angiotensin-i and Myocardial-Ischemia

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: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Biological Availability; Cardiovascular Diseases; Endothelium, Vascular; Humans; Hypertension; Kinins; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peptide Fragments; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Ventricular Remodeling

Topics: Angiotensin I; Angiotensin II; Animals; Blood Flow Velocity; Cardiomegaly; Coronary Vessels; Dogs; Humans; Hypoxia; In Vitro Techniques; Myocardial Ischemia; Peptidyl-Dipeptidase A; Rats; Renin-Angiotensin System; Swine

To evaluate the effects of left ventricular (LV) dysfunction upon the sympathetic nervous and renin-aldosterone-angiotensin systems, neurohormonal factors were measured in patients with ischemic heart disease. Eleven patients were divided into two groups by their LV ejection fraction based on previous catheterization; preserved (EF > or = 60%) and impaired (EF < 60%) LV systolic function groups. They performed supine ergometer exercise and blood samples were drawn at rest and at peak exercise. After dynamic exercise, plasma norepinephrine was significantly (p < 0.05) increased in patients with preserved LV function, whereas it was not altered in patients with impaired LV function (norepinephrine 20.8 +/- 20.5 vs 45.8 +/- 41.9, respectively). We observed no differences in basal or peak levels of neurohormonal factors, including plasma renin activity, aldosterone, and brain natriuretic peptide (BNP), between the groups. Although the plasma levels of angiotensin I and II were not different in the two groups at rest or at peak exercise, their increasing ratios from rest to peak exercise were significantly higher in patients with impaired LV function compared to those with preserved LV function (angiotensin I; -18.6 +/- 31.0% vs 64.8 +/- 66.5%, p < 0.05, angiotensin II; -5.9 +/- 41.2% vs 60.7 +/- 40.4% , p < 0.05). These results suggest that the increasing ratios of angiotensin I and II are superior to BNP as predictors of LV dysfunction, and that the sympathetic nervous system has already been activated even at rest and did not respond to dynamic exercise in patients with LV dysfunction in ischemic heart disease.

Topics: Aged; Angiotensin I; Angiotensin II; Exercise Test; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Pilot Projects; Renin-Angiotensin System; Stroke Volume; Sympathetic Nervous System; Ventricular Dysfunction, Left; Ventricular Function, Left

Heart chymase rather than angiotensin converting enzyme has higher specificity for angiotensin (Ang) I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. We address here whether Ang-(1-12) and chymase gene expression and activity are detected in the atrial appendages of 44 patients (10 females) undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation or ischemic heart disease.. Immunoreactive Ang-(1-12) expression was 54% higher in left atrial compared with right atrial appendages. This was associated with higher abundance of left atrial appendage chymase gene transcripts and chymase activity, but no differences in angiotensinogen mRNA. Atrial chymase enzymatic activity was highly correlated with left atrial but not right atrial enlargement as determined by echocardiography, while both tyrosine hydroxylase and neuropeptide Y atrial appendage mRNAs correlated with atrial angiotensinogen mRNAs.. Higher Ang-(1-12) expression and upregulation of chymase gene transcripts and enzymatic activity from the atrial appendages connected to the enlarged left versus right atrial chambers of subjects with left heart disease defines a role of this alternate Ang II forming pathway in the processes accompanying adverse atrial and ventricular remodeling.

Topics: Aged; Angiotensin I; Angiotensin II; Angiotensinogen; Atrial Fibrillation; Chymases; Echocardiography; Female; Gene Expression Regulation, Enzymologic; Heart Atria; Heart Valve Diseases; Humans; Male; Middle Aged; Myocardial Ischemia; RNA, Messenger; Up-Regulation; Ventricular Remodeling

The aim of this study was to evaluate the impact of Ang-(1-7) on calcium transient (CaT) in cardiomyocytes during the pathogenesis of heart failure. Cardiac dysfunction was induced by ligation of left anterior descending coronary artery in adult SD rats. Randomly selected rats were ligated and continuously infused with Ang-(1-7) [HF + Ang-(1-7) group] or saline (HF + saline group) via osmotic minipumps. After 28 days, hemodynamic parameters, the CaT, and the heart rate threshold of CaT alternans (CaT-Alt) were measured. Continuous Ang-(1-7) treatment could attenuate the impairment of cardiac function following LAD ligation. The amplitudes (F/F0) and 50%/90% recovery time of CaT were significantly different among HF + saline, HF + Ang-(1-7) and Sham-operated group. Compared to the Sham-operated group, the HF + saline group showed decreased CaT amplitude, and a prolonged 50%/90% CaT recovery time; Ang-(1-7) significantly improved these abnormalities. Compared with Sham-operated group, heart rate thresholds of CaT-Alt significantly reduced in HF + saline group, and Ang-(1-7) partly restored it. These findings indicate that Ang-(1-7) attenuates the CaT disturbance and increases the heart rate threshold of CaT-Alt during the pathogenesis of ischemic heart failure.

Topics: Angiotensin I; Animals; Calcium; Calcium Channels, L-Type; Heart; Hemodynamics; Male; Myocardial Ischemia; Myocardium; Peptide Fragments; Rats; Rats, Sprague-Dawley

The influence of hypertonic solution on dye coupling was investigated in cell pairs isolated from the left ventricle of adult Sprague Dawley rats.The hypertonic solution together with Lucifer Yellow CH, were dialyzed into one cell of the pair using the whole cell clamp tecnique, and the diffusion of dye in the dialyzed as well as in non-dialyzed cell, was followed by measuring the intensity of fluorescence in both cells as a function of time.The results indicated that: (1) Lucifer Yellow CH dialyzed into one cell of the pair diffuses easily into the nondialyzed cell through gap junctions; (2) the intracellular dialysis of an hypertonic solution into one cell of the pair, increases the area of the dialyzed cell and reduced the area of the non-dialyzed cell suggesting intercellular movement of water; (3) the hypertonic solution dialyzed into one cell of the pair abolished the dye coupling; (4) the gap junction permeability (Pj) estimated before and after administration of hypertonic solution showed an appreciably decrease of Pj; (5) angiotensin (1-7) (Ang (1-7) (10-9M) administered to the bath re-established the dye coupling abolished by hypertonic solution and reduced the cell area; (6) the effect of Ang (1-7) was related to the activation of Mas receptor and was dependent on the activation of PKA.. the reestablishment of dye coupling elicited by Ang (1-7) seen in cell pairs dialyzed with hypertonic solution, might indicate that under similar conditions like that seen during myocardial ischemia, the peptide might be of benefit preventing the impairment of cell communication and impulse propagation associated with cardiac reentrant arrhytmias.

Topics: Angiotensin I; Animals; Cell Communication; Cell Membrane Permeability; Cell Size; Cells, Cultured; Fluorescent Dyes; Gap Junctions; Hypertonic Solutions; Isoquinolines; Myocardial Ischemia; Myocytes, Cardiac; Peptide Fragments; Rats; Rats, Sprague-Dawley

The present study investigated the actions of des-aspartate-angiotensin I (DAA-I) on infarct size and three early inflammatory events in acute myocardial ischemia-reperfusion injury in rats. The rationale was based on earlier findings showing that chronic daily administration of DAA-I attenuated infarct size of ischemic-reperfused rat heart, and cardiac hypertrophy in pressure overload rats. Anesthetized rats were subjected to 45 min of ischemia and 5h of reperfusion. Infarcted area, serum creatine kinase, and tissue myeloperoxidase activity were determined. The expression of intercellular adhesion molecule-1 (ICAM-1) was also investigated by immunohistochemistry and Western blotting. Intravenous administration of DAA-I at 5 min post reperfusion reduced myocardial infarct size by 45.5%, lowered serum creatine kinase activity, decreased myeloperoxidase activity in cardiac tissue, and inhibited the expression of ICAM-1 in cardiac capillary endothelium. The maximum effective dose was 1013 pmol/kg, and the cardioprotective actions of DAA-I were blocked by indomethacin. The data showed that the cardioprotection accorded by DAA-I was the result of its anti-inflammatory actions on early inflammatory processes in myocardial ischemia-reperfusion injury. The anti-inflammatory processes were indomethacin sensitive and probably mediated by prostaglandins.

Topics: Angiotensin I; Animals; Creatine Kinase; Gene Expression Regulation; Intercellular Adhesion Molecule-1; Male; Myocardial Infarction; Myocardial Ischemia; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Myocardial infarction (MI) results in cell death, development of interstitial fibrosis, ventricular wall thinning and ultimately, heart failure. Angiotensin-(1-7) [Ang-(1-7)] has been shown to provide cardioprotective effects. We hypothesize that lentivirus-mediated overexpression of Ang-(1-7) would protect the myocardium from ischaemic injury. A single bolus of 3.5 × 10(8) transducing units of lenti-Ang-(1-7) was injected into the left ventricle of 5-day-old male Sprague-Dawley rats. At 6 weeks of age, MI was induced by ligation of the left anterior descending coronary artery. Four weeks after the MI, echocardiography and haemodynamic parameters were measured to assess cardiac function. Postmyocardial infarction, rats showed significant decreases in fractional shortening and dP/dt (rate of rise of left ventricular pressure), increases in left ventricular end-diastolic pressure, and ventricular hypertrophy. Also, considerable upregulation of cardiac angiotensin-converting enzyme (ACE) mRNA was observed in these rats. Lentivirus-mediated cardiac overexpression of Ang-(1-7) not only prevented all these MI-induced impairments but also resulted in decreased myocardial wall thinning and an increased cardiac gene expression of ACE2 and bradykinin B2 receptor (BKR2). Furthermore, in vitro experiments using rat neonatal cardiac myocytes demonstrated protective effects of Ang-(1-7) against hypoxia-induced cell death. This beneficial effect was associated with decreased expression of inflammatory cytokines (tumour necrosis factor-α and interleukin-6) and increased gene expression of ACE2, BKR2 and interleukin-10. Our findings indicate that overexpression of Ang-(1-7) improves cardiac function and attenuates left ventricular remodelling post-MI. The protective effects of Ang-(1-7) appear to be mediated, at least in part, through modulation of the cardiac renin-angiotensin system and cytokine production.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Interleukin-10; Interleukin-6; Lentivirus; Male; Myocardial Ischemia; Myocardium; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Renin-Angiotensin System; Transduction, Genetic; Ventricular Remodeling

Cardiac arrest resuscitation can present myocardial dysfunction determined by ischemic time, and inhibition of the angiotensin-converting enzyme (ACE) can reduce cardiac dysfunction during reperfusion.. To investigate the effects of angiotensin-I and different periods of ischemia on functional recovery in isolated rat hearts.. Isolated hearts from Wistar rats (n=45; 250-300 g) were submitted to different periods of global ischemia (20, 25 or 30 min) and reperfused (30 min) with Krebs-Henseleit buffer alone or with the addition of 400 nmol/L angiotensin-I, or 400 nmol/L angiotensin-I + 100 μmol/L captopril along the reperfusion period.. The maximal positive derivative of pressure (+dP/dt(max)) and rate-pressure product were reduced in hearts exposed to 25 min ischemia (~73%) and 30 min ischemia (~80%) vs. 20 min ischemia. Left ventricular end-diastolic pressure (LVEDP) and perfusion pressure (PP) were increased in hearts exposed to 25 min ischemia (5.5 and 1.08 fold, respectively) and 30 min ischemia (6 and 1.10 fold, respectively) vs. 20 min ischemia. Angiotensin-I caused a decrease in +dP/dt(max) and rate-pressure product (~85-94%) in all ischemic periods and an increase in LVEDP and PP (6.9 and 1.25 fold, respectively) only at 20 min ischemia. Captopril was able to partially or completely reverse the effects of angiotensin-I on functional recovery in 20 min and 25 min ischemia.. These data suggest that angiotensin-II directly or indirectly participates in the post-ischemic damage, and the ability of an ACE inhibitor to attenuate this damage depends on ischemic time.

Topics: Analysis of Variance; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Male; Models, Animal; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Random Allocation; Rats; Rats, Wistar; Recovery of Function; Time Factors

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be involved in the central regulation of autonomic function. During chronic heart failure (CHF), elevated central angiotensin II signaling contributes to the sustained increase of sympathetic outflow. This is accompanied by a downregulation of ACE2 in the brain. We hypothesized that central overexpression of ACE2 decreases sympathetic outflow and enhances baroreflex function in CHF. Transgenic mice overexpressing human ACE2 selectively in the brain (SYN-hACE2 [SA]) and wild-type littermates (WT) were used. CHF was induced by permanent coronary artery ligation. Four weeks after coronary artery ligation, both WT and SA mice exhibited a significant decrease in left ventricular ejection fraction (<40%). A slight decrease in mean arterial pressure was found only in SA mice. Compared with WT mice with CHF, brain-selective ACE2 overexpression attenuated left ventricular end-diastolic pressure; decreased urinary norepinephrine excretion; baseline renal sympathetic nerve activity (WT CHF: 71.6±7.6% max versus SA CHF: 49.3±6.1% max); and enhanced baroreflex sensitivity (maximum slope: WT sham: 1.61±0.16%/mm Hg versus SA CHF: 1.51±0.17%/mm Hg). Chronic subcutaneous blockade of mas receptor increased renal sympathetic nerve activity in SA mice with CHF (A779: 67.3±5.8% versus vehicle: 46.4±3.6% of max). An upregulation in angiotensin II type 1 receptor expression was detected in medullary nuclei in WT CHF mice, which was significantly attenuated in SA mice with CHF. These data suggest that central ACE2 overexpression exerts a potential protective effect in CHF through attenuating sympathetic outflow. The mechanism for this effect involves angiotensin (1-7) mas signaling, as well as a decrease in angiotensin II type 1 receptor signaling in the medulla.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Baroreflex; Enzyme Induction; Heart Failure; Humans; Male; Medulla Oblongata; Mice; Mice, Knockout; Myocardial Ischemia; Nerve Tissue Proteins; Nitric Oxide; Norepinephrine; Organ Specificity; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, Angiotensin; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins; Reflex, Abnormal; Sympathetic Nervous System

Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene and displaying an ACE level range similar to humans. Infarct size in ACE1c was 29% lower than in ACE2c (P<0.05). Pretreatment with a kinin B2 receptor antagonist suppressed this reduction. In ACE3c, infarct size was the same as in ACE2c. But ischemic preconditioning, which reduced infarct size in ACE2c (-63%, P<0.001) and ACE1c (-52%, P<0.05), was not efficient in ACE3c (-2%, NS, P<0.01 vs. ACE2c). In ACE3c, ischemic preconditioning did not decrease myocardial inflammation or cardiomyocyte apoptosis. Pretreatment with a renin inhibitor had no cardioprotective effect in ACE2c, but in ACE3c partially restored (38%) the cardioprotection of ischemic preconditioning. Thus, a modest genetic increase in ACE impairs myocardial tolerance to ischemia. ACE level plays a critical role in cardiac ischemia, through both kinin and angiotensin mediated mechanisms.

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Apoptosis; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Fumarates; Heart; Kinins; Lung; Mice; Mice, Mutant Strains; Myocardial Infarction; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Renin; Reperfusion Injury

We examined the influence of chronic treatment with ANG-(1-7) on development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with the nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). L-NAME administered orally (80 mg/l) for 4 wk significantly elevated mean arterial pressure (MAP) compared with SHR controls drinking regular water (269 +/- 10 vs. 196 +/- 6 mmHg). ANG-(1-7) (24 microg x kg(-1) x h(-1)) or captopril (300 mg/l) significantly attenuated the elevation in MAP due to L-NAME (213 +/- 7 and 228 +/- 8 mmHg, respectively), and ANG-(1-7) + captopril completely reversed the L-NAME-dependent increase in MAP (193 +/- 5 mmHg). L-NAME-induced increases in urinary protein were significantly lower in ANG-(1-7)-treated animals (226 +/- 6 vs. 145 +/- 12 mg/day). Captopril was more effective (96 +/- 12 mg/day), and there was no additional effect of captopril + ANG-(1-7) (87 +/- 5 mg/day). The abnormal vascular responsiveness to endothelin-1, carbachol, and sodium nitroprusside in perfused mesenteric vascular bed of SHR-L-NAME was improved by ANG-(1-7) or captopril, with no additive effect of ANG-(1-7) + captopril. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1-7)- or captopril-treated SHR-L-NAME, with additive effects of combined treatment. The beneficial effects of ANG-(1-7) on MAP and cardiac function were inhibited when indomethacin was administered with ANG-(1-7), but indomethacin did not reverse the protective effects on proteinuria or vascular reactivity. The protective effects of the ANG-(1-7) analog AVE-0991 were qualitatively comparable to those of ANG-(1-7) but were not improved over those of captopril alone. Thus, during reduced nitric oxide availability, ANG-(1-7) attenuates development of severe hypertension and end-organ damage; prostaglandins participate in the MAP-lowering and cardioprotective effects of ANG-(1-7); and additive effects of captopril + ANG-(1-7) on MAP, but not proteinuria or endothelial function, suggest common, as well as different, mechanisms of action for the two treatments. Together, the results provide further evidence of a role for ANG-(1-7) in protective effects of angiotensin-converting enzyme inhibition and suggest dissociation of factors influencing MAP and those influencing end-organ damage.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Diuresis; Enzyme Inhibitors; Heart; Hypertension; Kidney; Male; Myocardial Ischemia; Myocardium; NG-Nitroarginine Methyl Ester; Peptide Fragments; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recovery of Function; Reperfusion Injury; Severity of Illness Index; Vasomotor System

In this study we investigated the role of Mas on cardiac function during ischemia/reperfusion in isolated perfused mouse heart. Following a stabilization period of 30 min, hearts from WT and Mas KO mice were subjected to global ischemia. After 20 min of ischemia, the flow was restarted and the hearts were reperfused for 30 min. An additional group of WT mice was perfused with solution containing the Ang-(1-7) receptor Mas antagonist A-779. Isolated heart of Mas KO and WT treated with A-779 presented an increase in the perfusion pressure in the baseline period. This difference increased with 5 min of reperfusion reaching similar values to baseline period at the end of the reperfusion. Isolated hearts of Mas KO and WT treated with A-779 also presented a decreased systolic tension, +/-dT/dt, and HR. Upon global ischemia WT hearts showed a significant decrease in systolic tension and an increase in diastolic tension. During reperfusion an increase in systolic and diastolic tension was observed in WT mice. Deletion or blockade of Mas markedly attenuated these changes in isolated hearts. These results indicate that Mas plays an important role in cardiac function during ischemia/reperfusion which is in keeping with the cardiac and coronary effects previously described for Ang-(1-7).

Topics: Angiotensin I; Angiotensin II; Animals; Diastole; Mice; Mice, Knockout; Myocardial Ischemia; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Reperfusion; Systole

The cardiovascular role of angiotensin-(1-7), especially in the functional and metabolic alterations associated with ischemia-reperfusion (IR), is still not clearly defined. Our objective was to evaluate the cardiac effects of angiotensin-(1-7), the receptors involved, and their relationships with NADPH oxidase activation under non-ischemic conditions and, during an ischemia-reperfusion sequence. Isolated perfused rat hearts underwent 45 min of non-ischemic perfusion, or 30 min of global ischemia followed by 30 min of reperfusion. Angiotensin-(1-7) and/or AT1 receptor blocker losartan or angiotensin-(1-7) receptor antagonist (D-Ala7)-angiotensin-(1-7) were perfused. Our results showed that angiotensin-(1-7) was without effect at low concentrations (10(-10) to 10(-7) M). At a pharmacological concentration, 0.5 microM angiotensin-(1-7) induced vasoconstriction, which was antagonised by losartan. After ischemia, we noted a partial recovery of functional parameters, which was not modified by any of the treatments. The expression of AT1 receptor mRNA was increased by ischemia-reperfusion, except in (D-Ala7)-angiotensin-(1-7) treated hearts. Angiotensin-(1-7) further increased the AT1 expression. NADPH oxidase activity was enhanced in 0.5 microM angiotensin-(1-7)-treated hearts subjected to ischemia-reperfusion, this effect was totally reversed by losartan. This is the first time that it has been shown that, in the heart, angiotensin-(1-7) at pharmacological concentration activates NADPH oxidase, an enzyme thought to be involved in several angiotensin II effects.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Enzyme Activation; Heart; In Vitro Techniques; Losartan; Male; Myocardial Ischemia; Myocardium; NADPH Oxidases; Peptide Fragments; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Reperfusion

Occlusion of the left main coronary artery for 45 min caused sizable infarct scarring of the left ventricular wall in the rat heart at 14 days post-reperfusion. Daily oral administration of des-aspartate-angiotensin I (DAA-I) for 14 days attenuated the area of the infarct scar and transmurality. The attenuation was dose-dependent and biphasic; maximum effective dose was 1524 nmol/kg, and doses higher than this were progressively inactive. The exact mechanism of the biphasic attenuation is not known, and receptor down-regulation by internalization, which has been implicated in a similar biphasic nature for the anticardiac hypertrophic action of DAA-I, could be a likely cause. Indomethacin (101 micromol/kg, i.p.), administered sequentially after the daily oral dose of DAA-I (1524 nmol/kg), completely inhibited the attenuation at 14 days post-reperfusion, indicating that prostaglandins may be involved in transducing the attenuation. The present findings support earlier indications that DAA-I exerts protective actions in cardiovascular pathologies in which angiotensin II is implicated. It is suggested that DAA-I exerts the cardioprotective action by acting on the same indomethacin-sensitive angiotensin AT1 receptor. Although similar array of protective actions are also seen with another endogenous angiotensin, angiotensin-(1-7), the present findings demonstrate for the first time the ability of an endogenous angiotensin to reduce the infarct size of an ischemic-reperfusion injured rat heart.

Topics: Administration, Oral; Angiotensin I; Animals; Cardiovascular Agents; Indomethacin; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Prostaglandins; Rats; Rats, Sprague-Dawley

The effect of angiotensin (1-7) (Ang 1-7) on membrane potential and excitability of rat heart muscle under ischaemia/reperfusion was investigated.. The hearts of adult rats were removed under deep anaesthesia and perfused using the Langendorff method. After 40 minutes of global no-flow ischaemia, the heart was reperfused for five minutes and the right ventricle was dissected out and transferred to a transparent chamber, through which normal oxygenated Krebs solution flowed continuously (37 degrees C). Measurements of membrane potential were performed using an intracellular microelectrode connected to a high impedance preamplifier. The muscle was stimulated with rectangular current pulses (3 ms duration; 0.6 Hz) generated by an electronic stimulator and isolation unit. To study the influence of Ang (1-7) on sodium pump current, isolated myocytes were voltage-clamped at -40 mV and the current generated by the pump was recorded before and after the administration of Ang (1-7) (10-8 M) to the bath.. Ang (1-7) (10-8 M) hyperpolarised the ischaemic heart fibre and re-established impulse propagation. The increment of resting potential was related to the activation of the sodium pump. Indeed, Ang (1-7) (10-8 M) enhanced the transient outward current generated by an electrogenic sodium pump. Both effects of Ang (1-7) on membrane potential and pump current were abolished by ouabain (10-7 M). The cardiac refractoriness was also increased by Ang (1-7) (10-8 M).. Ang (1-7) activates the sodium pump, hyperpolarises the heart cell and re-establishes the impulse conduction during ischaemia/reperfusion. These effects of Ang (1-7), and the increment of cardiac refractoriness, provide an explanation for the reduced incidence of arrhythmias during ischaemia/reperfusion in the presence of Ang (1-7).

Topics: Angiotensin I; Animals; Electric Conductivity; Female; In Vitro Techniques; Membrane Potentials; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Neural Conduction; Papillary Muscles; Patch-Clamp Techniques; Peptide Fragments; Rats; Rats, Sprague-Dawley; Refractory Period, Electrophysiological; Sodium-Potassium-Exchanging ATPase

Accumulating evidence suggests that angiotensin-(1-7) (Ang-[1-7]) may play an important role in counteracting the pressor, proliferative, and profibrotic actions of angiotensin II in the heart. Thus, we evaluated whether Ang-(1-7) is expressed in the myocardium of normal rats and those in which myocardial infarction was produced 4 weeks beforehand.. The left coronary artery in 10-week-old Lewis rats was either ligated (n=5) or exposed but not occluded in age-matched controls (sham; n=5). Left ventricular end-diastolic pressures were significantly elevated 4 weeks after myocardial infarction (25+/-1 versus 5+/-1 mm Hg for sham; P<0.001), whereas left ventricular systolic pressures were significantly reduced (ligated 86+/-4 versus sham 110+/-5 mm Hg; P<0.01). Hemodynamic effects of coronary artery ligation were accompanied by significant cardiac hypertrophy (heart weight to body weight: ligated 4.3+/-0.1 versus sham 2.9+/-0.1 mg/g; P<0.001). In both ligated and sham rats, Ang-(1-7) immunoreactivity was limited to cardiac myocytes and absent in interstitial cells and coronary vessels. Ang-(1-7) immunoreactivity was significantly augmented in ventricular tissue surrounding the infarct area in the heart of rats with myocardial infarction.. Development of heart failure subsequent to coronary artery ligation leads to increased expression of Ang-(1-7),which was restricted to myocytes.

Topics: Angiotensin I; Animals; Cardiomyopathies; Disease Models, Animal; Hemodynamics; Immunohistochemistry; Ligation; Male; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Peptide Fragments; Rats; Rats, Inbred Lew

We evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) on post-ischemic function in isolated hearts from adult male Wistar rats perfused according to the Langendorff technique. Local ischemia was induced by coronary ligation for 15 min. After ischemia, hearts were reperfused for 30 min. Addition of angiotensin II (Ang II) (0.20 nM, N = 10) or Ang-(1-7) (0.22 nM, N = 10) to the Krebs-Ringer perfusion solution (KRS) before the occlusion did not modify diastolic or systolic tension, heart rate or coronary flow (basal values for Ang-(1-7)-treated hearts: 0.72 +/- 0.08 g, 10.50 +/- 0.66 g, 216 +/- 9 bpm, 5.78 +/- 0.60 ml/min, respectively). During the period of occlusion, the coronary flow, heart rate and systolic tension decreased (values for Ang-(1-7)-treated hearts: 2.83 +/- 0.24 ml/min, 186 +/- 7 bpm, 6.95 +/- 0.45 g, respectively). During reperfusion a further decrease in systolic tension was observed in control (4.95 +/- 0.60 g) and Ang II-treated hearts (4.35 +/- 0.62 g). However, in isolated hearts perfused with KRS containing Ang-(1-7) the further reduction of systolic tension during the reperfusion period was prevented (7.37 +/- 0.68 g). The effect of Ang-(1-7) on the systolic tension was blocked by the selective Ang-(1-7) antagonist A-779 (2 nM, N = 9), by the bradykinin B2 antagonist HOE 140 (100 nM, N = 10), and by indomethacin pretreatment (5 mg/kg, ip, N = 8). Pretreatment with L-NAME (30 mg/kg, ip, N = 8) did not change the effect of Ang-(1-7) on systolic tension (6.85 +/- 0.61 g). These results show that Ang-(1-7) at low concentration (0.22 nM) improves myocardial function (systolic tension) in ischemia/reperfusion through a receptor-mediated mechanism involving release of bradykinin and prostaglandins.

Topics: Analysis of Variance; Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Heart Rate; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Peptide Fragments; Rats; Rats, Wistar

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensinogen; Cardiomyopathy, Dilated; Cardiovascular Diseases; Chymases; Endothelin-1; Gene Expression; Gene Expression Regulation; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Iodine Radioisotopes; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Platelet-Derived Growth Factor; Protein Precursors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Serine Endopeptidases; Ventricular Function, Left

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

The cardiac ATP-sensitive potassium (K(ATP)) channel is potentially composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the cardiac type of sulfonylurea receptor (SUR2A). We reported that cardiac Kir6.1 mRNA and protein are specifically upregulated in the non-ischemic as well as the ischemic regions in rats with myocardial ischemia, suggesting that humoral and/or hemodynamic factors are responsible for this regulation. In the present study, pretreatment with TCV-116, an angiotensin (Ang) II type 1 receptor antagonist, completely inhibited the upregulation of Kir6.1 mRNA and protein expression in both regions of rat hearts subjected to 60 min of coronary artery occlusion followed by 24 h of reperfusion; whereas pretreatment with lisinopril, an Ang converting enzyme (ACE) inhibitor, partly inhibited this upregulation. Except for rats pretreated with TCV-116, Kir6.1 mRNA levels were positively correlated with those for brain natriuretic peptide (BNP), a molecular indicator of regional wall stress, in both the non-ischemic and the ischemic regions. Plasma Ang II levels were not elevated in rats with control myocardial ischemia compared with sham rats. Thus, the stress-related induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia is inhibited by pretreatment with an AT1 antagonist, but also in part by an ACE inhibitor, suggesting that activation of local renin-angiotensin system may play a role.

Topics: Angiotensin I; Angiotensin II; Animals; Benzimidazoles; Biphenyl Compounds; Blotting, Northern; Blotting, Western; DNA, Complementary; Lisinopril; Male; Myocardial Ischemia; Myocardium; Natriuretic Peptide, Brain; Potassium Channels; Potassium Channels, Inwardly Rectifying; Random Allocation; Rats; Rats, Wistar; Renin-Angiotensin System; RNA; RNA, Messenger; Tetrazoles; Time Factors; Up-Regulation

The Angiotensin I-converting enzyme (ACE) is a key component of the renin-angiotensin system thought to be important in the pathogenesis of hypertension and cardiovascular diseases. Previous studies showed that deletion polymorphism in the ACE gene might be a risk factor for myocardial infarction in the Caucasian population. However, this finding has not yet been reported in the Japanese population. In this study, a 287 base pair (bp) insertion/deletion polymorphism in intron 16 of the ACE gene was examined by polymerase chain reaction (PCR) in a cross-sectional study of 35 healthy subjects and 85 patients with ischemic heart diseases (IHD) (32 angina pectoris, 53 myocardial infarction). Polymorphism of the ACE gene was characterized by three genotypes; two deletion alleles (genotype DD), two insertion allele (genotype II) and heterozygotes alleles (genotype ID). No differences could be detected among the three genotypes for total cholesterol, high-density lipoprotein cholesterol, blood pressure and body mass index. The serum ACE activities in each II, ID and DD genotype were 10.1 +/- 2.1 microU/ml, 13 +/- 3.2 microU/ml, 14.2 +/- 5.4 microU/ml, respectively. In the population study the genotype DD was significantly associated with IHD when compared with the other two genotypes (ID and II). The frequency of deletion allele was higher (0.61) in the IHD group than in the normals (0.39) (chi 2 = 7.8, p < 0.01). These frequencies were not varied whether they had classic risk factors or not. Furthermore, coronary multivessel impairment was significantly associated with the deletion allele than with the insertion allele (chi 2 = 11.7, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin I; Base Sequence; Cross-Sectional Studies; Gene Deletion; Genotype; Humans; Japan; Middle Aged; Molecular Sequence Data; Myocardial Ischemia; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors

The anti-ischemic properties of the ACE inhibitor ramiprilat (ram) were investigated in electrically driven Langendorff hearts from rabbits whose endogenous angiotensin-I content has been previously shown to be very low (constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Cumulative concentration-response curves showed that the reduction in global coronary flow (CF) by exogenous angiotensin-I was concentration dependently inhibited by ram (P < 0.05). Myocardial ischemia (MI) was induced by occlusion of a left coronary artery branch and MI was quantified by NADH surface fluorescence photography. MI was significantly enlarged (+23%) (P < 0.05) by exogenous angiotensin-I (6 x 10(-9) mol/l). Addition of ram (10(-8) mol/l) to the perfusion buffer simultaneously with angiotensin-I, completely prevented the reduction of CF by angiotensin-I (P > 0.05) and significantly diminished MI even below control values (-25%) (P < 0.05). In the absence of exogenous angiotensin-I, ram alone (10(-8) mol/l) did not significantly enhance CF (P > 0.05), supporting findings demonstrating a very low endogenous angiotensin-I content in isolated rabbit hearts. However, ram alone (10(-8) mol/l) significantly diminished MI (-24%) (P < 0.05). We conclude that ram does possess direct cardioprotective properties that are independent of the inhibition of angiotensin-II generation but that may be related to potentiation of the effects of bradykinin.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Circulation; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Myocardial Ischemia; NAD; Rabbits; Ramipril

1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6. These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.

Topics: Anesthesia; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Enalaprilat; Female; Furosemide; Heart Rate; Imidazoles; Injections, Intravenous; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Renin-Angiotensin System; Tetrazoles

The endogenous activity of the local renin-angiotensin system (RAS) and the anti-ischaemic properties of captopril were investigated in electrically driven rabbit Langendorff hearts (constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol.l-1). Cumulative concentration-response curves showed no significant difference (P > 0.05) between the reduction of the global coronary flow (CF) by exogenous angiotensin-I or angiotensin-II (EC50 = 10(-10) mol.l-1). It is concluded that the local RAS in isolated rabbit hearts is highly sensitive, whereas its endogenous activity is very low due to very low endogenous angiotensin-I content. Myocardial ischaemia (MI) was induced by the occlusion of a left coronary artery branch and MI was quantified from NADH surface fluorescence photography. MI was significantly enlarged (+35%) (P < 0.05) by exogenous angiotensin-I (6 x 10(-9) mol.l-1). The reduction in CF and the increment in MI by angiotensin-I could be completely prevented by adding captopril at a low concentration (10(-6) mol.l-1) to the perfusion buffer. In the absence of exogenous angiotensin-I, captopril alone (10(-6) mol.l-1) neither significantly enhanced CF (P > 0.05), nor diminished MI (P > 0.05), supporting the finding of very low endogenous activity of the local RAS in this model. We, moreover, conclude that at a low concentration (10(-6) mol.l-1) captopril does not possess direct cardioprotective properties independent of its ACE inhibiting action.

Topics: Angiotensin I; Animals; Blood Flow Velocity; Captopril; Coronary Circulation; Dose-Response Relationship, Drug; Male; Myocardial Ischemia; Myocardial Reperfusion; NAD; Organ Culture Techniques; Rabbits; Renin-Angiotensin System