Involvement of angiotensin II type 1 receptors in interleukin-1β-induced interleukin-6 production in human gingival fibroblasts

The renin-angiotensin system is thought to be involved in inflammatory processes such as periodontitis. However, its precise role is still unclear. Therefore, in the present study the expression of the angiotensin II type 1 receptor (AT1R) was investigated in inflamed human gingival tissue, and the possible involvement of the AT1R in interleukin-1β (IL-1β)-induced interleukin-6 (IL-6) production by cultured human gingival fibroblasts (HGFs) was also studied. Immunohistochemical staining revealed that inflammatory cells and fibroblast-like cells were positive for the AT1R. However, in healthy gingival tissue, AT1R staining was very weak. The levels of AT1R mRNA and AT1R protein increased in HGFs after stimulation with IL-1β. The levels of IL-1β-induced IL6 mRNA and IL-6 protein were significantly reduced in AT1R gene-silenced HGFs compared with control HGFs. The data suggest that the AT1R may be involved in the regulation of gingival inflammation by modulating IL-1β-induced IL-6 production in HGFs.     

Effect of angiotensin-ll blockade on systemic and hepatic haemodynamics and on the renin-angiotensin-aldosterone system in cirrhosis with ascites

We have studied the effect of angiotensin-II blockade with saralasin on the cardiovascular and hepatic hemodynamics and on the renin-angiotensin-aldosterone system in fourteen patients with cirrhosis and ascites. Control measurements showed that most of the patients had a low mean arterial pressure, high plasma volume, normal or high cardiac index, low peripheral resistance and high plasma renin activity and aldosterone concentration. The wedged hepatic venous pressure was increased in each patient and the estimated hepatic blood flow was normal in most of them. Overall, saralasin induced a significant reduction of the mean arterial pressure, cardiac index and peripheral resistance. The decrease of the peripheral resistance was greater than that of the cardiac index. Six of the patients developed a marked reduction of the mean arterial pressure with low doses of saralasin (1--2.5 microgram/kg/min), and they had significantly higher plasma renin activity and lower mean arterial pressure than the remaining eight patients who showed a slight or no hypotensive response in spite of infusing saralasin up to a dose of 10 micrograms/kg/min. Overall, the decrease of the mean arterial pressure correlated directly with the baseline values of plasma renin activity. Angiotensin-II blockade induced a significant reduction of the wedged hepatic venous pressure. The hepatic blood flow did not show any significant change. The decrease of the wedged hepatic venous pressure was directly related to the reduction of the mean arterial pressure and also to the control plasma renin activity. Our study indicates that in most patients with cirrhosis, ascites and high plasma renin activity, arterial pressure is maintained by the effect of endogenous angiotensin II on the peripheral vasculature, and we suggest that a pre-existing arterial hypotension secondary to an arteriolar vasodilatation is the cause of renin release in these patients. Our results also show that angiotensin-II blockade is accompanied by a reduction of the post-sinusoidal hepatic vascular resistance.     

Effect of prostacyclin on renal kallikrein release in man

The aim of this research was to study exogenous prostacyclin effect on urinary kallikrein excretion (UKK) in man, to define whether prostacyclin-induced renin release and/or endogenously released cyclooxygenase products were responsible for prostacyclin-induced enhancement of UKK, to determine furosemide effect on UKK. Prostacyclin was infused in eight healthy men and repeated after propranolol and indomethacin treatment. Prostacyclin caused a dose-dependent increase of UKK. Pretreatment with propranolol and indomethacin did not affect prostacyclin-induced enhancement of UKK, although it reduced absolute values of plasma renin activity. Furosemide increased UKK and simultaneously urinary 6-keto-prostaglandin F1 alpha. We conclude that prostacyclin induces an increase in UKK in a dose-dependent manner; furosemide-induced renal prostacyclin synthesis is temporally related to enhancement of UKK; partial dissociation of UKK from plasma renin activity under propranolol and indomethacin treatment and in response to furosemide might suggest a direct effect of prostacyclin on UKK.     

Physiology of the normal heart

The mechanical events of the cardiac cycle provide the circulation with normal cardiac output and blood pressure. This requires an appropriate venous return, regulation of outflow resistance, a normal myocardial contractile state and heart rate control, together with an adequate supply of oxygenated blood via the coronary circulation. Other neural influences contribute to cardiac regulation, including natriuretic peptides and the renin–angiotensin system. The atria and ventricles are richly supplied with adrenergic nerves that may augment cardiac function, particularly with increased cardiac output during exercise. Inhibitory vagal fibres are largely confined to the sinus and atrioventricular nodes. Exercise causes increased sympathetic outflow, with a decrease in peripheral vascular resistance and increased cardiac output, heart rate, systolic blood pressure and venous return. Regular rhythmic exercise has a training effect, which enhances cardiac performance. This is important for the maintenance of many aspects of cardiovascular health.     

Drugs acting on the heart: antihypertensive drugs

Antihypertensive drugs are used commonly in anaesthesia and intensive care medicine. Patients might require antihypertensive drugs before surgery for the treatment of essential hypertension, pre-eclampsia or, occasionally for conditions such as phaeochromocytoma; during surgery as part of a deliberate hypotensive anaesthetic technique; or to reduce postoperative cardiovascular complications. Here, we discuss the physiology of blood pressure control, the pharmacology of antihypertensive drugs, current guidelines, and practical applications of antihypertensive therapy.     

Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/β-Catenin Signaling

Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor (LEF)-binding sites, and β-catenin induced the binding of LEF-1 to these sites in kidney tubular cells. Overexpression of either β-catenin or different Wnt ligands induced the expression of all RAS genes. Conversely, a small-molecule β-catenin inhibitor ICG-001 abolished RAS induction. In a mouse model of nephropathy induced by adriamycin, either transient therapy or late administration of ICG-001 abolished established proteinuria and kidney lesions. ICG-001 inhibited renal expression of multiple RAS genes in vivo and abolished the expression of other Wnt/β-catenin target genes. Moreover, ICG-001 therapy restored expression of nephrin, podocin, and Wilms’ tumor 1, attenuated interstitial myofibroblast activation, repressed matrix expression, and inhibited renal inflammation and fibrosis. Collectively, these studies identify all RAS genes as novel downstream targets of Wnt/β-catenin. Our results indicate that blockade of Wnt/β-catenin signaling can simultaneously repress multiple RAS genes, thereby leading to the reversal of established proteinuria and kidney injury.     

Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance

Abstract. Renal tubular sodium handling was evaluated in 27 non-azotemic cirrhotic patients with ascites and positive sodium balance and in 17 controls after at least 5 days of a constant sodium intake using the lithium clearance as an index of fluid delivery to the distal tubule. Plasma renin activity and plasma aldos-terone were also evaluated. Sodium fractional excretion, filtered sodium load, absolute sodium distal delivery, lithium fractional excretion and absolute distal sodium reabsorption were significantly lower in cirrhotics than in controls (0.58 ± 0.11 vs. 1.29 ± 0.12%, < 0.001; 12529± 677 vs. 15707±796 μEq min^-1 1.73 m^-2 BSA, <0.005; 2384±135.2 vs. 3685±219.3 μEq min^-1 1.73 m^-2 BSA, < 0.001; 19.5±1.0 vs. 24.2±l.3%, < 0.01; 2299±127 vs. 3485±214 μEq min^-1 1.73 m^-2 BSA, <0.001, respectively). A correlation was found between lithium clearance and sodium clearance only in cirrhotic patients ( r = 0.62; <0.01). Distal sodium reabsorption evaluated as a per cent of filtered sodium load was lower in cirrhotics than in controls (19.1 ±1.0 vs. 22.4±1.2%, <0.05) while distal sodium reabsorption evaluated as a per cent of sodium distal delivery was higher in cirrhotics than in controls (96.7 ± 0.4 vs. 94.4± 0.5%,< 0.005). In both groups a correlation was found between log plasma aldosterone and distal sodium reabsorption evaluated as a per cent of absolute sodium distal delivery ( r = 0.61, <0.01 and r =0.52,<0.05 respectively).
Our study indicates that a decrease in filtered sodium load and an increase in proximal sodium reabsorption play a critical role in the impairment of renal sodium handling in non-azotemic cirrhotic patients with ascites.     

Developmental programing of thirst and sodium appetite

Thirst and sodium appetite are the sensations responsible for the motivated behaviors of water and salt intake, respectively, and both are essential responses for the maintenance of hydromineral homeostasis in animals. These sensations and their related behaviors develop very early in the postnatal period in animals. Many studies have demonstrated several pre- and postnatal stimuli that are responsible for the developmental programing of thirst and sodium appetite and, consequently, the pattern of water and salt intake in adulthood in need-free or need-induced conditions. The literature systematically reports the involvement of dietary changes, hydromineral and cardiovascular challenges, renin–angiotensin system and steroid hormone disturbances, and lifestyle in these developmental factors. Therefore, this review will address how pre- and postnatal challenges can program lifelong thirst and sodium appetite in animals and humans, as well as which neuroendocrine substrates are involved. In addition, the possible epigenetic molecular mechanisms responsible for the developmental programing of drinking behavior, the clinical implications of hydromineral disturbances during pre- and postnatal periods, and the developmental origins of adult hydromineral behavior will be discussed.     

强利尿心钠素对急性心肌缺血犬的心脏及外周循环中肾素-血管紧张素系统的影响

在犬急性缺血性心功能不全模型中，应用冠状动脉（冠脉）内灌注给药的方法观察了两种剂量的强利尿心钠素（ＡＮＰ０．６，０．３μｇｋｇ－１／ｍｉｎ）对外周循环及心脏肾素－血管紧张素（ＲＡＳ）的影响。结果发现，缺血性心功能不全时外周循环及心脏ＲＡＳ均较对照组显著升高；两种剂量均可使循环及心脏ＲＡＳ降低，剂量越大，作用越明显；而且，冠状静脉窦血中激素水平下降幅度及持续时间大于外周静脉（Ｐ＜０．０１）。结论：（１）急性缺血性心功能不全时，外周循环及心脏ＲＡＳ明显激活；（２）冠脉内灌注强利尿心钠素不仅可抑制循环ＲＡＳ，对心脏局部ＲＡＳ也有明显抑制作用。