Atrial natriuretic peptide augments coronary collateral blood flow: A study during coronary angioplasty

Background and hypothesis: In vitro studies have shown that atrial natriuretic peptide (ANP) causes relaxation of pre-constricted blood vessel strips and inhibits the contraction of isolated vessels in response to norepinephrine and angiotensin II. The present study examined the effects of exogenous ANP on the coronary collateral blood flow during angioplasty. Methods: We studied 15 patients undergoing elective balloon angioplasty during the second and third balloon inflations. A Doppler flow guidewire was advanced distal to the lesion and used for the estimation of coronary blood flow velocity. After the second balloon inflation, 25 ng/kg/min of ANP were administered intracoronarily for 8 min. Electrocardiogram, pressure, and flow velocity were recorded immediately before each balloon deflation. Fourteen other patients served as controls and received normal saline infusion. Results: Velocity time integral increased from 65 ± 40 to 79 ± 46 mm (p < 0.05) during the third balloon inflation, whereas ST deviation decreased from 1.3 ± 0.9 to 0.7 ± 1.0 mV (p< 0.05). These variables did not change in the control group during the two tested balloon inflations. Conclusion: Exogenous ANP augments coronary collateral blood flow and ameliorates myocardial ischemia during angioplasty.     

GABA inhibition of immortalized gonadotropin-releasing hormone neuronal excitability involves GABA(A) receptors negatively coupled to cyclic adenosine monophosphate formation

γ-Aminobutyric acid (GABA) has been implicated in the regulation of reproduction, particularly in the developmental modulation of gonadotropin-releasing hormone (GnRH) secretion. GnRH neurons are innervated by GABA-containing processes, and the administration of GABA stimulates and inhibits GnRH secretion in vivo and in vitro. We have previously shown that GABA can exert both of these actions in sequence, by acting directly on immortalized GnRH neurons. While the stimulation is the result of a GABA_A receptor-mediated depolarization of the plasma membrane, the mechanism involved in the delayed inhibition is the subject of the present investigation. GABA (1 nM-10 μM) decreased the intracellular concentration of cyclic adenosine monophosphate (cAMP) in a dose- and time-dependent fashion. This effect was blocked by bicuculline and mimicked by muscimol but not by baclofen. To analyze the effect of GABA on cellular excitability, we used fura-2 loaded GT1-7 cells. Activation of voltage-sensitive calcium channels by high K⁺-induced depolarization (35 mM) increased [Ca²⁺]_i. GABA (10μM) and muscimol (10 μM) reduced the amplitude of K⁺-induced [Ca²⁺]_i transients. This inhibition was blocked by forskolin (20μM) or 8-Br-cAMP (1 mM). Altogether, these results show that GABA_A receptors mediate a sustained inhibitory effect of GABA on GnRH neurons, and suggest the involvement of the cAMP pathway decreasing cellular excitability.     

Exhaled nitric oxide and asthma in young children

Exhaled nitric oxide (eNO) has been used to diagnose asthma in adults and children using either the slow vital capacity method (SVCm) or, in younger children, the tidal breathing method (TBm). Adenosine 5'-monophosphate (AMP) challenge also has been found to be a sensitive and specific test for the diagnosis of asthma. In the present study, we used the AMP provocation concentration that caused wheezing (PCW) to confirm the diagnosis of asthma (PCW < or = 200 mg/mL). We studied 36 children (2-7 years) with mild intermittent asthma, 13 children (3-7 years) with moderate persistent asthma treated with inhaled steroids, 20 nonasthmatic children (2-7 years) with chronic cough and recurrent pneumonia, and 15 healthy children (4-6 years). Expired gas was collected in collection bags by the TBm, and eNO was measured. We evaluated the efficacy of eNO values in diagnosing asthma. The mean eNO level of the mild intermittent asthmatic children (5.6 +/- 0.4 ppb) not receiving inhaled corticosteroids was significantly higher (ANOVA P < 0.0001) than that of the moderate persistent asthmatics who were treated with inhaled steroids, the nonasthmatic children with chronic cough, and the group of healthy children (3.7 +/- 0.6 ppb, P < 0.05; 3.2 +/- 0.3 ppb, P < 0.001; 2.2 +/- 0.2 ppb, P < 0.001, respectively). The points of intersection for sensitivity and specificity curves of eNO to differentiate mild intermittent asthmatics from nonasthmatic children with chronic cough and from healthy children were 77% and 88% for eNO values of 3.8 ppb and 2.9 ppb, respectively. We conclude that eNO collected by the TBm can differentiate steroid-naive young children with intermittent asthma from healthy children, from nonasthmatic children with chronic cough, and from asthmatic children treated with inhaled steroids.     

Exhaled nitric oxide is age-dependent in asthma

We determined whether the exhaled nitric oxide (eNO) level in asthmatics is age-dependent. Eighty-seven asthmatic patients aged 2-41 years were studied. Hyperreactivity to adenosine 5'-monophosphate (AMP) was used to confirm asthma (相似文献   

Adenine pool catabolism in the ischemic, the calcium-depleted ischemic, and the substrate free anoxic isolated rat heart: Relationship to contracture development

Metabolic changes in the myocardial adenine and hypoxanthine pools of isolated rat hearts subjected to global ischemia, hypocalcemic global ischemia, and global substrate-free anoxia were compared. At timed intervals between 0 and 60 min separate aliquots of extracts of the ventricles were used to determine either tissue pH, or the components of the adenine pool and their catabolites by reverse phase high performance liquid chromatography (HPLC). The coronary perfusate draining from anoxically perfused hearts was collected over perchloric acid, neutralised and chromatographed by HPLC. The development of left ventricular resting tension (contracture) was recorded in the three groups of hearts. After 60 min ischemia the major catabolites, (AMP, inosine and hypoxanthine) comprised 70% of the total pool (11, 7 and 4 mumol/g dry wt, respectively). After the same period of anoxia 50% of the total pool, comprising adenosine, inosine, hypoxanthine and uric acid in approximately equal proportions, was recovered from the coronary perfusate. The major products remaining in the tissue were IMP and, to a lesser extent AMP (8 and 5 mumol/g dry wt, respectively). Left ventricular contracture developed at different rates in the three groups of hearts but always correlated closely with the maximum rate of adenine pool catabolism. The loss of components from the tissue and the divergence in pathway from adenosine to IMP production which occurs during anoxic perfusion should possibly be considered when assessing the biochemical events occurring in regionally ischemic heart muscle with significant residual flow.     

Epac信号分子与哮喘关系研究进展

支气管哮喘是临床常见的气道慢性炎症性疾病,以气道高反应性、慢性气道炎症和气道重塑为病理生理特征,其发病机制目前尚未完全阐明。环磷酸腺苷(cAMP)是体内重要的第二信使,参与调控机体新陈代谢、细胞钙信号传导、细胞生长与分化、凋亡等多种病理生理过程。长期以来,蛋白激酶A (PKA)被认为是介导cAMP生物学效应的唯一下游信号分子。但新近发现的新型cAMP靶分子——cAMP直接激活的交换蛋白(Epac)的发现打破了这一说法。大量研究证实,Epac可单独或协同PKA介导cAMP的多种生物学效应。本文就Epac在支气管哮喘发病中的作用及其可能机制作一综述,为寻找哮喘治疗新靶点奠定基础。     

腺苷酸活化蛋白激酶途径与肿瘤的研究进展

腺苷酸活化蛋白激酶(AMPK)是哺乳动物细胞中高度保守的蛋白质,是细胞的重要的代谢感受器。哺乳动物雷帕霉素靶蛋白(m TOR)信号通路,是一种不典型的丝/苏氨酸激酶,在进化中也具有高度保守性,主要通过调控蛋白合成来调节细胞的生长,m TOR激酶通过多种信号通路来实现对细胞生长的调节作用,其中营养信号激活通路为细胞外的氨基酸通路LKB1-AMPK途径。二甲双胍(LKB1/AMPK的激活剂),可抑制m TOR的活性,从而可以应用于多种肿瘤的治疗,目前研究表明AMPK信号通路及其相关的信号通路与多种肿瘤的发生、发展有关。