysis by direct phosphorylation of hormone-sensitive lipase (HSL) and perilipin (14–16) and indirect activation of adipose triglyceride lipase (ATGL) (17–19). Lipolysis involves hydrolysis of TAG stored in the lipid droplet to produce diacylglycerol (DAG), monoacylglycerol (MAG), fatty acids, and glycerol. These lipolytic products are important energy substrates that can act as precursors for other lipids and impact cellular signaling. However, their potential role as signaling molecules has been underappreciated (20).In this study, we provide insight into the mechanisms that link β-adrenergic stimulation to the inhibition of insulin-stimulated glucose uptake. Namely, we show that activation of lipolysis is crucial. Moreover, we find that products of lipolysis themselves cause mTOR inhibition by complex dissociation, which inhibits glucose uptake in adipocytes. This mechanism of mTOR regulation (i.e., by complex dissociation) has major implications in the regulation of cellular metabolism and likely contributes to stress-induced hyperglycemia and obesity-induced insulin resistance.     

Noradrenergic Function in Suicide

Although abnormalities in serotonergic function have been the major focus of studies on suicidal behavior, several studies indicate that abnormalities of noradrenergic function may also be involved in the pathophysiology of suicide. In this paper, we have reviewed some of the noradrenergic studies in sucide, including studies of the biosynthetic enzyme for norepinephrine, tyrosine hydroxylase (TH), the receptors for norepinephrine, α- and β-adrenergic receptors, as well as the signaling cascades linked to β-adrenergic receptors. In general, these studies indicate that the protein expression of TH, as well as α₂- and β₂-adrenergic receptors, is increased in the postmortem brain of suicide victims. More studies are needed in order to examine extensively the role of noradrenergic function in suicidal behavior.     

Perioperative Cardiac Risk Stratification and Modification in Abdominal Aortic Aneurysm Repair

Cardiovascular complications are important causes of morbidity and mortality following vascular surgery. Adequate preoperative risk assessment and perioperative management may modify postoperative mortality and morbidity and improve long-term prognosis. The objective of this review is to examine the present day knowledge regarding the preoperative evaluation and perioperative management of patients undergoing noncardiac surgery, focusing specifically on abdominal aortic aneurysm (AAA) repair.

Clinical markers combined with ECG and surgical risk assessment can effectively divide patients in a truly low-risk, intermediate and high-risk population. Low-risk patients can probably be operated on without additional cardiac testing. Notably, due to the surgical risk, AAA patients are never low-risk patients. Intermediate-risk and high-risk patients are referred for cardiac testing to exclude extensive stress induced myocardial ischemia, as beta-blockers provide insufficient myocardial protection in this case and preoperative coronary revascularization might be considered. Whether patients at intermediate risk without ischemic heart disease should be treated with statins and/or beta-blockers is still controversial. In high-risk patients, it is strongly advised to administer beta-blockers with heart rate determined dose adjustment, while the effects of preoperative revascularization remain subject to debate.     

Salivary secretion effects of the antipsychotic drug olanzapine in an animal model

Oral Diseases (2012) Objective: Olanzapine, introduced as an alternative to clozapine in schizophrenia therapy, is thought to display a receptor affinity similar to that of clozapine. Antipsychotics are well‐known xerogenic drugs. However, clozapine exerts both antagonistic and agonistic salivary effects (‘clozapine‐induced sialorrhea’), the latter probably via muscarinic M1 type of receptor. We hypothesise that olanzapine also has dual salivary effects. Material and methods: Effects of intravenous olanzapine were examined in rats, including those subjected to chronic preganglionic parasympathetic denervation (submandibular glands) or combined postganglionic parasympathetic and sympathetic denervation (parotid glands). Secretion was evoked reflexly, and by intravenous methacholine and the tachykinin substance P. Results: At 0.01–1 mg kg^?1, olanzapine dose dependently reduced secretion in response to methacholine or reflex stimulus but not that to substance P. At 10 mg kg^?1, olanzapine evoked a long‐lasting secretion, independent of the autonomic innervation as well as of α‐ and β‐adrenergic receptors and muscarinic receptors. The secretion was reduced, but not abolished, by a substance P receptor antagonist. Conclusions: Like clozapine, olanzapine evoked secretion. The response to olanzapine was greater and, in contrast to clozapine, involved non‐traditional gland receptors (such as substance P receptors). The findings imply that olanzapine plays an excitatory role via tachykinin receptors in humans.     

Focal initiation of sustained and nonsustained ventricular tachycardia in a canine model of ischemic cardiomyopathy

Focal Initiation of Ventricular Tachycardia in Ischemic HF. Introduction: To define the role of focal and reentrant mechanisms underlying nonsustained (NSVT) and sustained ventricular tachycardia (SuVT) induced by programmed stimulation, 3‐dimensional cardiac mapping was performed in 8 dogs with heart failure (HF) created by multiple intracoronary microsphere embolizations. Methods and Results: Continuous recording from 232 intramural sites throughout the left and right ventricles and the interventricular septum was performed during programmed stimulation in the absence and presence of isoproterenol (Iso, 0.1 μg/kg/min). Sinus beats and the last extrastimuli preceding induced VT conducted with total activation times (TA) of 51 ± 10 and 111 ± 8 milliseconds, respectively, that did not change during Iso infusion (47 ± 4 and 109 ± 5 milliseconds, P = NS). NSVT was induced in 75% of HF dogs; SuVT was induced in 38%. In all cases, initiation and maintenance of SuVT and NSVT arose by a focal mechanism. Compared to NSVT, SuVT had a shorter coupling interval (CI; 150 ± 7 vs 186 ± 16, P < 0.05) and a predilection for certain critical subendocardial initiation sites (that were initiation sites for only 29% of NSVT beats). After 21–30 beats, acceleration of SuVT by a focal mechanism to a CI less than 120 milliseconds led to functional conduction delay (TA increasing from 111 ± 3 to 137 ± 3 milliseconds, P < 0.0001), intramural reentry, and transition to ventricular fibrillation. Conclusions: Thus, initiation of SuVT in a model of ischemic HF is due to a focal mechanism. However, subsequent acceleration of this focal mechanism can ultimately lead to functional conduction delay and development of intramural reentry. (J Cardiovasc Electrophysiol, Vol. 23, pp. 543‐552, May 2012)