Soluble angiotensin IV receptor levels in preeclampsia: is there a variation?

OBJECTIVE: To measure the concentration of plasma soluble angiotensin IV receptor (sAT-4), a component of the renin-angiotensin system in healthy normotensive pregnancies and preeclampsia. STUDY DESIGN: Stored maternal plasma samples obtained at the time of diagnosis from pregnant women of African ancestry were stratified into normotensive and preeclampsia groups. Preeclampsia was subdivided into early-onset, late-onset, and into and severe preeclampsia. Plasma concentrations of sAT-4 were measured at 450 nm using the ELISA technique (LNPEP KIT). RESULTS: The systolic and diastolic blood pressure (BP) levels of the normotensive group were statistically lower compared to preeclampsia groups (p < .05) and the mean gestational age in early-onset preeclampsia was lower compared to late-onset preeclampsia and the normotensive group (p < .05). Plasma sAT-4 levels were significantly elevated (p < .0001) in the normotensive group (median 1.95, range 1.89-2.02 ng/ml) compared to the preeclampsia group (median 1.55, range 1.42-1.74 ng/ml), regardless of gestational age. Soluble AT-4 was decreased in relation to the severity of preeclampsia (p < .001), the level in preeclampsia without severe features (median 1.57, range 1.42-1.74 ng/ml) was significantly higher than in preeclampsia with severe features (median 1.51, range 1.42-1.55 ng/ml). There was no significant difference in the sAT-4 level between early-onset preeclampsia (1.60 ± 0.13 ng/ml) and late-onset preeclampsia (1.65 ± 0.29 ng/ml) groups (p = .59). CONCLUSION: Plasma circulating levels of sAT-4 in women with severe features of preeclampsia had lower levels than normotensives and those with preeclampsia without severe features.

Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation.

Advanced age is associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed central event is diminished amounts of nitric oxide (NO) due to reduced generation by endothelial NO synthase (eNOS) and increased oxidative stress. In addition, it is widely accepted that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10-15mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased insulin responses, reduced plasma creatinine as well as improved endothelial relaxation to acetylcholine and attenuated contractility to ANG II in resistance arteries. Mechanistically, nitrate reduced NADPH oxidase-mediated oxidative stress in the cardiovascular system and increased cGMP signaling. Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2 ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate for age-related disturbances in endogenous NO generation via inhibition of NADPH oxidase and modulation of ANG II receptor expression. These novel findings may have implications for nutrition-based preventive and therapeutic strategies against cardiovascular and metabolic diseases.

Neonatal growth restriction-related leptin deficiency enhances leptin-triggered sympathetic activation and central angiotensin II receptor-dependent stress-evoked hypertension.

BACKGROUND: Neonatal growth restriction (nGR) leads to leptin deficiency and increases the risk of hypertension. Previous studies have shown nGR-related hypertension is normalized by neonatal leptin (nLep) and exacerbated by psychological stress. With recent studies linking leptin and angiotensin signaling, we hypothesized that nGR-induced nLep deficiency increases adult leptin sensitivity; leading to leptin- or stress-induced hypertension, through a pathway involving central angiotensin II type 1 receptors. METHODS: We randomized mice with incipient nGR, by virtue of their presence in large litters, to vehicle or physiologic nLep supplementation (80 ng/g/d). Adult caloric intake and arterial pressure were monitored at baseline, during intracerebroventricular losartan infusion and during systemic leptin administration. RESULTS: nGR increased leptin-triggered renal sympathetic activation and hypertension with increased leptin receptor expression in the arcuate nucleus of the hypothalamus; all of those nGR-associated phenotypes were normalized by nLep. nGR mice also had stress-related hyperphagia and hypertension, but only the stress hypertension was blocked by central losartan infusion. CONCLUSION: nGR leads to stress hypertension through a pathway that involves central angiotensin II receptors, and nGR-associated leptin deficiency increases leptin-triggered hypertension in adulthood. These data suggest potential roles for preservation of neonatal growth and nLep supplementation in the prevention of nGR-related hypertension.

Rosiglitazone reduces the development and rupture of experimental aortic aneurysms.

BACKGROUND: Development and rupture of aortic aneurysms involve a combination of complex biological processes. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to have a broad spectrum of effects in vivo. The hypothesis that rosiglitazone would reduce aneurysm expansion or rupture was tested in the angiotensin II (Ang II)-induced hypercholesterolemic mouse model. METHODS AND RESULTS: Apolipoprotein E-deficient mice, 12 months of age, were allocated to 4 groups. Three groups were infused with Ang II (1 microg . min(-1) . kg(-1)), and the fourth was infused with saline. Rosiglitazone was given 1 week before infusion and 1 week after infusion. At day 28, aortic size was measured, and tissues were collected for analyses. Both pretreatment and posttreatment with rosiglitazone inhibited the occurrence of fatal rupture (11 of 30 versus 0 of 30 versus 0 of 15; P=0.0013) and reduced maximal dilatation of the aorta (4.6+/-0.13 versus 2.4+/-0.48 versus 2.15+/-0.46 mm2; P<0.0001). Blood glucose, total cholesterol, body weight, and atherosclerosis did not differ between groups. Pretreatment with rosiglitazone inhibited the Ang II-induced expression of angiotensin type 1a Ang II receptor while having no effect on the angiotensin type 2 Ang II receptor, in addition to reducing Ang II-induced expression of E-selectin, tumor necrosis factor-alpha, and interleukin-6. CONCLUSIONS: Pretreatment or posttreatment with RGZ reduced aortic expansion and rupture in this mouse model. Reduction of lesions in animals pretreated with rosiglitazone is concomitant with decreased expression of inflammatory mediators. Further studies are needed to elucidate the precise mechanism.

Insulin-regulated aminopeptidase/placental leucil Aminopeptidase (IRAP/P-lAP) and angiotensin IV-forming activities are modified in serum of rats with breast cancer induced by N-methyl-nitrosourea.

BACKGROUND: In previous reports, changes in oxytocinase activity in human breast cancer tissue and in the serum of N-methyl-nitrosourea (NMU)-induced rat mammary tumors were described. Insulin-regulated aminopeptidase (IRAP) has been identified with oxytocinase and has also been referred to as placental leucine aminopeptidase (P-LAP). MATERIALS AND METHODS: The IRAP/P-LAP activity in rat serum was assayed to analyze the putative role that IRAP/P-LAP may play in regulating mammary gland carcinogenesis induced by NMU. Furthermore, as it has been recently described that IRAP/P-LAP is the angiotensin IV (Ang IV) receptor AT4, the activities of Ang IV-forming aminopeptidase N (APN) and aminopeptidase B (APB) were also assayed. RESULTS: Changes in serum IRAP/P-LAP and Ang IV-forming APB activities were found in rats with mammary tumors induced by NMU. Both activities were greatly increased, although the Ang IV-forming APN activity was not modified. CONCLUSION: These changes in aminopeptidase activities may reflect the local functional status of their substrates, which can be selectively activated or inhibited in the affected tissue as a result of specific conditions brought about by the tumor. Thus, these enzymatic activities may be involved in the promotion and progression of breast cancer through oxytocin (OT), vasopressin (AVP) and/or renin-angiotensin system (RAS) misregulation.

[Effects of angiotensin II on male rats with diabetic erectile dysfunction].

OBJECTIVE: To investigate the changes of angiotensin II (Ang II) and its receptors in male rats with diabetic erectile dysfunction (DED) so as to study its effects. METHODS: Out of 40 male SD rats, 30 were taken at random for diabetic models. After 8 weeks, the rats with erectile dysfunction were selected from these models. All the rats were divided into 3 groups: control ( n = 10), diabetes mellitus( DM, n = 9) and DED (n = 8). For each rat, the Ang II levels in the blood and homogenate prepared from part of the isolated penile tissues were determined respectively, and the Ang II receptors of the rest of the penile tissues were analyzed through immunohistochemical (IHC) assay. RESULTS: Compared with the control group, Ang II levels in the blood and penile tissues in the DM group, and that in the blood of the DED group were very high and the differences were statistically significant (P < 0.05). Ang II in the penile tissues of the DED increased sharply (P < 0.01). The receptors of Ang II changed contrariwise to the level of Ang ll. CONCLUSION: Ang II may play an important role in the pathogenesis of DED, and the Ang II antagonist or inhibitor of the angiotensin-converting enzyme (ACEI) may become a therapeutic method for DED in the future.

Cardiac angiotensin II receptors as predictors of transplant coronary artery disease following heart transplantation.

AIMS: We tested the hypothesis that cardiac angiotensin II (Ang II) receptor gene transcription may predict the development of transplant coronary artery disease (TCAD) following heart transplantation. METHODS AND RESULTS: We examined the gene transcripts of Ang II type 1 (AT1R) and type 2 receptors (AT2R) in endomyocardial biopsy specimens from 50 heart transplant recipients. The progression of TCAD was measured as change in maximal intimal thickness (CMIT) and change in plaque volume (CPV) by intravascular ultrasound (IVUS) examinations from baseline to one year after transplantation. The development of transplant vasculopathy was defined as a CMIT of > or = 0.3 mm over one year. The level of AT(1)R mRNA was associated with that of AT2R in transplanted hearts (regression coefficient=1.77, 95% CI 0.85-2.89, p<0.0001). AT1R and AT2R gene transcripts were univariate predictors of CMIT (AT1R: regression coefficient 0.10, 95% CI 0.06-0.14, p<0.0001; AT2R: regression coefficient 0.28, 95% CI 0.17-0.40, p<0.0001 ) or CPV (AT1R: regression coefficient 0.41, 95% CI 0.17-0.65, p<0.0001 ; AT2R: regression coefficient 1.25, 95% CI 0.49-2.01, p=0.002 ). By one year, 21 (46%) transplant recipients showed evidence of transplant vasculopathy and the rest did not. The vasculopathic group demonstrated a higher level of expression of cardiac AT1R than the non-vasculopathic group (3.7+/-2.9 vs 1.6+/-1.7 folds; p=0.006). The level of AT(1)R mRNA in transplanted heart was identified as a discriminator that predicted the development of transplant vasculopathy with a sensitivity of 75% and specificity of 83%. CONCLUSIONS: Cardiac Ang II receptor gene transcripts are associated with the progression of TCAD following heart transplantation. Only AT1R gene transcripts predicted the development of transplant vasculopathy in this preliminary study. These findings potentially support a role of Ang II receptors in the progression of TCAD following cardiac transplantation.

The renin-angiotensin system in experimental radiation nephropathy.

Irradiation of the kidneys is followed by a well-defined sequence of changes leading eventually to kidney failure. In the rat, inhibition of angiotensin-converting enzyme or blockade of angiotensin II receptors can prevent the structural and functional changes that occur after kidney irradiation. These interventions are particularly effective between 3 and 10 weeks after irradiation. However, in a series of studies with the rat model we failed to find any evidence that the renin-angiotensin system (RAS) is activated in the first 10 weeks after kidney irradiation. First, if the RAS was activated during this interval, one would expect hypertension followed by proteinuria and azotemia. However, hypertension is significant only at the end of this period and is preceded by significant proteinuria and azotemia. This evolution is not in favor of an obviously activated RAS during the 3- to 10-week postirradiation interval that is critical for interventions aimed at the RAS. Second, plasma renin activity and active plasma renin protein concentrations are not significantly increased over the first 10 weeks after irradiation. Third, whole-blood and intrarenal angiotensin II levels are not increased and may even be decreased over this interval. This last observation is particularly important because the assay used is sensitive enough to detect the effects of dietary salt manipulation. We hypothesize that even the normal activity of the RAS contributes to injury after kidney irradiation, possibly by supporting the proliferation of cells that carry potentially lethal radiation injuries.

Vasoconstriction is determined by interstitial rather than circulating angiotensin II.

1. We investigated why angiotensin (Ang) I and II induce vasoconstriction with similar potencies, although Ang I-II conversion is limited. 2. Construction of concentration-response curves to Ang I and II in porcine femoral arteries, in the absence or presence of the AT(1) or AT(2) receptor antagonists irbesartan and PD123319, revealed that the approximately 2 fold difference in potency between Ang I and II was not due to stimulation of different AT receptor populations by exogenous and locally generated Ang II. 3. Measurement of Ang I and II and their metabolites at the time of vasoconstriction confirmed that, at equimolar application of Ang I and II, bath fluid Ang II during Ang I was approximately 18 times lower than during Ang II and that Ang II was by far the most important metabolite of Ang I. Tissue Ang II was 2.9+/-1.5% and 12.2+/-2.4% of the corresponding Ang I and II bath fluid levels, and was not affected by irbesartan or PD123319, suggesting that it was located extracellularly. 4. Since approximately 15% of tissue weight consists of interstitial fluid, it can be calculated that interstitial Ang II levels during Ang II resemble bath fluid Ang II levels, whereas during Ang I they are 8.8 - 27 fold higher. Consequently at equimolar application of Ang I and II, the interstitial Ang II levels differ only 2 - 4 fold. 5. Interstitial, rather than circulating Ang II determines vasoconstriction. Arterial Ang I, resulting in high interstitial Ang II levels via its local conversion by ACE, may be of greater physiological importance than arterial Ang II.

Selective down-regulation of AT2 receptors in uterine arteries from pregnant ewes given 24-h intravenous infusions of angiotensin II.

Previously, we showed that uterine arteries from late gestation pregnant ewes infused intravenously with angiotensin II (Ang II) for 24 h, displayed heightened responsiveness to Ang II in vitro. Furthermore, we found that a small population of ewes with a "preeclampsia-like" disorder also displayed this. Therefore, we have investigated the density and affinity of Ang II receptor subtypes in the uterine arteries from these groups. Ang II receptor binding was measured using 125I [Sar1Ile8] Ang II. Proportions of AT1 and AT2 receptors were determined by inhibiting 125I [Sar1Ile8] Ang II with losartan (AT1 antagonist) or PD 123319 (AT2 antagonist). Uterine arteries from 24-h Ang II-infused ewes had a lower proportion of AT2 receptors (56.2+/-2.3%) than control (saline-infused) ewes (84.1+/-1.0%; P<0.05). The density of AT2 receptors was reduced (P<0.05) while the density of AT1 receptors was not different. Thus, 24-h infusions of Ang II selectively down-regulated AT2 receptors in the uterine artery, resulting in heightened Ang II reactivity. By contrast, the binding properties of Ang II receptor subtypes in uterine arteries from ewes with the "preeclampsia-like" disorder were not different from control ewes.

[Evaluation of the platelet angiotensin receptor in pregnancy complicated by preeclampsia]. / Ocena receptorów angiotensynowych na plytkach krwi u kobiet z ciaza powiklana stanem przedrzucawkowym.

UNLABELLED: Preeclampsia is a major complication during human pregnancy. It results from a breakdown in the balance between the vasoconstrictor and vasodilator substances. Angiotensin II is a potent vasoconstrictor, which participates in the regulation of blood pressure and may be involved in the control of vascular tone. OBJECTIVE: The purpose of this study was to determine the platelet angiotensin II receptor number and angiotensin II level in pregnancies complicated by preeclampsia. Preeclampsia was defined according to American College of Obstetricians and Gynecologists (ACOG) classification. PATIENTS AND METHODS: Ligand binding techniques were used for the examination of platelet angiotensin II binding sites in the third trimester pregnant women. The study was carried out in 13 patients with singleton pregnancy complicated by preeclampsia. A control group consisted of 17 healthy normotensive patients with singleton uncomplicated pregnancy and normal laboratory tests. All studied patients were nonsmokers. RESULTS AND CONCLUSIONS: There were no statistically significant differences in patient profiles between groups including gravidity, parity, maternal age, gestational age and height. Maternal weight, BMI and systolic, diastolic blood pressure and mean arterial blood pressure (MAP) were higher in the study group in comparison with the control group. Our study revealed elevated platelet angiotensin II receptor number and decreased maternal angiotensin II level in singleton pregnancies complicated by preeclampsia. There were no correlations between platelet angiotensin II receptor number and plasma angiotensin II level in the studied subjects. Our results are in accord with other published data and point out to the significant role of renin-angiotensin-aldosterone system and angiotensin II receptors in the pathogenesis of preeclampsia.

Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II.

BACKGROUND: The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II). METHODS AND RESULTS: Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, (125)I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during (125)I-Ang I infusion. Ang II type 1 (AT(1)) receptor-mediated uptake of circulating (125)I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT(1) receptor-mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT(1) receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%. CONCLUSIONS: Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT(1) receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT(1) receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.

Expression of renal and vascular angiotensin II receptor subtypes in children.

Angiotensin II (Ang II) AT1 receptors modulate most of the known physiological functions of Ang II in the kidney and cardiovascular structures. In contrast, the physiological role of AT2 receptors, which are abundantly expressed in fetal tissues, is not clearly defined. The changes that occur in the expression and distribution of AT2 receptors in the kidney and arteries during the first 2 years of life have not been studied. We have localized and characterized the expression of Ang II receptor subtypes, AT1 and AT2, in the kidney, interlobular arteries, thoracic aorta, and middle cerebral artery, in children during their first 2 years of life, using quantitative autoradiography. Renal glomeruli and middle cerebral arteries expressed exclusively AT1 receptors. In contrast, more than 80% of the Ang II receptors expressed in thoracic aorta and interlobular arteries belonged to the AT2 subtype. These findings demonstrate that the expression of Ang II receptor subtypes in different vascular structures in young children varies according to the tissue.

Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.

Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.

Long-term blood pressure telemetry in AT2 receptor-disrupted mice.

OBJECTIVES: The hypertension in AT2 receptor knockout mice is imperfectly defined. Therefore, we investigated the influence of dietary salt loading and deoxycorticosterone (DOCA)-salt treatment on blood pressure and diurnal patterns of blood pressure in these mice by radiotelemetry. METHODS: We used telemetry in AT2 receptor knockout and wild-type mice to measure blood pressure, heart rate, aortic pressure dp/dt, locomotor activity, and circadian rhythms. Salt-related effects were studied by increasing the salt in chow to 4%, adding 1% saline in drinking water, and by DOCA-salt treatment RESULTS: Baseline blood pressures were higher in AT2 receptor knockout than in wild-type mice and were not affected by increasing the salt intake. The blood pressure increase was steeper and greater in AT2 receptor knockout than in wild-type mice after DOCA-salt treatment A circadian rhythm of blood pressure and heart rate, with higher values during the night, was seen in wild-type, but not in AT2 receptor knockout mice. In AT2 receptor knockout mice, this rhythm was only significant when daily salt intake was increased or when DOCA-salt hypertension was induced. The acrophase of blood pressure and heart rate was found between 2000 and 2400 h and was in accordance with the maximum physical activity. CONCLUSION: These data suggest that AT2 knockout mice display slight hypertension which is not salt-sensitive. On the other hand, the susceptibility to develop DOCA-salt hypertension is increased. The study also illustrates the power of telemetry in monitoring long-term cardiovascular changes and circadian blood pressure and heart rate rhythms in genetically engineered mice.

[Polymorphism of vascular angiotensin II receptor gene and cardiovascular disorders]. / Polimorfizm gena sosudistogo retseptora angiotenzina II i serdechno-sosudistye zabolevaniia.

AIM: To study polymorphism of the gene of vascular angiotensin II receptor. MATERIALS AND METHODS: Polymorphism that consists in variability of adenine (A) and cytosine (C) residues at position 1166 of the gene for vascular angiotensin II receptor (AT1R) was analyzed in a Moscow population (n = 98) and three groups of affected patients with myocardial infarction (n = 32, MI), left ventricular hypertrophy (LVH, n = 38) and essential hypertension (EH, n = 178). Polymorphic region of the AT1R gene was amplified using the polymerase chain reaction (PCR) and genomic DNAs from human whole blood as template. PCR products were electrophoresied in a gel after digestion with BstDEI restriction nuclease. Significance of differences in distribution of both allele and genotype frequencies at the population sample and in affected patients were estimated via exact Fisher's test. RESULTS: A significant decrease in the frequency of the A genotype was detected in all the three affected groups compared to healthy controls. Besides, the frequency of the A allele was significantly decreased in EH group with a corresponding increase in the frequency of both the AC genotype and the C allele. CONCLUSION: The A1166C polymorphism of the AT1R gene is associated with EH, MI and LVH in a Moscow population. The association is stronger with EH. The A allele and the AA genotype protect against development of disorders at early onset while the other genotypes and the C-allele are risk factors. A protective role of the AA genotype is more significant than predisposition action of the CC homozygote.

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension.

Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT1 and AT2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT2 receptor mediated the vasodepressor response to footshocks in the presence of angiotensin AT1 receptor antagonist. We studied the role of kinins and nitric oxide in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan treated rats was blunted by systemic or IVT administration of icatibant (HOE 140) or N(G)-nitro-L-arginine-methyl ester, indicating that peripheral or brain kinins and nitric oxide are involved in the hypotensor response to footshocks during angiotensin AT1 receptor blockade. Our results suggest a role for angiotensin AT2 receptor in the regulation of arterial blood pressure, possibly through the release of vasodilator autacoids such as bradykinins and nitric oxide.

Genetic polymorphisms and coronary artery disease in the south of France.

Vascular disease is a multifactorial disease that involves atherosclerotic and thrombotic factors. Genetic polymorphisms have been associated with myocardial infarction and angina pectoris. The aim of the present study was to assess the relationship between some genetic polymorphisms and myocardial infarction (MI) or vasospastic angina pectoris in a population from southern France. Genetic polymorphisms of the renin angiotensin system (the D/I polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor [AT1R]) and of haemostatic factors (the -675 4G/5G polymorphism of the plasminogen-activator inhibitor 1[PAI-1] gene, and the G to T common point mutation in exon 2, codon 34 of the Factor XIII A-subunit gene) were examined. We assessed the genotype distribution in consecutive coronary artery disease (CAD) patients with MI (n = 201) and vasospastic angina pectoris (n = 43) and in 244 healthy controls comparable in age, sex, body mass index and total cholesterol level. The genotype distribution of AT1R polymorphism was significantly different between controls and patients, the prevalence of the C allele carriers being higher in patients with MI after the age of 45 than in control individuals (61 vs 45%, p <0.01), leading to an odds ratio (OR) of 2 (CI: 1.2-3.4). When looking at the group of patients with vasospastic angina the difference was even higher (76 vs 45%, p <0.01) yielding an OR of 4.3 (CI: 1.4-17.4). Genotype distributions of ACE, PAI-1 and Factor XIII polymorphisms were similar in patients and in controls. This study is in favor of a role of ATIR gene polymorphism in myocardial infarction and vasospastic angina.

Angiotensin converting enzyme DD genotype affects the changes of plasma plasminogen activator inhibitor-1 activity after primary percutaneous transluminal coronary angioplasty in acute myocardial infarction patients.

Angiotensin converting enzyme (ACE) DD genotype, and plasminogen activator inhibitor (PAI-1) 4G/4G genotype have been reported to affect PAI-1 activity in control subjects and atherosclerotic patients, but no data are available on the influence of angiotensin II type 1 receptor (AT1R) A1166C polymorphism on the inhibitor levels. The degree of fibrinolytic activation after percutaneous transluminal coronary angioplasty (PTCA) has been found to affect the risk of restenosis. The aim of this study was to investigate the possible influence of ACE I/D, AT1R A1166C, and PAI-1 4G/5G polymorphisms on the changes of PAI-1 activity after primary successful percutaneous transluminal angioplasty. In 29 consecutive acute myocardial infarction patients, undergoing primary successful angioplasty, genotyping of ACE I/D, AT1R A1166C, and PAI-1 4G/5G polymorphisms was performed by polymerase chain reaction and restriction fragment length polymorphism analysis, and PAI-1 plasma activity (chromogenic method) was assessed before and after angioplasty. Following angioplasty, PAI-1 activity increased in 10 of 29 patients and decreased or remained unchanged in 19 of 29. ACE DD genotype was significantly (P = 0.04) associated with an increase of PAI-1 activity post angioplasty (OR DD/ID+II = 6.5, CI 95% 4.83-8.22). Whereas no effect of PAI-1 4G/5G and AT1R A1166C polymorphisms on PAI-1 response to angioplasty was demonstrated, these data suggest that renin-angiotensin system genes are involved in the regulation of the fibrinolytic response to balloon injury, possibly affecting angiotensin converting enzyme activity. This interaction between the renin-angiotensin system and hemostasis may be a mechanism by which ACE DD genotype affects the risk of restenosis after percutaneous transluminal angioplasty.