Search

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter‐regulatory or non‐canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre‐clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type‐2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro‐inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang‐(1–7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G‐protein‐coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher‐order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Aim: The kaliuretic action of the renin–angiotensin–aldosterone system (RAAS) is well established as highlighted by hyperkalemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study addresses the involvement of intrarenal RAAS in K+ homeostasis with emphasis on locally generated renin within the collecting duct (CD). Methods: Wild‐type (Floxed) and CD‐specific deletion of renin (CD renin KO) mice were treated for 7 days with a high K+ (HK) diet to investigate the role of CD renin in kaliuresis regulation and further define the underlying mechanism with emphasis on analysis of intrarenal aldosterone biosynthesis. Results: In floxed mice, renin levels were elevated in the renal medulla and urine following a 1‐week HK diet, indicating activation of the intrarenal renin. CD renin KO mice had blunted HK‐induced intrarenal renin response and developed impaired kaliuresis and elevated plasma K+ level (4.45 ± 0.14 vs. 3.89 ± 0.04 mM, p < 0.01). In parallel, HK‐induced intrarenal aldosterone and CYP11B2 expression along with expression of renal outer medullary K+ channel (ROMK), calcium‐activated potassium channel subunit alpha‐1 (α‐BK), α‐Na+‐K+‐ATPase, and epithelial sodium channel (β‐ENaC and cleaved‐γ‐ENaC) expression were all significantly blunted in CD renin KO mice in contrast to the unaltered responses of plasma aldosterone and adrenal CYP11B2. Conclusion: Taken together, these results support a kaliuretic action of CD renin during HK intake. [ABSTRACT FROM AUTHOR]

Aim: The use of calcineurin inhibitors such as cyclosporine A (CsA) for immunosuppression after solid organ transplantation is commonly limited by renal side effects. CsA‐induced deterioration of glomerular filtration rate and sodium retention may be related to juxtaglomerular dysregulation as a result of suppressed cyclooxygenase 2 (COX‐2) and stimulated renin biosynthesis. We tested whether CsA‐induced COX‐2 suppression is caused by hyperactive renin‐angiotensin system (RAS) and whether RAS inhibition may alleviate the related side effects. Methods: Rats received CsA, the RAS inhibitor candesartan, or the COX‐2 inhibitor celecoxib acutely (3 days) or chronically (3 weeks). Molecular pathways mediating effects of CsA and RAS on COX‐2 were studied in cultured macula densa cells. Results: Pharmacological or siRNA‐mediated calcineurin inhibition in cultured cells enhanced COX‐2 expression via p38 mitogen‐activated protein kinase and NF‐kB signalling, whereas angiotensin II abolished these effects. Acute and chronic CsA administration to rats led to RAS activation along with reduced cortical COX‐2 expression, creatinine clearance and fractional sodium excretion. Evaluation of major distal salt transporters, NKCC2 and NCC, showed increased levels of their activating phosphorylation upon CsA. Concomitant candesartan treatment blunted these effects acutely and completely normalized the COX‐2 expression and renal functional parameters at long term. Celecoxib prevented the candesartan‐induced improvements of creatinine clearance and sodium excretion. Conclusion: Suppression of juxtaglomerular COX‐2 upon CsA results from RAS activation, which overrides the cell‐autonomous, COX‐2‐stimulatory effects of calcineurin inhibition. Angiotensin II antagonism alleviates CsA nephrotoxicity via the COX‐2‐dependent normalization of creatinine clearance and sodium excretion. [ABSTRACT FROM AUTHOR]

The renin angiotensin system (RAS) plays an important role in the pathogenesis of variety of diseases. Targeting the formation and action of angiotensin II (Ang II), the main RAS peptide, has been the key therapeutic target for last three decades. ACE‐related carboxypeptidase (ACE2), a monocarboxypeptidase that had been discovered 20 years ago, is one of the catalytically most potent enzymes known to degrade Ang II to Ang‐(1‐7), a peptide that is increasingly accepted to have organ‐protective properties that oppose and counterbalance those of Ang II. In addition to its role as a RAS enzyme ACE2 is the main receptor for SARS‐CoV‐2. In this review, we discuss various strategies that have been used to achieve amplification of ACE2 activity including the potential therapeutic potential of soluble recombinant ACE2 protein and novel shorter ACE2 variants. [ABSTRACT FROM AUTHOR]

Hypertension is the primary cause of cardiovascular mortality. Despite multiple existing treatments, only half of those with the disease achieve adequate control. Therefore, understanding the mechanisms causing hypertension is essential for the development of novel therapies. Many studies demonstrate that immune cell infiltration of the vessel wall, kidney and central nervous system, as well as their counterparts of oxidative stress, the renal renin‐angiotensin system (RAS) and sympathetic tone play a critical role in the development of hypertension. Genetically modified mice lacking components of innate and/or adaptive immunity confirm the importance of chronic inflammation in hypertension and its complications. Depletion of immune cells improves endothelial function, decreases oxidative stress, reduces vascular tone and prevents renal interstitial infiltrates, sodium retention and kidney damage. Moreover, the ablation of microglia or central nervous system perivascular macrophages reduces RAS‐induced inflammation and prevents sympathetic nervous system activation and hypertension. Therefore, understanding immune cell functioning and their interactions with tissues that regulate hypertensive responses may be the future of novel antihypertensive therapies. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme-2 (ACE-2) is the cell-surface receptor enabling viral uptake of corona virus 2019 (SARS-CoV-2), thus ACE-2 is a first step towards COVID-19 disease. A stable dimeric variant reveals potent SARS-CoV-2 and SARS-CoV neutralization in vitro. B, SARS-CoV-2 gains entry into the cell by binding to angiotensin-converting enzyme 2 (ACE-2) (left panel). [Extracted from the article]

Aim Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney. Methods Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF- kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed. Results Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure ( MAP). Conclusion Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 ( AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney. [ABSTRACT FROM AUTHOR]

The article explores whether exercise can improve insulin sensitivity in skeletal muscle through angiotensin (Ang) 1-7 signalling. The author finds that exercise does not only increase insulin-mediated glucose transport, but also enhances whole-body insulin sensitivity. The role of the renin-angiotensin system, a cardiovascular homeostasis regulator, in the formation of Ang II and Ang 1-7 peptides is also discussed.

Aim The renal renin-angiotensin system ( RAS) has been implicated in the pathogenesis of diabetic nephropathy. The aim of this study was to investigate sex differences in renal renin-angiotensin system ( RAS) and the roles of androgens in diabetes-associated renal injury. Methods Renal injury and fibrosis were studied in streptozotocin-induced diabetic rats by albuminuria and by gene expression of collagen I and fibronectin. RAS was investigated by analysing the plasma angiotensinogen ( AOGEN) and renin activity ( PRA) and their renal gene expression. Also, a group of diabetic rats was treated with the anti-androgen flutamide. Results Albuminuria was significantly lower in diabetic females than in males (1.2 [0.8-1.5] versus 4.4 [2.2-6.1] mg/24 h, data are median [ IQR] values, P < 0.05). Renal AOGEN mRNA levels were increased by diabetes in males (8.1 ± 0.8% in diabetes versus 0.8 ± 0.2% in control, P < 0.001) but not in females (1.0 ± 0.1% in diabetes versus 0.8 ± 0.1% in control, P > 0.05), as were collagen I and fibronectin mRNAs. Furthermore, AOGEN mRNA levels were strongly correlated with albuminuria (Spearman r = 0.64, 95% [ CI] 0.36-0.81, P < 0.0001). Diabetes decreased PRA, renal renin mRNA and plasma AOGEN in both females and males. Anti-androgen treatment decreased albuminuria only in diabetic males without affecting the endocrine or renal RAS. Conclusions These data indicate that renal but not hepatic AOGEN or renin is positively associated with diabetic albuminuria and contribute to the sex-dependent differences in renal injury. Androgens may contribute to albuminuria in male independently of the RAS. [ABSTRACT FROM AUTHOR]

Aim Nitric oxide ( NO) interacts with the local brain renin-angiotensin system to modulate sympathetic outflow and cardiovascular homoeostasis. This study investigated whether NO influenced the ability of angiotensin AT2 receptor activation to modify the high-pressure baroreceptor regulation of renal sympathetic nerve activity ( RSNA) and heart rate ( HR). Methods Anaesthetized (chloralose/urethane) rats were prepared to allow generation of baroreflex gain curves for RSNA or HR following intracerebroventricular (I.C.V.) CGP42112 ( AT2 receptor agonist), PD123319 ( AT2 receptor antagonist) or losartan ( AT1 receptor antagonist), and then in combination with L- NAME ( NO synthase inhibitor). Results I.C.V. PD123319, CGP42112, and Losartan did not change baseline mean arterial pressure, HR or RSNA. Baroreflex sensitivities for RSNA and HR were increased following AT2 receptor activation with CGP42112 by 112 and 157%, respectively, but were reduced following PD123319 by 20% (all P < 0.05). L- NAME alone increased baroreflex sensitivity for both RSNA and HR, by 62 and 158%, respectively, but when co-infused with either CGP42112 or PD123319, the baroreflex sensitivity fell to values comparable to those obtained during I.C.V. saline infusion. The baroreflex sensitivities for RSNA and HR were increased by losartan by 92% and 192%, respectively, but in the presence of L- NAME were no different from those obtained during I.C.V. saline infusion. Conclusion There is an important facilitatory role for AT2 receptors in the high-pressure baroreflex regulation of RSNA and HR which is dependent on a functional NO/ NOS system. Conversely, AT1 receptors have an inhibitory effect on the baroreflex, an action that relies on a tonic inhibition of NO. [ABSTRACT FROM AUTHOR]

Haemorrhagic shock is a common cause of acute kidney injury ( AKI), which is a major risk factor for developing chronic kidney disease. The mechanism is superficially straightforward. An arterial pressure below the kidney's autoregulatory region leads to a direct reduction in filtration pressure and perfusion, which in turn cause renal failure with reduced glomerular filtration rate and AKI because of hypoxia. However, the kidney's situation is further worsened by the hormonal and neural reactions to reduced perfusion pressure. There are three major systems working to maintain arterial pressure in shock: sympathetic signalling, the renin-angiotensin system and vasopressin. These work to retain electrolytes and water and to increase peripheral resistance and cardiac output. In the kidney, the increased electrolyte reabsorption consumes oxygen. At the same time, at the signalling level seen in shock, all of these hormones reduce renal perfusion and thereby oxygen delivery. This creates an exaggerated hypoxic situation that is liable to worsen the AKI. The present review will examine this mechanistic background and identify a number of areas that require further studies. At this time, the ideal treatment of haemorrhagic shock appears to be slow fluid resuscitation, possibly with hyperosmolar sodium, low chloride and no artificial colloids. From the standpoint of the kidney, renin-angiotensin system inhibitors appear fruitful for further study. [ABSTRACT FROM AUTHOR]

Aim This study aimed to evaluate the combined effects of exercise and antagonists of the angiotensin II and aldosterone receptors on cardiac autonomic regulation and ventricular repolarization in rats chronically treated with nandrolone decanoate ( ND), a synthetic androgen. Methods Thirty male Wistar rats were divided into six groups: sedentary, trained, ND-treated, trained and ND-treated, trained and treated with both ND and spironolactone, and trained and treated with both ND and losartan. ND (10 mg kg−1 weekly) and the antagonists (20 mg kg−1 daily) of the angiotensin II AT1 (losartan) and aldosterone (spironolactone) receptors were administered for 8 weeks. Exercise training was performed using a treadmill five times each week for 8 weeks. Following this 8-week training and treatment period, electrocardiogram recordings were obtained to determine the time and frequency domains of heart rate variability ( HRV) and corrected QT interval ( QTc). Results Nandrolone decanoate treatment increased the QTc interval and reduced the parasympathetic indexes of HRV (RMSSD, pNN5 and high-frequency power) in sedentary and trained rats. The ratio between low- and high-frequency power (LF/HF) was higher in ND-treated groups. Both losartan and spironolactone treatments prevented the effects of ND on the QTc interval and the HRV parameters (RMSSD, pNN5, high-frequency power, and the LF/HF ratio). Conclusion Our results show that chronic treatment with a high dose of ND induces cardiac parasympathetic dysfunction and disturbances in ventricular repolarization in both sedentary and exercised rats. Furthermore, inhibiting the renin-angiotensin-aldosterone system using losartan, or spironolactone, prevented these deleterious effects. [ABSTRACT FROM AUTHOR]

Adverse events during foetal development can predispose the individual for cardiovascular disease later in life, a correlation known as foetal programming of adult hypertension. The 'programming' events have been associated with the kidneys due to the significant role in extracellular volume control and long-term blood pressure regulation. Previously, nephron endowment and functional consequences of a low nephron number have been extensively investigated without achieving a full explanation of the underlying pathophysiological mechanisms. In this review, we will focus on mechanisms of postnatal development in the renal medulla with regard to the programming effects. The renin-angiotensin system is critically involved in mammalian kidney development and impaired signalling gives rise to developmental renal lesions that have been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given. [ABSTRACT FROM AUTHOR]

Aim This study investigates whether a local renin-angiotensin system ( RAS) exists in mouse colon and whether angiotensin II (Ang II) may play a role in the regulation of the contractile activity. Methods Isometric recordings were performed in vitro on the longitudinal muscle of mouse proximal and distal colon. Transcripts encoding for RAS components were investigated by RT- PCR. Results Ang II caused, in both preparations, a concentration-dependent contractile effect, antagonized by losartan, AT1 receptor antagonist, but not by PD123319, AT2 receptor antagonist. The combination of losartan plus PD123319 caused no change on the Ang II-induced contraction than losartan alone. Tetrodotoxin, neural blocker, reduced the contractile response to Ang II in the proximal colon, whilst the response was abolished in the distal colon. In both preparations, atropine, muscarinic receptor antagonist, or SR140333, NK1 receptor antagonist, reduced the Ang II responses. Ondansetron, 5- HT3 receptor antagonist, SR48968, NK2 receptor antagonist, or hexamethonium, nicotinic receptor antagonist, were ineffective. The joint application of atropine and SR140333 produced no additive effect. Atropine reduced NK1-induced contraction. Transcripts encoding RAS components were detected in the colon samples. However, just AT1A mRNA was expressed in both preparations, and AT2 m RNA was expressed only in the distal colon. Conclusion In the murine colon, local RAS may play a significant role in the control of contractile activity. Ang II positively modulates the spontaneous contractile activity via activation of post-junctional and pre-junctional AT1A receptors, the latter located on the enteric neurones, modulating the release of tachykinins and acetylcholine. [ABSTRACT FROM AUTHOR]

Aim The renin-angiotensin system ( RAS) depressor arm, particularly renal angiotensin type 2 receptor ( AT2 R) and Mas receptor (mas R) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that mas R activation increases renal blood flow ( RBF) at rest and attenuates the reduction in RBF in response to angiotensin II (Ang II) infusion in female rats. Furthermore, we postulated that combined activation of the AT2 R and mas R would produce a greater response than mas R activation alone. Methods In anaesthetized male and female Wistar rats, mean arterial pressure ( MAP) and RBF responses during graded Ang II infusion (30-1000 ng kg−1 min−1 i.v.) were assessed following pre-treatment with vehicle, the mas R antagonist A779, or A779 plus the AT2 R antagonist PD123319. Results Basal MAP was not altered by any pre-treatment. Basal RBF decreased approx. 20% in female ( P < 0.05), but not male rats in response to A779. However, basal RBF was not altered by A779 + PD123319. Ang II infusion reduced RBF in a dose-related fashion ( Pdose < 0.0001) and mas R blockade did not alter the RBF response to Ang II infusion in male or female rats. However, A779 + PD123319 attenuated the reduction in RBF response to Ang II in females ( Pgroup < 0.005), but not males. Conclusion The impact of the mas R on renal haemodynamics appears to be sexually dimorphic, with greater effects in female than male rats. However, the paradoxical effects of dual AT2 R and mas R blockade suggest that a greater understanding of the complex interactions between RAS components is required before the therapeutic opportunities of AT2 R and/or mas R stimulation can be advanced. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is fundamental for the intake of fluid and electrolytes and accommodates a large proportion of bodily hemodynamics and host defence systems. Despite that the renin-angiotensin system (RAS) is a prominent regulatory system for fluid and electrolyte homeostasis its impact on GI physiology is only little explored. Recent data indicate that RAS is well expressed and active in the GI tract although exact physiological roles are to be settled. There are several reports showing influences by RAS and its key mediator angiotensin II (AngII) on intestinal epithelial fluid and electrolyte transport and data are accumulating, suggesting involvement in GI mucosal inflammation and carcinogenesis. Of particular interest is the increasing amount of experimental support for the involvement of AngII formation and actions via the AngII subtype 1 (AT1) receptor in the pathogenesis and treatment of inflammatory bowel disease. The picture of RAS in the GI tract is, however, far from complete. Because RAS is an important application area for reno-cardiovascular diseases, a number of pharmacological agents as well as research technologies already exist and can in the future be used for GI research. A marked expansion of knowledge concerning the role of RAS in GI physiology and pathophysiology is to be expected. [ABSTRACT FROM AUTHOR]

Aim: Angiotensin II is well known for its contractile effects on smooth muscle cells. This effect is also present in the gut previously shown in animal models. The aim of this study was to clarify expression and localization of angiotensin II receptors in the human small intestine and to explore the pharmacological profile of angiotensin II effects in vitro. Methods: Strips of jejunal muscle wall from 32 patients undergoing bariatric surgery were used to record isometric tension in vitro in response to angiotensin II (10−10–10−5 m) alone and in the presence of PD123319 (10−7 m), losartan (10−7 m), PD123319 (10−7 m) and losartan (10−7 m) in combination, tetrodotoxin (TTX) (10−6 m), atropine (10−6 m) and guanethidine (3 × 10−6 m). Western blot, immunohistochemistry and RT-PCR were performed on corresponding muscle samples to identify expression and localization of key components of the renin–angiotensin system. Results: Angiotensin II elicited concentration-dependent contraction in both longitudinal and circular jejunal muscle wall strips; neither TTX, atropine nor guanethidine affected this action. Losartan alone and in combination with PD123319 shifted the concentration–response curve to the right. Transcription of angiotensinogen, ACE and angiotensin II types 1 and 2 receptor RNA was detected in all patients. Immunohistochemistry detected angiotensin II type 1 receptors in the musculature; both angiotensin II types 1 and type 2 receptors were found in the myenteric plexus. Conclusion: This pharmacological analysis indicates that the contractile action elicited by angiotensin II on jejunal wall musculature is primarily mediated through the angiotensin II type 1 receptor located on the musculature. [ABSTRACT FROM AUTHOR]

Aim: We investigated how the brain renin–angiotensin system is involved in regulation of the sympathetic activity and arterial pressure in rats with chronic renal failure. Methods: Systolic arterial pressure, heart rate and diurnal urinary noradrenaline excretion were measured for 12 weeks in spontaneously hypertensive rats (SHR) with or without subtotal nephrectomy. Expression of mRNAs related to the brain renin–angiotensin system was measured using polymerase chain reaction. Effects of a 6-day intracerebroventricular infusion of a type 1 angiotensin II receptor antagonist (candesartan) or bilateral dorsal rhizotomy on these variables were also investigated. Results: Systolic arterial pressure and urinary excretion of noradrenaline were consistently higher in subtotally nephrectomized SHR than in sham-operated SHR (262 ± 5 vs. 220 ± 3 mmHg, P < 0.001; 2.71 ± 0.22 vs. 1.69 ±0.19 ng g−1 body weight day−1, P < 0.001). Expression of renin, angiotensin-converting enzyme and type 1 angiotensin II receptor mRNAs in the hypothalamus and lower brainstem was greater in subtotally nephrectomized SHR than in sham-operated SHR. Continuous intracerebroventricular infusion of candesartan attenuated hypertension and the increase in urinary noradrenaline excretion in subtotally nephrectomized SHR. Dorsal rhizotomy decreased arterial pressure, urinary excretion of noradrenaline and expression of renin–angiotensin system-related mRNAs in brains of subtotally nephrectomized SHR. Conclusion: The brain renin–angiotensin system in subtotally nephrectomized SHR appears to be activated via afferent nerves from the remnant kidney, resulting in sympathetic overactivity and hypertension in this chronic renal failure model. [ABSTRACT FROM AUTHOR]

Aims: The study was designed to determine (i) whether the effects of angiotensin III (AngIII) are similar to those of angiotensin II (AngII) at identical plasma concentrations and (ii) whether AngIII operates solely through AT1- receptors. Methods: Angiotensin II (3 pmol kg−1 min−1–3.1 ng kg−1 min−1) or AngIII (15 pmol kg−1 min−1–14 ng kg−1 min−1) was infused i.v. during acute inhibition of angiotensin converting enzyme (enalaprilate; 2 mg kg−1) and of aldosterone (canrenoate; 6 mg kg−1 plus 1 mg kg−1 h−1). Arterial plasma concentrations of angiotensins were determined by radioimmunoassay using a cross-reacting antibody to AngII. During ongoing peptide infusion, candesartan (2 mg kg−1) was administered to block the AT1-receptors. Results: Angiotensin immunoactivity in plasma increased to 60 ± 10 pg mL−1 during infusion of AngII or infusion of AngIII. AngII significantly increased mean arterial blood pressure (+14 ± 4 mmHg) and plasma aldosterone by 79% (+149 ± 17 pg mL−1) and reduced plasma renin activity and sodium excretion (−41 ± 16 mIU L−1 and −46 ± 6 μmol min−1 respectively). AngIII mimicked these effects and the magnitude of AngIII responses was statistically indistinguishable from those of AngII. All measured effects of both peptides were blocked by candesartan. Conclusion: At the present arterial plasma concentrations, AngIII is equipotent to AngII with regard to effects on blood pressure, aldosterone secretion and renal functions, and these AngIII effects are mediated through AT1- receptors. The metabolic clearance rate of AngIII is five times that of AngII. [ABSTRACT FROM AUTHOR]

Background: Angiotensin II (Ang II) is a well-known activator of smooth muscle in the vasculature but has been little explored with regard to intestinal wall muscular activity. This study investigates pharmacological properties of Ang II and expression of its receptors in small-intestinal smooth muscle from rats and humans. Methods: Isometric recordings were performed in vitro on small intestinal longitudinal muscle strips. Protein expressions of Ang II typ 1 (AT1R) and typ 2 (AT2R) receptors were assessed by Western blot. Results: Ang II elicited concentration-dependent contractions of rat jejunal and ileal muscle preparations. The concentration–response curve (rat ileum, EC50: 1.5 ± 0.9 × 10−8 m) was shifted to the right by the AT1R receptor antagonist losartan (10−7 m) but was unaffected by the AT2R antagonist PD123319 (10−7 m) as well as by the adrenolytic guanethidine (3 × 10−6 m) and the anticholinergic atropine (10−6 m). Human duodenal, jejunal and ileal longitudinal muscle preparations all contracted concentration-dependently in response to Ang II. The concentration–response curve (human jejunum, EC50: 1.5 ± 0.8 × 10−8 m) was shifted to the right by losartan (10−7 m) but was unaffected by PD123319 (10−7 m). Both AT1R and AT2R were detected in all segments of the rat small intestinal wall musculature, whereas only AT1R was readily detectable in the human samples. Conclusion: Ang II elicits contractions of small-intestinal longitudinal muscle preparations from the small intestine of rats and man. The pharmacological pattern and protein expression analyses indicate mediation via the AT1R. [ABSTRACT FROM AUTHOR]

Aim: This study was performed to examine thyrotropin-releasing hormone (TRH) secretion and regulation in rat heart. Methods: Expression of prepro-TRH gene in left atrium and left ventricle was studied by RT-PCR. TRH secretion from slices of left auricle and left ventricle in response to cell swelling (induced by hypotonic medium or ethanol in isosmotic medium), angiotensin II and losartan and their combinations was studied. Results: RT-PCR revealed two times higher prepro-TRH expression in left auricle than left ventricle. In transgenic rats with extra copy of mouse renin gene a marked increase of prepro-TRH expression in the heart was noted but the relative difference between left atrium and left ventricle persisted. The swelling stimulated TRH release from both left auricle and left ventricle and this stimulation could not be inhibited by bumetanide. Angiotensin II (10 nmol L−1) added into medium significantly decreased basal secretion of TRH. The inhibiting effect of Angiotensin II was prevented by 1 μmol L−1 losartan, an angiotensin II AT1 receptor blocker. When angiotensin II and hypotonicity were applied simultaneously, swelling-induced secretion persisted. Conclusion: TRH secretion from heart slices has attributes of regulated secretion – depending on the stimulus it could be either stimulated or inhibited. Renin positively affects prepro-TRH expression in the heart. Angiotensin II inhibits TRH secretion from heart tissue by a mechanism involving AT1 receptors. Swelling-induced TRH secretion overrides inhibitory effect of angiotensin II. Swelling could be a useful tool when natural or pharmacological secretagogue is unknown. Peptides and proteins released by swelling could be mediators of local and remote ischaemic preconditioning protecting from subsequent ischaemia. [ABSTRACT FROM AUTHOR]

The article focuses on the renin-angiotensin system (RAS) that regulates blood pressure and water (fluid) balance. It mentions that the discovery of the RAS began in 1898 with the studies made by Robert Tigerstedt and Per Bergman, who reported the pressure effect of renal extracts. Various publications in support of RAS are also presented including the publication dealing with the peptide angiotensin III and systemic effects in comparison with angiotensin II in conscious dogs.

The angiotensin AT2‐receptor is a main receptor of the protective arm of the renin‐angiotensin system. Understanding of this unconventional G‐protein coupled receptor has significantly advanced during the past decade, largely because of the availability of a selective non‐peptide AT2‐receptor agonist, which allowed the conduct of a multitude of studies in animal disease models. This article reviews such preclinical studies that in their entirety provide strong evidence for an anti‐fibrotic effect mediated by activation of the AT2‐receptor. Prevention of the development of fibrosis by AT2‐receptor stimulation has been demonstrated in lungs, heart, blood vessels, kidney, pancreas and skin. In lungs, AT2‐receptor stimulation was even able to reverse existing fibrosis. The article further discusses intracellular signalling mechanisms mediating the AT2‐receptor‐coupled anti‐fibrotic effect, including activation of phosphatases and subsequent interference with pro‐fibrotic signalling pathways, induction of matrix‐metalloproteinases and hetero‐dimerization with the AT1‐receptor, the TGF‐βRII‐receptor or the RXFP1‐receptor for relaxin. Knowledge of the anti‐fibrotic effects of the AT2‐receptor is of particular relevance because drugs targeting this receptor have entered clinical development for indications involving fibrotic diseases. [ABSTRACT FROM AUTHOR]

Aim: Common kidney alterations early after the onset of insulinopenic diabetes include glomerular hyperfiltration, increased oxygen consumption and tissue hypoxia. Increased activity of the renin‐angiotensin‐aldosterone system (RAAS) has been implicated in most of these early alterations. The RAAS peptide angiotensin (1‐7) has the potential to modulate RAAS‐mediated alterations in kidney function. Thus, the aim of the present study was to determine the acute effects of angiotensin (1‐7) in the kidney of insulinopenic type 1 diabetic rat and the results compared to that of normoglycaemic controls. Methods: Renal haemodynamics and oxygen homeostasis were measured 3 weeks after administration of streptozotocin before and after acute intrarenal infusion of angiotensin (1‐7) at a dose of 400 ng min−1. Results: Arterial pressure and renal blood flow were similar between groups and not affected by exogenous angiotensin (1‐7). Diabetics presented with glomerular hyperfiltration, increased urinary sodium excretion and elevated kidney oxygen consumption. Angiotensin (1‐7) infusion normalized glomerular filtration, increased urinary sodium excretion, decreased proximal tubular reabsorption, and elevated kidney oxygen consumption even further. The latter resulting in tubular electrolyte transport inefficiency. Angiotensin (1‐7) did not affect tissue oxygen tension and had no significant effects in controls on any of the measured parameters. Conclusion: Diabetes results in increased responsiveness to elevated levels of angiotensin (1‐7) which is manifested as inhibition of tubular sodium transport and normalization of glomerular filtration. Furthermore, elevated angiotensin (1‐7) levels increase kidney oxygen consumption in the diabetic kidney even further which affects tubular electrolyte transport efficiency negatively. [ABSTRACT FROM AUTHOR]