Angiotensin and aldosterone

The object of this review is to describe the role of the renin–angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin–angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT₁ and AT₂ receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT₁ receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and amplified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described.     

Angiotensin II-Generating Enzymes

The renin–angiotensin system (RAS) is a system of enzymes and hormones that regulate blood pressure and electrolyte and fluid homeostasis in mammals. Angiotensin II (Ang-II) is one of the most important and well-known components of RAS. It is formed from the protein precursor angiotensinogen by the sequential actions of proteolytic enzymes. The classic pathway of Ang-II generation includes a reaction catalyzed by angiotensin-converting enzyme (ACE). However, there are alternative pathways for the generation of Ang-II. In this paper, possible routes of formation of Ang-II in the human body are reviewed. Various Ang-II-generating enzymes (tonin, cathepsin G, chymase, etc.) and their properties are considered. The classification of these enzymes is also considered.     

Angiotensin and diabetic retinopathy

Diabetic retinopathy develops in patients with both type 1 and type 2 diabetes and is the major cause of vision loss and blindness in the working population. In diabetes, damage to the retina occurs in the vasculature, neurons and glia resulting in pathological angiogenesis, vascular leakage and a loss in retinal function. The renin-angiotensin system is a causative factor in diabetic microvascular complications inducing a variety of tissue responses including vasoconstriction, inflammation, oxidative stress, cell hypertrophy and proliferation, angiogenesis and fibrosis. All components of the renin-angiotensin system including the angiotensin type 1 and angiotensin type 2 receptors have been identified in the retina of humans and rodents. There is evidence from both clinical and experimental models of diabetic retinopathy and hypoxic-induced retinal angiogenesis that the renin-angiotensin system is up-regulated. In these situations, retinal dysfunction has been linked to angiotensin-mediated induction of growth factors including vascular endothelial growth factor, platelet-derived growth factor and connective tissue growth factor. Evidence to date indicates that blockade of the renin-angiotensin system can confer retinoprotection in experimental models of diabetic retinopathy and ischemic retinopathy. This review examines the role of the renin-angiotensin system in diabetic retinopathy and the potential of its blockade as a treatment strategy for this vision-threatening disease.     

Angiotensin stimulates oxytocin release

A sensitive and specific radioimmunoassay for oxytocin (OT) was developed to study the effect of angiotensin II (ANG II) upon neurohypophyseal OT release in conscious rats. ANG II injected into the lateral cerebral ventricle (i.c.v.) produced within 60 seconds a steep increase in plasma OT concentration from a control value of 10.46 ± 1.35 fmol/ml to 88.95 ± 5.06 fmol/ml and 119.56 ± 11.46 fmol/ml following 10 and 100 ng i.c.v. ANG II, respectively. Inhibition of OT release by simultaneous application of the ANG II antagonist {Sar¹, Ile⁸}-ANG II suggests that ANG II acted via specific angiotensin receptors in the brain.     

Angiotensin II-Like Material Extracted from the Rat Brain Is Distinct from Authentic Angiotensin II

Specific radioimmunoassay and radioreceptor assay for angiotensin II (A II) were used for the possible identification of this peptide in the rat brain. An A II-like material (A II-LM) was detected with both assays applied to acidic extracts of various brain structures. The regional distribution of A II-LM was uneven, but absolute levels (in A II equivalents) could not be accurately determined, as they were highly dependent on the assay used. Partial purification of A II-LM by Sep-Pak C 18 chromatography and affinity chromatography using anti-A II antibodies bound to Ultrogel gave a compound coeluting with authentic A II in reverse-phase HPLC. However, gel filtration through Sephadex G-25 and TSK Spherogel 3000 SW as well as anion exchange HPLC demonstrated that A II-LM did not correspond to authentic A II. Partial characterization of A II-LM indicated that this compound was probably a peptide with an apparent molecular weight of 5,000-7,000 (instead of 1,046 for A II) and more polar but less positively charged than A II. Whether A II-LM is, in fact, the endogenous ligand of A II binding sites in brain remains an interesting hypothesis for further investigations.     

Angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (ANG II) (200 micrograms/kg sc) to the rat induced a hypothermic response that was characterized within 12 min by a reduction in the rate of O2 consumption, vasodilation of the tail, and a 1.3 degrees C fall in colonic temperature. Administration of ANG II in doses ranging from 10 to 200 micrograms/kg resulted in a decrease in colonic and an increase in tail skin temperature. Angiotensin I (ANG I) (200 micrograms/kg sc) induced a similar hypothermic response which was abolished by pretreatment with the ANG I-converting enzyme inhibitor, captopril (35 mg/kg ip). The interaction of ANG II with cholinergic and adrenergic pathways was evaluated to determine possible mechanisms. Treatment with ANG II (200 micrograms/kg sc) and propranolol, a beta-adrenoceptor antagonist (6 mg/kg ip), resulted in a greater depression of colonic temperature (Tco) than was observed with ANG II alone but did not affect the increase in tail skin temperature (Tsk) accompanying administration of ANG II. When ANG II was administered in combination with the beta-adrenergic agonist, isoproterenol (50 micrograms/kg ip), Tco remained at control levels, whereas an enhancement of the ANG II-induced increase in Tsk occurred. Administration of ANG II in combination with atropine sulfate (6 mg/kg ip), a muscarinic receptor antagonist which crosses the blood-brain barrier, significantly reduced the extent of the fall in Tco without affecting the increase in Tsk. The combined treatment of ANG II and the quaternary analogue, atropine methyl nitrate (3.25 mg/kg ip), which does not cross the blood-brain barrier, failed to affect the hypothermic responses to ANG II. These results suggest that the hypothermic responses to ANG II may be mediated through a central cholinergic pathway and possibly influenced by an adrenergic component. The inability of both adrenergic and cholinergic blockers to affect the vasodilatory response of the tail of the rat to administration of ANG II suggests that the mechanisms subserving heat production can be blocked independently of those subserving heat loss.     

Angiotensin receptors--evolutionary overview and perspectives

The structure of the angiotensin molecule has been well preserved throughout the vertebrate scale with some amino acid variations. Specific angiotensin receptors (AT receptors) that mediate important physiological functions have been noted in a variety of tissues and species. Physiological and pharmacological characterization of AT receptors and, more recently, molecular cloning studies have elucidated the presence of AT receptor subtypes. Comparative studies suggest that an AT receptor subtype homologous to the mammalian type 1 receptor subtype (AT(1)), though pharmacologically distinct, is present in amphibians and birds, whereas AT receptors cloned from teleosts show low homology to both AT(1) and AT(2) receptor subtypes. Furthermore, receptors differing from both the AT(1)-homologue receptor and AT(2) receptor exist in some non-mammalian species. This may suggest that the prototype AT receptor evolved in primitive vertebrates and diverged to more than one type of AT receptor subtype during phylogeny. Furthermore, phenotypic modulation of AT receptors appears to occur during individual development/maturation.     

Angiotensin preconditioning of the heart

Angiotensin II (Ang II) has been found to exert preconditioning-like effect on mammalian hearts. Diverse mechanisms are known to exist to explain the cardioprotective abilities of Ang II preconditioning. The present study hypothesized, based on the recent report that Ang II generates reactive oxygen species (ROS) through NADPH oxidase, that Ang II preconditioning occurs through redox cycling. To test this hypothesis, a group of rat hearts was treated with Ang II in the absence or presence of an NADPH oxidase inhibitor, apocynin; or a cell-permeable ROS scavenger, N-acetyl cysteine (NAC). Ang II pretreatment improved postischemic ventricular recovery; reduced myocardial infarction; and decreased the number of cardiomyocyte apoptosis, indicating its ability to precondition the heart against ischemic injury. Both apocynin and NAC almost abolished the preconditioning ability of Ang II. Ang II resulted in increase in ROS activity in the heart, which was reduced by either NAC or apocynin. Ang II also increased both the NADPH oxidase subunits gp91 phox and p22phox mRNA expression, which was abolished with apocynin and NAC. Our results thus demonstrate that the Ang II preconditioning was associated with enhanced ROS activities and increased NADPH oxidase subunits p22phox and gp91phox expression. Both NAC and apocynin reduced ROS activities simultaneously abolishing preconditioning ability of Ang II, suggesting that Ang II preconditioning occurs through redox cycling. That both NAC and apocynin reduced ROS activities and abolished Ang II-mediated increase in p22phox and gp91phox activity further suggest that such redox cycling occurs via both NADPH oxidase-dependent and -independent pathways.     

Angiotensin II and aldosterone regulation

The circulating renin-angiotensin system is a major regulator of the secretion of the adrenocortical hormone, aldosterone. This renin-angiotensin aldosterone system is important in the control of salt and water balance and blood pressure. This review describes the historical background leading to the discovery of aldosterone in the 1950s and the recognition in the 1960s that angiotensin II was involved in its control. Although angiotensin II is important in the regulation of aldosterone secretion, its action is influenced by multiple other factors, especially potassium and atrial natriuretic peptide. In addition to the circulating renin-angiotensin system, a local renin-angiotensin system is present in the zona glomerulosa cell. This local system also appears to be involved in the regulation of aldosterone production. The mechanism by which angiotensin II stimulates the adrenal zona glomerulosa cell is described in some detail. Angiotensin II interacts with the angiotensin receptor (AT1) membrane receptor that is coupled to cellular second messengers. Specific AT1 receptor antagonists are now clinically used to block angiotensin II's action on various target organs, including the adrenal gland.