angiotensin-i and Arrhythmias--Cardiac

The influence of angiotensin II and angiotensin (1-17) on cell volume and on the activation of ionic channels including the swelling-dependent chloride channel was reviewed. Particular emphasis was given to the influence of the balance between the ACE-angiotensin II and of the ACE2-angiotensin (1-7)-Mas receptor axis on heart cell volume regulation and on the swelling-dependent chloride current. The implications for myocardial ischemia and cardiac arrhythmias are discussed.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Arrhythmias, Cardiac; Cell Size; Chlorides; Humans; Models, Biological; Myocardial Ischemia; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System

Topics: Action Potentials; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Arrhythmias, Cardiac; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Signal Transduction

The octapeptide hormone, angiotensin II, binds to two major subtypes of cell surface receptors: the AT1 and the AT2 angiotensin receptors. The important physiological and pathophysiological effects of angiotensin II on cardiovascular regulation and salt-water balance are mediated by the AT1 receptor subtype. As a consequence of the outstanding clinical success of angiotensin-converting enzyme inhibitors, the appearance of AT1 receptor inhibitors in the therapy of hypertension and other cardiovascular diseases was preceded with great expectations. The available experimental and clinical data indicate that the first AT1 receptor inhibitor, losartan, has the same therapeutic potential as angiotensin-converting enzyme inhibitors, but it does not evoke the angiotensin-independent side-effects of ACE inhibitors, such as dry cough or angioedema. The physiological importance and the biochemical, molecular biological and pharmacological properties of AT1 and AT2 receptors are reviewed in this paper, and a summary of the available clinical data is presented.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Female; Heart Failure; Humans; Hypertension; Losartan; Renin-Angiotensin System

The octapeptide hormone, angiotensin II, binds to two major subtypes of cell surface receptors: the AT1 and the AT2 angiotensin receptors. The important physiological and pathophysiological effects of angiotensin II on cardiovascular regulation and salt-water balance are mediated by the AT1 receptor subtype. As a consequence of the outstanding clinical success of angiotensin-converting enzyme inhibitors, the appearance of AT1 receptor inhibitors in the therapy of hypertension and other cardiovascular diseases was preceded with great expectations. The available experimental and clinical data indicate that the first AT1 receptor inhibitor, losartan, has the same therapeutic potential as angiotensin-converting enzyme inhibitors, but it does not evoke the angiotensin-independent side-effects of ACE inhibitors, such as dry cough or angioedema. The physiological importance and the biochemical, molecular biological and pharmacological properties of AT1 and AT2 receptors are reviewed in this paper, and a summary of the available clinical data is presented.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Female; Heart Failure; Humans; Hypertension; Losartan; Renin-Angiotensin System

What is the central question of this study? Recently, there have been many studies exploring the biological effects of angiotensin-(1-7), which has been proved to have cardioprotective actions. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. What is the main finding and its importance? We investigated protective effects of angiotensin-(1-7) on cardiac arrhythmias in vivo, which were not properly explored in terms of cellular mechanisms. To verify effects of angiotensin-(1-7), we used different but complementary experimental approaches. Our data provide new evidence on the cellular mechanism and an in vivo demonstration of the acute antiarrhythmic effect of angiotensin-(1-7). Angiotensin-(1-7) [Ang-(1-7)] has been proved to have cardioprotective effects. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. The aim of this study was to investigate the protective effects of Ang-(1-7) against cardiac arrhythmias, its in vivo effects and cellular mechanism of action. We analysed the ECG upon inducement of arrhythmias in vivo in rats using a combination of halothane and adrenaline. To analyse the effects of Ang-(1-7) on cells, fresh mouse ventricular cardiomyocytes were isolated. The cardiomyocytes were superfused with a solution containing halothane and isoprenaline as a model to induce arrhythmias and used in three different approaches, namely a contractility assay, patch-clamp technique and confocal microscopy. The in vivo ECG showed that the injection of Ang-(1-7) (4 nm i.v.) significantly reduced cardiac arrhythmias [before, 49 ± 43 arrhythmic events versus after Ang-(1-7), 16 ± 14 arrhythmic events]. This effect was blocked by injection of A-779 and l-NAME, without changes in haemodynamic parameters. In addition, contractility experiments showed that Ang-(1-7) significantly decreased the number of arrhythmic events without changing the fractional shortening. This protection was associated with a reduction of the action potential repolarization and membrane hyperpolarization. Moreover, Ang-(1-7) decreased the number of calcium waves without any changes in the amplitude of the calcium transient, despite a significant reduction in the decay rate. Our data provide new evidence on the cellular mechanism together with an in vivo demonstration of the antiarrhythmic effects of Ang-(1-7).

Topics: Action Potentials; Angiotensin I; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Cardiotonic Agents; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NG-Nitroarginine Methyl Ester; Peptide Fragments; Rats; Rats, Wistar

It has been shown that Ang-(1-7) has cardioprotective actions. To directly investigate the effects of Ang-(1-7) specifically in the heart, we generated and characterized transgenic (TG) rats which express an Ang-(1-7)-producing fusion protein driven by the alpha-MHC promoter.. After microinjection of the transgene into fertilized rat zygotes, we obtained four different transgenic lines. Homozygous animals were analyzed with regard to the expression profile of the transgene by ribonuclease protection assay. Transgene expression was detected mainly in the heart with weak or no expression in other organs. Heterozygous TG(hA-1-7)L7301 rats presented a significant increase in cardiac Ang-(1-7) concentration compared with control rats (17.1+/-2.1 versus 3.9+/-1.4 pg/mg protein in SD rats). Radiotelemetry analysis revealed that TG rats presented no significant changes in blood pressure and heart rate compared with normal rats. Overexpression of Ang-(1-7) in the heart produced slight improvement in resting cardiac function (+ dT/dt: 81530+/-1305.0 versus 77470+/-345.5 g/s bpm in SD rats, p < 0.05), which was in keeping with the enhanced [Ca(2+)] handling observed in cardiomyocytes of TG rats. TG(hA-1-7)L7301 rats also showed a greater capacity to withstand stress since TG rats showed a less pronounced deposition of collagen type III and fibronectin induced by isoproterenol treatment in the subendocardial area than in corresponding controls. In addition, hearts from TG rats showed reduced incidence and duration of reperfusion arrhythmias in comparison with SD rats.. These results indicate that Ang-(1-7) has blood pressure-independent, antifibrotic effects, acting directly in the heart.

Topics: Angiotensin I; Animals; Arrhythmias, Cardiac; Blood Pressure; Calcium; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Heart Rate; Heart Ventricles; Isoproterenol; Male; Myocardial Reperfusion Injury; Myocytes, Cardiac; Myosin Heavy Chains; Peptide Fragments; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Telemetry

Mas stimulation with angiotensin (Ang)-(1-7) produces cardioprotective effects and vasorelaxation. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate G protein-coupled receptors, we discovered a novel Mas agonist peptide, CGEN-856S. An endothelium- and NO-dependent vasodilating effect was observed for CGEN-856S in thoracic aorta rings of rats (maximal value for the relaxant effect: 39.99+/-5.034%), which was similar to that produced by Ang-(1-7) (10(-10) to 10(-6) mol/L). In addition, the vasodilator activity of this peptide depended on a functional Mas receptor, because it was abolished in aorta rings of Mas-knockout mice. CGEN-856S appears to bind the Mas receptor at the same binding domain as Ang-(1-7), as suggested by the blocking of its vasorelaxant effect with the Ang-(1-7) analogue d-Ala(7)-Ang-(1-7), and by its competitive inhibition of Ang-(1-7) binding to Mas-transfected cells. The effect of CGEN-856S on reperfusion arrhythmias and cardiac function was studied on ischemia reperfusion of isolated rat hearts. We found that picomolar concentration of CGEN-856S (0.04 nmol/L) had an antiarrhythmogenic effect, as demonstrated by a reduction in the incidence and duration of reperfusion arrhythmias. Furthermore, acute infusion of CGEN-856S produced a shallow dose-dependent decrease in mean arterial pressure of conscious spontaneously hypertensive rats. The maximum change during infusion was observed at the highest dose. Strikingly, blood pressure continued to drop in the postinfusion period. The results presented here indicate that the novel Mas agonist, CGEN-856S, might have a therapeutic value, because it induces vasorelaxing, antihypertensive, and cardioprotective effects.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Aorta; Arrhythmias, Cardiac; Disease Models, Animal; Heart; Hypertension; Male; Membrane Proteins; Mice; Mice, Knockout; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Vasodilation

The influence of hypotonic solution on cell volume and electrophysiology properties of the failing heart of cardiomyopathic hamsters (TO-2) was investigated. The results showed an increase in cell volume of quiescent isolated ventricular myocytes by 66% within 30 min. Angiotensin (1-7) [Ang (1-7)] (10(-8) M) administered to isotonic solution, elicited a gradual decline in cell volume and a significant decrease of the swelling-activated chloride current (I (Clswell)). The effect of Ang (1-7) on cell volume was inhibited by ouabain (10(-7) M). Angiotensin II (10(-8) M) caused cell swelling and increased I (Clswell). Experiments performed on isolated left ventricles of cardiomyopathic hamsters at an advanced stage of the disease, indicated that hypotonic solution prepared by diluting the normal Krebs solution by 25%, showed a gradual decrease of conduction velocity, generation of early after depolarizations and block of impulse conduction within 10 min. Implications to myocardial ischemia are discussed.

Topics: Angiotensin I; Angiotensin II; Animals; Arrhythmias, Cardiac; Cardiomyopathies; Cell Size; Cells, Cultured; Cricetinae; Electrophysiology; Heart Conduction System; Heart Failure; Heart Ventricles; Hypotonic Solutions; Male; Membrane Potentials; Myocytes, Cardiac; Peptide Fragments; Pulse

Angiotensin-(1-7) [ANG-(1-7)] is a recently described heptapeptide product of the renin-angiotensin system. Because biosynthesis of ANG-(1-7) increases in animals treated with cardioprotective drugs and inactivation of the gene for angiotensin converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1-7)] leads to the development of cardiac dysfunction, it has been suggested that ANG-(1-7) has cardioprotective properties. To directly test this possibility, we have generated transgenic rats that chronically overproduce ANG-(1-7) by using a novel fusion protein methodology. TGR(A1-7)3292 rats show testicular-specific expression of a cytomegalovirus promoter-driven transgene, resulting in a doubling of circulating ANG-(1-7) compared with nontransgenic control rats. Radiotelemetry hemodynamic measurements showed that transgenic rats presented a small but significant increase in daily and nocturnal heart rate and a slight but significant increase in daily and nocturnal cardiac contractility estimated by dP/d t measurements. Strikingly, TGR(A1-7)3292 rats were significantly more resistant than control animals to induction of cardiac hypertrophy by isoproterenol. In addition, transgenic rats showed a reduced duration of reperfusion arrhythmias and an improved postischemic function in isolated Langendorff heart preparations. These results support a cardioprotective role for circulating ANG-(1-7) and provide a novel tool for evaluating the functional role of ANG-(1-7).

Topics: Angiotensin I; Animals; Animals, Genetically Modified; Arrhythmias, Cardiac; Cardiomegaly; Cardiotonic Agents; Gene Expression; Heart Rate; Male; Myocardial Contraction; Organ Culture Techniques; Peptide Fragments; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; RNA, Messenger; Testis

The influence of angiotensin I (Ang I) on heart excitability and refractoriness was investigated in isolated right ventricular muscle of adult rats as well as in isolated ventricular myocytes. The results indicated that Ang I (10(-8) M) added to the bath solution, decreased the action potential duration from 50.4 +/- 3.6 to 33.9 +/- 3.9 ms (P < 0.05) and reduced significantly the cardiac refractoriness. Consequently, a discharge of spontaneous action potentials was elicited when a second stimulus was applied during the relative refractory period. Moreover, the conduction velocity was reduced from 56.9 +/- 2.9 to 40 +/- 3.2 cm/s (P < 0.05). The question whether the effect of Ang I was related to its conversion to Ang II, was investigated on tissues exposed to enalapril maleate (10(-8) M). Under these conditions, the effect of Ang I was totally suppressed. Similar results were found with losartan (10(-7) M). To investigate if the conversion of Ang I to Ang II occurs at the level of surface cell membrane, measurements of inward calcium current (ICa) were performed in myocytes isolated from the rat ventricle. ICa was measured before and after the administration of Ang I (10(-8) M). The results indicated that Ang I (10(-8) M), added to the bath solution, reduced the peak ICa density by 26.3 +/- 2.6% (P < 0.05), an effect abolished by enalapril maleate (10(-8)M).. Evidence is presented for the first time, that Ang I is converted to Ang II at the surface cell membrane in cardiac muscle with consequent generation of cardiac arrhythmias which are elicited by Ang II.

Topics: Angiotensin I; Animals; Arrhythmias, Cardiac; Calcium; Cell Membrane; Female; Heart Ventricles; Myocytes, Cardiac; Peptidyl-Dipeptidase A; Rats

In this study we evaluate the effects of angiotensin-(1-7) on reperfusion arrhythmias in isolated rat hearts. Rat hearts were perfused according to Langendorff technique and maintained in heated (37+/-1 degrees C) and continuously gassed (95% O(2)/5% CO(2)) Krebs-Ringer solution at constant pressure (65 mm Hg). The electrical activity was recorded with an ECG (bipolar). Local ischemia was induced by coronary ligation for 15 minutes. After ischemia, hearts were reperfused for 30 minutes. Cardiac arrhythmias were defined as the presence of ventricular tachycardia and/or ventricular fibrillation after the ligation of the coronary artery was released. Angiotensin II (0.20 nmol/L, n=10) produced a significant enhancement of reperfusion arrhythmias. On the other hand, Ang-(1-7) presented in the perfusion solution (0.22 nmol/L, n=11) reduced incidence and duration of arrhythmias. The antiarrhythmogenic effects of Ang-(1-7) was blocked by the selective Ang-(1-7) antagonist A-779 (2 nmol/L, n=9) and by indomethacin pretreatment (5 mg/kg IP, n=8) but not by the bradykinin B(2) antagonist HOE 140 (100 nmol/L, n=10) or by L-NAME pretreatment (30 mg/kg IP, n=8). These results suggest that the antiarrhythmogenic effect of low concentrations of Ang-(1-7) is mediated by a specific receptor and that release of endogenous prostaglandins.by Ang-(1-7) contributes to the alleviation of reversible and/or irreversible ischemia-reperfusion injury.

Topics: Angiotensin I; Angiotensin II; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradykinin; Heart Ventricles; In Vitro Techniques; Indomethacin; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Peptide Fragments; Rats; Rats, Wistar

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 microgram kg(-1) min(-1) intravenously) decreased arterial blood pressure (by 11+/-3%; P<0. 05) and increased coronary blood flow (by 12+/-4%, P<0.05). There were no other significant haemodynamic changes. Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2+/-0.1 c.p. 10.7+/-3.3; P<0. 05). Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia-reperfusion insult 67% c.p. 0% in controls; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin. British Journal of Pharmacology (2000) 129, 671 - 680

Topics: Adrenergic beta-Antagonists; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Blood Pressure; Bradykinin; Coronary Circulation; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Female; Kidney; Lung; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Neprilysin; Peptidyl-Dipeptidase A; Phenylalanine