angiotensinogen and Hypertension--Pulmonary

The renin-angiotensin system is an important regulator of vascular resistance in many patients with hypertension and congestive heart failure. To quantitatively evaluate this contribution requires correlation of markers of the renin-angiotensin system with haemodynamic parameters, notably blood pressure, cardiac output, and calculated systemic vascular resistance. In addition, to determine ventricular loading properties, assessment of cardiac filling pressures is also required. The availability of specific pharmacological inhibitors of the renin-angiotensin system greatly enhances such correlation, as the haemodynamic consequence of blocking the renin-angiotensin system can then more fully identify its contribution. In the last decade, highly specific pharmacological inhibitors have become available to serve such a purpose. Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin. However, this method of blockade is still at the early stages of investigation. More readily available are converting enzyme inhibitors which block the formation of angiotensin II, the potent vasoconstrictor which mediates increased systemic vascular resistance, and angiotensin II analogues which compete with endogenous angiotensin II for vascular and adrenal receptors. Although hypertension and chronic congestive heart failure are clinically distinct entities in many respects, their common bond is the fact that both pathological mechanisms are mediated by an increase of systemic vascular resistance. The implications of blocking the resulting vasoconstriction in both entities are therefore quite similar. This review summarises our present knowledge of the contribution of the renin-angiotensin system to the vasoconstriction of hypertension and congestive heart failure, and also summarises the haemodynamic consequences of such inhibition. The implications of the response to these specific pharmacological probes, as well as their limitations, are discussed. Their importance rests not only in their therapeutic application, but also in their contribution as probes for pathophysiological mechanisms of vasoconstriction in cardiovascular disease.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Dipeptides; Enalapril; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Kinetics; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin; Renin-Angiotensin System; Teprotide

We have recently reported that transgenic (mRen2)27 rats (Ren2 rats) exhibit pulmonary arterial hypertension (PAH), which is, in part, mediated by oxidative stress. Since 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exhibit beneficial vascular effects independent of cholesterol synthesis, we hypothesized that rosuvastatin (RSV) treatment ameliorates PAH and pulmonary vascular remodeling in Ren2 rats, in part, by reducing oxidative stress. Six-week-old male Ren2 and Sprague-Dawley rats received RSV (10 mg x kg(-1) x day(-)1 ip) or vehicle for 3 wk. After treatment, right ventricular systolic pressure (RVSP) and mean arterial pressure (MAP) were measured. To evaluate treatment effects on pulmonary arteriole remodeling, morphometric analyses were performed to quantitate medial thickening and cell proliferation, whereas whole lung samples were used to quantitate the levels of 3-nitrotyrosine, superoxide, stable nitric oxide (NO) metabolites [nitrates and nitrites (NO(x))], and expression of NO synthase isoforms. In the Ren2 rat, RVSP is normal at 5 wk of age, PAH develops between 5 and 7 wk of age, and the elevated pressure is maintained with little variation through 13 wk. At 8 wk of age, left ventricular function and blood gases were normal in the Ren2 rat. Ren2 rats exhibited elevations in medial hypertrophy due to smooth muscle cell proliferation, 3-nitrotyrosine, NO(x), NADPH oxidase activity, and endothelial NO synthase expression compared with Sprague-Dawley rats. RSV significantly blunted the increase in RVSP but did not reduce MAP in the Ren2 rat; additionally, RSV significantly attenuated the elevated parameters examined in the Ren2 rat. These data suggest that statins may be a clinically viable adjunct treatment of PAH through reducing peroxynitrite formation.

Topics: Angiotensinogen; Animals; Fluorobenzenes; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Magnetic Resonance Imaging; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Peptidyl-Dipeptidase A; Pulmonary Artery; Pyrimidines; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Rosuvastatin Calcium; Sulfonamides; Ventricular Function, Left; Ventricular Function, Right

In congenital diaphragmatic hernia (CDH), pulmonary hypertension increases right ventricle (RV) afterload, which could impair heart function and contribute to poor outcome for most affected infants. Nevertheless, the real significance of vascular pulmonary alterations in perinatal hemodynamics is largely unknown. It is defined that ventricular pressure overload induces increased myocardium gene expression of B-type natriuretic peptide (BNP) and components of the renin-angiotensinogen and endothelin (ET)-1 systems. Our aim was to evaluate perinatal myocardium expression of these genes associated with ventricular pressure overload in a nitrofen-induced CDH rat model.. In the nitrofen-induced CDH rat model, fetuses from dated pregnant Sprague-Dawley rats at 15.5, 17.5, 19.5 and 21.5 days postcoitum as well as newborn pups were assigned to 3 experimental groups: control, nitrofen (exposed to nitrofen, without CDH), and CDH (exposed to nitrofen, with CDH). Myocardial samples collected from the RV and left ventricle (LV) were processed for quantification of messenger RNA (mRNA) of BNP, angiotensinogen, and ET-1.. The perinatal expression of BNP, angiotensinogen, and ET-1 mRNA in the RV and LV of the control group revealed daily changes. During gestation, the expression of BNP and angiotensinogen mRNA underwent significant oscillation compared with control in both nitrofen-exposed fetuses, although we cannot identify significant differences between the nitrofen and CDH groups. After birth, we found a significant increasing expression of all studied genes only in the RV of CDH pups.. Perinatal myocardial quantification of BNP, angiotensinogen, and ET-1 mRNA levels suggests that both nitrofen-exposed and control pups revealed prenatal variations of expression of the studied genes. Moreover, CDH is associated with significant molecular alterations only in the RV after birth.

Topics: Adaptation, Biological; Angiotensinogen; Animals; Base Sequence; Biomarkers; Endothelin-1; Gene Expression; Genetic Markers; Heart Ventricles; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Phenyl Ethers; Rats; Rats, Sprague-Dawley; RNA, Messenger

In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Bosentan; Cytochrome P-450 CYP11B2; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Myocardial Contraction; Natriuretic Peptide, Brain; Neurotransmitter Agents; Peptides, Cyclic; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Sulfonamides; Ventricular Function; Ventricular Remodeling

The present study aimed to investigate the effects of olmesartan, an antagonist for angiotensin II receptor type 1(AT1), on the activation of extracellular signal-regulated kinases (ERK)1/2, tissue remodeling, and pro-inflammatory signals in the right ventricle and lung of mice during the early phase of hypobaric hypoxia. Phosphorylation of ERK1/2 in both tissue types in response to hypoxia peaked at 1-3 days, and declined rapidly in the right ventricle, whereas in the lung it was sustained for at least 8 days. Upregulation of angiotensinogen mRNA was observed in the hypoxic lung at 4-9 days, but not in the hypoxic right ventricle and pulmonary artery. Olmesartan inhibited the hypoxia-induced phosphorylation of ERK1/2 in the lung, but not in the right ventricle. Neither right ventricular hypertrophy nor the thickening of the intrapulmonary arterial wall was ameliorated by olmesartan. However, this drug inhibited the expression of the mRNA for angiotensinogen and several pro-inflammatory factors, including interleukin-6 and inducible nitric oxide synthase in the hypoxic lung. These results suggest that olmesartan blocks a potential positive feedback loop of the angiotensin II-AT1 receptor system, which may lead to attenuate pro-inflammatory signals in the mouse lung, that are associated with hypoxic pulmonary hypertension, without inducing any appreciable effects on the compensatory cardiopulmonary hypertrophy at an early phase of exposure to a hypobaric hypoxic environment.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Gene Expression Regulation; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Imidazoles; Inflammation Mediators; Lung; Male; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Olmesartan Medoxomil; Phosphorylation; Pulmonary Artery; RNA, Messenger; Tetrazoles; Up-Regulation

The renin-angiotensin system plays an important role in pulmonary artery remodelling. Several polymorphisms of genes encoding for components of the renin angiotensin system such as the angiotensin converting enzyme (ACE), the angiotensinogen (AGT) gene, and the angiotensin II type 1 receptor (ATIR) have been associated with the development of pulmonary hypertension. The aim of this study was to investigate the ACE I/D genotype, the M235 T polymorphism of the AGT gene and the A1166 C polymorphism of AT1R in the lungs of congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) in the newborn.. Genomic DNA was extracted from archival paraffin-embedded lung tissue from 13 newborns with CDH complicated by PPH and from 9 controls. Genotyping for the I/D-ACE, the M235 T-AGT, and the A1166 C-ATIR gene polymorphisms were determined by a polymerase chain reaction-based method with appropriate restriction digest when required.. In controls, ACE genotype distribution of DD, ID, and II was 11%, 33%, and 55%, respectively, whereas in CDH it was 70%, 15%, and 15%, respectively. The ACE-DD genotype was significantly higher in CDH compared with controls (P <.05). In CDH samples, the prevalence of AGT-MM genotype was lower (8% v. 33%; P <.05), whereas the AGT-TT genotype was higher (61% v. 22%; P <.05) compared with controls. There were no differences in allele frequencies of AT1R between CDH patients and controls.. These data suggest that D allele of the ACE gene insertion/deletion polymorphism and angiotensinogen M235 T polymorphism may be associated with PPH in newborns with congenital diaphragmatic hernia.

Topics: Alleles; Angiotensin II; Angiotensinogen; Case-Control Studies; Gene Frequency; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Receptors, Angiotensin; Renin-Angiotensin System