Anu Vaajanen

Activities of Angiotensin-Converting Enzymes ACE1 and ACE2 and Inhibition by Bioactive Peptides in Porcine Ocular Tissues

PURPOSE An active local renin-angiotensin system (RAS) has recently been found in the human eye. The aim of the present study was to compare the activities of central RAS enzymes (ACE1 and 2) in porcine ocular tissues, morphologically and physiologically close to the human eye. In addition, the effects of three ACE-inhibitory tripeptides on these enzymes were evaluated. METHODS Enucleated fresh porcine eyes were used. Activities of ACE1 and ACE2 and their inhibition by bioactive tripeptides (Ile-Pro-Pro, Val-Pro-Pro, Leu-Pro-Pro) as well as by a standard ACE-inhibitor captopril were assayed in the vitreous body, the retina and the ciliary body using fluorometric detection methods. RESULTS Activity of ACE1 as well as ACE2 was found in all tissues evaluated. ACE1 activity was markedly higher in the ciliary body (3.7 +/- 0.7 mU/mg protein) than in retina (0.2 +/- 0.02 mU/mg), whereas ACE2 activities in the ciliary body (0.2 +/- 0.02 mU/mg) and retina (0.2 +/- 0.01 mU/mg) were at the same level. In the vitreous body ACE1 activity (8.2 +/- 0.31 nmol/min/mL) was manifold compared to that of ACE2 (0.1 +/- 0.02 nmol/min/mL). The tripeptides inhibited ACE1 at one-thousandth of the concentration needed to inhibit ACE2. All peptides studied evinced about equal inhibitory activities. CONCLUSION To our knowledge the present findings constitute the first evidence of ACE2 activity in the ciliary and vitreous bodies, in addition to previously described activity in the retina. The known favorable effects of ACE2 products vs. those of ACE1 suggest a counterbalancing interaction of these two enzyme homologues in physiological regulation of ocular circulation and pressure and possible protective role in certain ophthalmic disorders such as glaucoma and diabetic retinopathy.

Angiotensin (1-7) Reduces Intraocular Pressure in the Normotensive Rabbit Eye

PURPOSE In the present study the effects of exogenous angiotensin II and its breakdown metabolite angiotensin (1-7) on the intraocular pressure (IOP) and on aqueous humor dynamics in normotensive rabbit eye were evaluated. METHODS Male New Zealand White rabbits with normal IOP were used for intravitreous and topical administration of the test compounds. IOP was measured in conscious rabbits by pneumatonometer after topical anesthesia. Outflow measurements were made with a two-level constant pressure method in anesthetized animals. RESULTS Angiotensin (1-7) administered intravitreously reduced IOP within 1 to 5 hours (P < 0.05). This effect was abolished by the selective angiotensin (1-7) antagonist A-779, and partially by the selective angiotensin II type 2 receptor antagonist PD123319. When olmesartan, an angiotensin II type 1 receptor blocker, was administered simultaneously with angiotensin (1-7), no antagonism was seen. Intravitreous administration of CGP42112 A, an angiotensin II type 2 receptor agonist, and angiotensin II did not significantly influence IOP, nor did topical administration of these compounds alter IOP. Angiotensin II significantly reduced outflow facility (P < 0.01) dose dependently, whereas angiotensin (1-7) had no effect. CONCLUSIONS Angiotensin (1-7) is a biologically active vasodilatory and antiproliferative heptapeptide, and its vascular effects counteract those of angiotensin II. It reduces intraocular pressure possibly by a selective Mas receptor, without changing aqueous humor outflow facility in the normotensive rabbit eye.

Does the renin-angiotensin system also regulate intra-ocular pressure?

The renin-angiotensin-aldosterone system is known to play an essential role in controlling sodium balance and body fluid volumes, and thus blood pressure. In addition to the circulating system which regulates urgent cardiovascular responses, a tissue-localized renin-angiotensin system (RAS) regulates long-term changes in various organs. Many recognized RAS components have also been identified in the human eye. The highly vasoconstrictive angiotensin II (Ang II) is considered the key peptide in the circulatory RAS. However, the ultimate effect of RAS activation at tissue level is more complex, being based not only on the biological activity of Ang II but also on the activities of other products of angiotensinogen metabolism, often exerting opposite effects to Ang II action. In recent studies, orally administered angiotensin II type 1 receptor blockers and angiotensin-converting enzyme inhibitors lower intra-ocular pressure (IOP), likewise topical application of these compounds, the effect being more prominent in ocular hypertensive eyes. Based on previous findings and our own experimental data, it can strongly be suggested that the RAS not only regulates blood pressure but is also involved in the regulation of IOP.

Is There a Relationship Between Blood Pressure and Intraocular Pressure? An Experimental Study in Hypertensive Rats

Purpose: Evaluation of relation between blood pressure (BP) and intraocular pressure (IOP) in two hypertensive rat strains: spontaneously hypertensive rats (SHR) and double transgenic (dTGR) (harboring human renin and angiotensinogen genes) rats, and in their normotensive control Wistar Kyoto and Sprague Dawley rats, respectively. Methods: Each rat strain was divided into medicated and non-medicated groups. Medicated rats were treated orally with an angiotensin II receptor type 1 blocker. IOP was measured using a specific rebound tonometer and BP by a tail-cuff method. Both parameters were determined in conscious animals every second week. For comparison, at the end of the study, IOP was measured in conscious and anesthetized rats. Results: The baseline IOP was higher in hypertensive rats vs their normotensive controls. Eight weeks of treatment with an angiotensin type 1 receptor blocker did not prevent a slight increase in IOP, although it abolished the development of hypertension in SHR. The markedly elevated IOP was reduced in medicated and non-medicated dTGR animals during the short follow-up period. General anesthesia reduced IOP significantly. Conclusion: The results suggest a positive relation between BP and IOP in hypertensive rats.

Angiotensin receptors in the eyes of arterial hypertensive rats

Purpose:  The aim of the present study was to determine whether the eye tissues of arterial hypertensive rats evince expression of angiotensin receptors (AT1 and AT2) as well as the novel Mas receptor, whose endogenous ligand is vasorelaxing Angiotensin (1–7) [Ang (1–7)].

Angiotensin(1-7) and ACE2, “The Hot Spots” of Renin-Angiotensin System, Detected in the Human Aqueous Humor

Background: The main purpose of the study was to establish whether essential components of the renin-angiotensin system (RAS) exist in the human aqueous humor. Methods: Forty-five patients ≥ 60 (74±7) years of age undergoing cataract surgery at Tampere University Hospital were randomly selected for the prospective study. The exclusion criterion was the use of oral antihypertensive medicine acting via renin-angiotensin system. Aqueous humor samples were taken at the beginning of normal cataract extraction. The samples were frozen and stored at -80 °C. The concentrations of intraocular endogenous RAS components Ang(1-7), ACE2, and ACE1 were measured using ELISA. Results: Concentration medians of Ang(1-7), ACE2, and ACE1 in the aqueous humor were: Ang(1-7) 4.08 ng/ml, ACE2 2.32 ng/ml and ACE1 0.35 ng/ml. The concentrations were significantly higher in glaucomatous than in non-glaucomatous eyes, ACE1 (p=0.014) and Ang(1-7) (p=0.026) vs non-glaucomatous eyes. Conclusions: Ang(1-7), ACE2 and ACE1 are found in the human aqueous humor. The observations are consistent with the conception that local tissue-RAS exists in the human eye and it might have a role in the control of intraocular pressure.

Many Faces of Renin-angiotensin System - Focus on Eye

The renin-angiotensin system (RAS), that is known for its role in the regulation of blood pressure as well as in fluid and electrolyte homeostasis, comprises dozens of angiotensin peptides and peptidases and at least six receptors. Six central components constitute the two main axes of the RAS cascade. Angiotensin (1-7), an angiotensin converting enzyme 2 and Mas receptor axis (ACE2-Ang(1-7)-MasR) counterbalances the harmful effects of the angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor axis (ACE1-AngII-AT1R) Whereas systemic RAS is an important factor in blood pressure regulation, tissue-specific regulatory system, responsible for long term regional changes, that has been found in various organs. In other words, RAS is not only endocrine but also complicated autocrine system. The human eye has its own intraocular RAS that is present e.g. in the structures involved in aqueous humor dynamics. Local RAS may thus be a target in the development of new anti-glaucomatous drugs. In this review, we first describe the systemic RAS cascade and then the local ocular RAS especially in the anterior part of the eye.

A Single Drop in the Eye – Effects on the Whole Body?

Introduction: Although the local adverse effects of ophthalmic drugs, including allergic reactions, are well recognized, less is known about the systemic side- effects of eye drops, especially during pregnancy, breast-feeding and early childhood. Ophthalmologists should also be aware of unusual, in some cases even life-threatening, effects of commonly used eye drops. Conclusion: This brief review outlines the routes of systemic absorption and the kinetics of active components present in eye drops, and identifies the clinically relevant systemic adverse effects.

Does the Renin-Angiotensin System (RAS) Regulate also Intraocular Pressure (IOP)?~!2010-03-23~!2010-08-05~!2010-08-27~!

The central role of Renin-Angiotensin System (RAS) in the regulation of blood pressure is widely accepted, and drugs which inhibit the formation of the potent vasoconstrictor angiotensin II (AngII) i.e. ACE inhibitors or drugs which block the Ang receptors of type 1 (AT1R) form the cornerstone in the treatment of hypertension. However, from AngI and AngII also vasodilating and blood pressure lowering products, such as Ang(1-7) are formed by another ACE isoenzyme (ACE2). Ang(1-7) acts by stimulating newly described, vasodilatory and antiproliferative Mas-receptors. Furthermore, AngII itself has also vasodilatory and antiproliferative properties via angiotensin type 2 receptors (AT2R). We and others have described different components of RAS in various parts of the eye. It can be suggested that these components play a role in regulation of IOP either by reducing aqueous humour formation or by increasing its outflow or both.

Does the Renin-Angiotensin System (RAS) Regulate also Intraocular Pressure (IOP)?

The central role of Renin-Angiotensin System (RAS) in the regulation of blood pressure is widely accepted, and drugs which inhibit the formation of the potent vasoconstrictor angiotensin II (AngII) i.e. ACE inhibitors or drugs which block the Ang receptors of type 1 (AT1R) form the cornerstone in the treatment of hypertension. However, from AngI and AngII also vasodilating and blood pressure lowering products, such as Ang(1-7) are formed by another ACE isoenzyme (ACE2). Ang(1-7) acts by stimulating newly described, vasodilatory and antiproliferative Mas-receptors. Furthermore, AngII itself has also vasodilatory and antiproliferative properties via angiotensin type 2 receptors (AT2R). We and others have described different components of RAS in various parts of the eye. It can be suggested that these components play a role in regulation of IOP either by reducing aqueous humour formation or by increasing its outflow or both.