angiotensin-i and Cardiomyopathies

In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease.. PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm.. The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed.. The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Atrial Fibrillation; Blood Coagulation; Capillary Permeability; Cardiomyopathies; COVID-19; Cytokine Release Syndrome; Cytokines; Endothelium, Vascular; Fibroblasts; Fibrosis; Humans; Liver Cirrhosis; Myocarditis; Receptors, Coronavirus; Renin-Angiotensin System; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Thrombosis; Virus Internalization

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, at a young age, contributes to skele

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Autonomic Nervous System; Cardiomyopathies; Disease Models, Animal; Genotype; Heart; Humans; Mice, Knockout; Motor Activity; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Myocardium; Peptide Fragments; Phenotype; Renin-Angiotensin System; Sarcoglycans; Ventricular Dysfunction, Left; Ventricular Function, Left

Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. We hypothesized that angiotensin-(1-9) [Ang-(1-9)] attenuates cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Rats were injected with a single intraperitoneal injection of STZ (55 mg/kg body weight) to induced diabetic cardiomyopathy. 4 weeks later, diabetic rats were treated with Ang-(1-9) (200 ng/kg/min), angiotensin type 2 receptor (AT2R) blocker PD123319 (100 ng/kg/min), or Mas antagonist A779 (100 ng/kg/min) for 4 weeks. Although Ang-(1-9) treatment did not affect blood glucose and insulin levels, it significantly attenuated cardiac hypertrophy, reduced cardiac fibrosis and improved ventricular function in STZ-induced diabetic rats. Ang-(1-9) treatment suppressed cardiac NADPH oxidase activity and reduced formation of reactive oxygen species. Ang-(1-9) suppressed NFκB activation and reduced myeloperoxidase (MPO) activity and mRNA levels of TNFα and IL-1β in hearts of diabetic rats. In addition, Ang-(1-9) treatment suppressed activity of ACE and reduced angiotensin II (Ang II) formation in hearts of diabetic rats. The beneficial effect of Ang-(1-9) was blunted by coadministration of PD123319 but not by coadministration of A779. Finally, it was found that Ang-(1-9) treatment could alleviate STZ-induced cardiomyopathy in a dose-dependent manner. In conclusions, Ang-(1-9) attenuates cardiac dysfunction in STZ-induced diabetic rats. The Ang-(1-9)/AT2R axis should be investigated as a novel target for treatment of type 1 diabetic cardiomyopathy.

Topics: Angiotensin I; Animals; Cardiomyopathies; Diabetes Mellitus, Experimental; Infusions, Intravenous; Male; Oxidative Stress; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; Streptozocin; Treatment Outcome

Stress-induced cardiomyopathy (SIC) has gained increasing attention worldwide and is characterized by extensive ventricular akinesis, Beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are the main treatments for SIC patients. The pharmacological mechanism of action of beta-blockers results in the inhibition of the biological effects of catecholamines. However, the mechanism of action of ACEIs in the treatment of cardiomyopathy is not known. Our aim is to assess changes in levels of angiotensin II, angiotensin-II receptors and ACE responses to SIC.. A model of inverted SIC was established in rabbits by vagal electrical stimulation. The serum concentration of angiotensin II and angiotensin (1-7) was detected by enzyme-linked immunosorbent assay. Expression of angiotensin-II receptors was measured by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR), with localization detected by immunofluorescent staining. ACE-II expression in the myocardium was measured by Western blotting.. From one day after vagal stimulation, concentrations of angiotensin II were significantly higher in the experimental group than those in the control group (P <0.05). Stress induced a time-dependent decrease in angiotensin subtype-1 (AT1) expression and a time-dependent increase in AT2 expression only in the apical portion of the myocardium. From three days after vagal stimulation, angiotensin (1-7) levels were significantly lower in the experimental group compared with the control group (P <0.05). Expression of the ACE-II protein was significantly downregulated in the experimental group compared with the control group from three days after vagal stimulation (P <0.05).. Expression of angiotensin II, its receptors, ACE-II and angiotensin (1-7) was altered in response to SIC. The renin-angiotensin system could represent a therapeutic target in the prevention of SIC.

Topics: Angiotensin I; Angiotensin II; Animals; Cardiomyopathies; Disease Models, Animal; Female; Myocardium; Peptide Fragments; Rabbits; Receptors, Angiotensin; Renin-Angiotensin System; Stress, Physiological

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

The objective of this study was to clarify the relationship between angiotensin II and the pathogenesis of diabetic cardiomyopathy by observing the effects of related drugs on diabetic cardiomyopathy in rats. Captopril and Valsartan, an automatic biochemical analyzer, and radioimmunoassay technology were used to an experimental rat model of diabetic cardiomyopathy to dynamically measure the levels of creatine kinase-MB, lactate dehydrogenase-1 in the serum, and angiotensin I and II in the plasma, and to observe changes in the myocardial ultrastructure. The content of angiotensin I and II was increased and the renin-angiotensin system was in a hyperfunctional state in experimental rats with myocardial damage. Angiotensin-converting enzyme inhibitors and angiotensin II receptor 1 antagonists improved the myocardial structure and cardiac function. It is concluded that hyperfunction of the renin-angiotensin system is involved in the pathogenesis of diabetic cardiomyopathy, with an increase in angiotensin being a key factor. Preventing the increase in angiotensin II or the action of angiotensin II on its receptor can prevent the occurrence and development of diabetic cardiomyopathy.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cardiomyopathies; Creatine Kinase, MB Form; Diabetes Mellitus, Experimental; Female; Isoenzymes; L-Lactate Dehydrogenase; Male; Microscopy, Electron; Myocardium; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

The presence of Angiotensin (1-7) (Ang 1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters as well as the influence of Ang (1-7) on membrane potential, impulse propagation and cardiac excitability were investigated.. Histology and immunochemistry were used to demonstrate the presence of Ang (1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters. Measurements of transmembrane potentials, conduction velocity and refractoriness were made using conventional intracellular microelectrodes. The influence of Ang (1-7) on sodium pump current was investigated in voltageclamped myocytes isolated from the ventricle.. The results indicated the presence of Ang (1-7) and ACE 2 in myocytes of cardiomyopathic hamsters. Moreover,Ang (1-7) (10(-8) M) hyperpolarised the heart cell, increased the conduction velocity, and reduced transiently the action potential duration. The cardiac refractoriness was also increased by the heptapeptide, an effect in part reduced by an inhibitor of mas receptor. These findings indicate that Ang (1-7) has important antiarrhythmic properties. However, the beneficial effects of Ang (1-7) are dose-dependent because at higher concentration (10(-7) M) the heptapeptide elicited an appreciable increase of action potential duration and early-after depolarisations. Since losartan (10(-7) M) did not counteract this effect of the high dose of the heptapeptide, it is possible to conclude that activation of AT(1)-receptors is not involved in this effect of Ang (1-7). To investigate the mechanism of the hyperpolarising action of Ang (1-7) the influence of the heptapeptide on the sodium potassium pump current was studied in myocytes isolated from the ventricle of cardiomyopathic hamsters. The peak pump current density was measured under voltage clamp using the whole cell configuration. The results indicated that Ang (1-7) (10(-8) M) enhanced the electrogenic sodium pump, an effect suppressed by ouabain (10(-7) M).. Ang (1-7) has beneficial effects on the failing heart by activating the sodium pump, hyperpolarising the cell membrane and increasing the conduction velocity. These effects as well as the increment of refractoriness indicate that Ang (1-7) has antiarrhythmic properties. At higher concentrations (10(-7) M), however, the heptapeptide induced early-after depolarisations which leads to the conclusion that an optimal generation of Ang (1-7) must be achieved to permit a protective role of Ang (1-7) on cardiac arrhythmias.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Cardiomyopathies; Cricetinae; Disease Models, Animal; Heart; Heart Rate; Immunohistochemistry; Membrane Potentials; Myocardium; Peptide Fragments; Sodium Channels

The influence of intracellular and extracellular angiotensin II (Ang II) on the L-type calcium current of cardiomyocytes isolated from cardiomyopathic hamsters was investigated. The results indicated that Ang II (10(-8) mmol/L), added to the bath, increased the peak inward calcium current (I(Ca)) density by 37+/-3.4% (P<0.05), an effect that depends on the activation of protein kinase C. Intracellular administration of the same dose of Ang II (10(-8) mmol/L) also elicited an increase of peak I(Ca) density but enhanced the rate of I(Ca) inactivation, an effect not seen with extracellular Ang II. Moreover, in control animals, no change in the rate of I(Ca) inactivation was seen with intracellular Ang II. Thapsigargin (1 micromol/L), a potent inhibitor of sarcoplasmic reticulum (SR) ATPase, which depletes the SR, decreased the rate of I(Ca) inactivation elicited by intracellular Ang II, although the cytoplasmic calcium concentration was highly buffered with 10 mmol/L EGTA. These findings might indicate that intracellular Ang II releases calcium from the SR and inactivates I(Ca). The effect of intracellular Ang II on peak I(Ca) was not altered by extracellular losartan (10(-7) mmol/L), supporting the notion that the peptide acted intracellularly. Other studies showed that intracellular Ang I administration (10(-8) mmol/L) enhanced the peak I(Ca) density and the rate of I(Ca) inactivation, an effect that was reduced by intracellular enalaprilat (10(-8) mmol/L). Moreover, intracellular enalaprilat by itself reduced the peak I(Ca) density. These observations might indicate that endogenous Ang II is contributing to I(Ca) modulation in the failing heart.

Topics: Adenosine Triphosphatases; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Calcium Channels, L-Type; Calcium Signaling; Cardiomyopathies; Cells, Cultured; Cricetinae; Enalaprilat; Enzyme Activation; Extracellular Fluid; Intracellular Fluid; Losartan; Male; Mesocricetus; Myocytes, Cardiac; Protein Kinase C; Sarcoplasmic Reticulum; Staurosporine; Thapsigargin

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

Cross talk between angiotensin AT1 and alpha1-adrenergic receptors has been reported previously and points to the existence of physiologic regulation between the renin-angiotensin system and the sympathetic nervous system at the receptor level. This regulation may play an important role in the control of blood pressure and may be modified in different cardiovascular pathologies. Nevertheless, neither the physiologic actions nor the clinical relevance of the interaction between these 2 receptors has yet been established. To reveal these aspects in relation to heart failure, the interaction between vascular AT1 and alpha1-adrenergic receptors was evaluated in the Syrian cardiomyopathic hamster model.. The vascular response of each individual receptor to vasoactive agonist was assessed in the presence and absence of antagonists of the other receptor using aortic rings from 11-month-old Syrian cardiomyopathic hamsters. Age-matched golden hamsters were used as controls. In control hamsters, concentration-response curves for the norepinephrine (NE)-induced contraction were significantly displaced to the left after 100 mmol/L losartan incubation. The maximal tension achieved (Emax) values increased by 26+/-4.3% after incubation (P < .05). Similar results were obtained when 20 micromol/L enalapril was used to block angiotensin II (Ang II) synthesis. NE concentration-response curves were also displaced to the left and Emax increased by 27%+/-8.0% (P < .05). The concentrations that induce 50% of the maximal contraction (EC50) were 22.2+/-0.2 nmol/L for untreated and 27.1+/-2.0 nmol/L for losartan-treated aortic rings (n = 8, P > .05). However, EC50 values were significantly reduced in aortic rings treated with enalapril (7.51+/-0.16 nmol/L, n = 8, P < .05). Blockade of alpha1 receptor with 10 micromol/L prazosin increased the response to Ang II by 32% (n = 6, P < .05). In contrast, when these experiments were repeated in aortic rings from cardiomyopathic animals, no interaction between the 2 receptors was observed. NE concentration-response curves, Emax (9.6%+/-2.8% increase after enalapril. and 5.8%+/-6.5% increase after losartan, P > .05) and EC50 values (14.7+/-0.7 nmol/L without treatment, 17.5+/-1.5 nmol/L with enalapril and 11.1+/-0.8 with losartan, n = 8, P > .05) were similar. Furthermore, in cardiomyopathic animals, prazosin did not modify the vascular response to Ang II.. An interaction exists between vascular AT1 and alpha1-adrenergic receptors in control hamsters but not in cardiomyopathic animals. This interaction seems to be bidirectional and counterregulatory. The lack of this regulation may promote a state of enhanced vascular wall activity, which could contribute to the increased vasoconstriction and total peripheral resistance characteristic of heart failure.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Aorta; Cardiomyopathies; Cricetinae; Disease Models, Animal; Enalapril; Humans; Losartan; Male; Mesocricetus; Muscle Contraction; Muscle, Smooth, Vascular; Prazosin; Receptor Cross-Talk; Receptors, Adrenergic, alpha-1; Receptors, Angiotensin; Vascular Resistance

We examined the hypothesis that the positive inotropic effect of angiotensin I (Ang I) may be retained in the presence of angiotensin converting enzyme inhibitors so that it may have a direct beneficial effect on the heart. Accordingly, isolated perfused hearts (Langendorff preparation) of 300-day-old cardiomyopathic hamsters (a model of spontaneous cardiomyopathy) and age-matched normal hamsters (controls) were infused with Ang I in the presence of captopril; propranolol was added to the perfusing medium to block catecholamine-mediated effects of angiotensins on the heart. Left ventricular developed pressure and the rate of increase in left ventricular developed pressure increased significantly (p less than 0.001) in both the cardiomyopathic and the normal hamster heart despite concomitant reduction in myocardial flow rate favoring a direct inotropic effect of Ang I in both normal and myopathic hearts; these changes were significantly higher by almost threefold in the cardiomyopathic than in the normal hamsters (p less than 0.01) and were blocked by the angiotensin II (Ang II) antagonist [Sar1,Thr8]Ang II. Comparing dose-left ventricular contractility response curves for Ang I and Ang II, ED50 for responses was identical in both normal and myopathic hearts, whereas peak responses to Ang II were double those to Ang I in normal hearts but were almost identical in the myopathic hearts. Binding of [125I]Ang II in six cardiomyopathic and four normal hamster hearts was of high affinity, but there was no evidence for Ang I-saturable high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensins; Animals; Captopril; Cardiac Output, Low; Cardiomyopathies; Cricetinae; Drug Synergism; Heart; Male; Mesocricetus; Myocardial Contraction; Myocardium; Receptors, Angiotensin

Angiotensin II has been reported to have both a positive inotropic effect and a coronary constrictor action in the hamster heart. To study the contribution to these responses of phenylalanine in position 8, we assessed the direct cardiac effects of angiotensin-(1-7), which lacks phenylalanine in position 8. Syrian hamsters were used to determine the effects of angiotensin-(1-7) on cardiac performance in the diseased and normal hearts. We used the isolated isovolumic heart preparation perfused either at a constant pressure of 50 mm Hg or at a constant coronary (myocardial) flow rate of 7 ml/min (seven cardiomyopathic hamsters [CMH] and seven normal hamsters [NH] in each subgroup). At constant perfusion pressure, coronary (myocardial) flow rate decreased (p less than 0.01) in both CMH and NH (-31 +/- 8% vs. -39 +/- 4% of baseline, respectively); but the percent decrease in left ventricular pressure and the first derivative of left ventricular pressure over time (LV + dP/dt) was significant only in NH (-8 +/- 1% and -9 +/- 4%) but not in CMH (-14 +/- 5% and -21 +/- 8%). On the other hand, at a constant coronary (myocardial) flow rate, left ventricular pressure and LV + dP/dt tended to increase in both CMH and NH (+10 +/- 3% and +6 +/- 2% of baseline vs. +7 +/- 7% and +7 +/- 5%, respectively) but these changes were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin II; Animals; Cardiac Output; Cardiomyopathies; Coronary Circulation; Cricetinae; Heart; Male; Mesocricetus; Peptide Fragments; Perfusion; Pressure; Reference Values