Can we identify response markers to antihypertensive drugs? First results from the IDEAL Trial.

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25-70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was -11.5 mm Hg (indapamide) and -8.3 mm Hg (perindopril). In men, the response was significantly smaller: -4.8 mm Hg (indapamide) and -4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

[Renal denervation for treating hypertension: experience at the University Hospital in Lyon]. / Dénervation rénale dans le traitement de l'hypertension artérielle résistante : expérience du CHU de Lyon.

AIM: We report the first experience of Lyon's university hospital regarding renal denervation to treat patients with resistant essential hypertension. PATIENTS AND METHODS: Over a one-year period, 17 patients were treated (12 men, 5 women) with renal denervation. Baseline characteristics were as follows: age 56.5±11.5 years, BMI 33±5kg/m(2) and ambulatory blood pressure 157±16/87±13mmHg with 4.2±1.5 anti-hypertensive treatment. RESULTS: We did not observe intra-operative or early complications. After a median follow-up of 3 months and with the same anti-hypertensive treatment, office systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease respectively of 20±15 (P<0.001) and 10±13mmHg (P=0.014) (n=17). After six months of follow-up, ambulatory blood pressure (ABPM) decrease of 17.5±14.9mmHg (P=0.027) for SBP and of 10.5±9.6mmHg (P=0.029) for DBP (n=6). Among these patients, five of them were controlled (ABPM inferior to 130/80mmHg) and electrical left ventricular hypertrophy indexes decreased: R wave in aVL lead of 4±3mm (P=0.031), Sokolow index of 3±3mm (P=0.205), Cornell voltage criterion of 9±7mm (P=0.027) and Cornell product of 1310±1104 (P=0.027). CONCLUSION: Our results are in accordance with data from other centers. On average blood pressure decreases significantly but important inter individual variations are observed. The procedure seems safe.

Microarray analysis reveals overexpression of IBSP in human carotid plaques.

PURPOSE: Vascular calcification was considered to be a passive, degenerative, and end-stage process of vascular disease. However, bone associated proteins such as bone morphogenetic proteins, osteopontin, osteonectin, osteocalcin, and matrix Gla protein (MGP) have been found in the calcified atherosclerotic lesions. We studied by microarray analysis whether intact tissue and carotid plaque from the same patient differ in transcriptional profiling in response to arterial calcification. MATERIAL AND METHODS: mRNA gene expression was measured by an Affymetrix GeneChip Human Gene 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 68 specimens of endarterectomy from 34 patients. RESULTS: Integrin-binding sialoprotein (IBSP) was found to be differentially expressed. IBSP mRNA is over expressed in atheroma plaque (3.74 fold, p = 1.41E-09) in an intraindividual comparison. Besides, Carbonic anhydrase II (CA2) which known to be a putative calcification inhibitory molecule is over expressed more than 1.7 fold in carotid plaque (p = 1.26E-06). CONCLUSION: Although further evidence is needed, our results support previously available data. To our knowledge, this is the first report comparing gene expression between intact arterial tissue and carotid plaque using microarray analysis in order to identify calcification related genes. We suggest that plaques show a more pronounced induction of IBSP that may cause arterial calcification.

Time course of liver nitric oxide concentration in early septic shock by cecal ligation and puncture in rats.

An overwhelming nitric oxide (NO) production is a crucial step in the circulatory events as well as in the cellular alterations taking place in septic shock. However, evidences of this role arise from studies assessing the NO production on an intermittent basis precluding any clear evaluation of temporal relationship between NO production and circulatory alterations. We evaluated this relationship by using a NO specific electrode allowing a continuous measurement of NO production. Septic shock was induced by a cecal ligation and puncture (CLP) in a first group of anesthetized rats. After the same CLP, a second group received a selective iNOS inhibitor (L-NIL). Control rats were sham operated or sham operated with L-NIL administration. While NO concentration was measured every 2 min by a NO-sensitive electrode over 7h following CLP, the liver microcirculation was recorded by a laser-Doppler flowmeter. CLP induced a severe septic shock with hypotension occurring at a mean time of 240 min after CLP. At the same time, an increase in liver NO concentration was observed, whereas a decrease in microvascular liver perfusion was noted. In the septic shock group, L-NIL administration induced an increase in arterial pressure whereas the liver NO concentration returned to baseline values. In addition, shock groups experienced an increase in iNOS mRNA. These data showed a close temporal relationship between the increase in liver NO concentration and the microvascular alteration taking place in the early period of septic shock induced by CLP. The iNOS isoform is involved in this NO increase.

Lipogenesis in arterial wall and vascular smooth muscle cells of Psammomys obesus: its regulation and abnormalities in diabetes.

AIM: Lipogenesis is expressed in vascular smooth muscle cells (VSMCs), and such in situ lipogenesis could be providing the fatty acids for triglyceride synthesis and cholesterol esterification, and contributing to lipid accumulation in the arterial wall. This study investigated both the expression and regulation of lipogenesis in VSMCs to determine if they are modified in Psammomys obesus gerbils fed a high-fat diet as a model of insulin resistance and diabetes. METHODS: Aortas were collected from diabetic and non-diabetic P. obesus for histological examination, measurement of lipogenic gene expression and VSMC culture. RESULTS: The aortas of diabetic animals exhibited lipid deposits and foam cells as well as disorganization of elastic fibres. However, lipogenic gene expression was not modified. VSMCs in vitro from the aortas of diabetic animals had, compared with cells from non-diabetic animals, lower mRNA levels of SREBP-1c and ChREBP. An adipogenic medium stimulated moderate FAS and ACC1 expression in cells from both diabetic and non-diabetic animals, but glucose and insulin on their own had no such stimulatory action. Also, triiodothyronine (T3) had a clear stimulatory action, while angiotensin II had a moderate effect, in cells from non-diabetic P. obesus, but not from diabetic animals, whereas LXR agonists stimulated lipogenesis in cells from both animal groups. CONCLUSION: Lipogenesis is expressed in the arterial walls and VSMCs of P. obesus. However, its expression was not increased in diabetes, and did not respond to either T3 or angiotensin II. Therefore, lipogenesis in situ is unlikely to contribute to the accumulation of lipids in the arterial walls of diabetic P. obesus gerbils.

[Williams-Beuren syndrome: a multidisciplinary approach]. / Le syndrome de Williams-Beuren: une approche pluridisciplinaire.

Williams-Beuren syndrome (WBS) (OMIM# 194050) is a rare, most often sporadic, genetic disease caused by a chromosomal microdeletion at locus 7q11.23 involving 28 genes. Among these, the elastin gene codes for the essential component of the arterial extracellular matrix. Developmental disorders usually associate an atypical face, cardiovascular malformations (most often supravalvular aortic stenosis and/or pulmonary artery stenosis) and a unique neuropsychological profile. This profile is defined by moderate mental retardation, relatively well-preserved language skills, visuospatial deficits and hypersociability. Other less known or rarer features, such as neonatal hypercalcemia, nutrition problems in infancy, ophthalmological anomalies, hypothyroidism, growth retardation, joint disturbances, dental anomalies and hypertension arising in adolescence or adulthood, should be treated. The aim of this paper is to summarize the major points of WBS regarding: (i) the different genes involved in the deletion and their function, especially the elastin gene and recent reports of rare forms of partial WBS or of an opposite syndrome stemming from a microduplication of the 7q11.23 locus, (ii) the clinical features in children and adults with a focus on cardiovascular injury, and (iii) the specific neuropsychological profile of people with WBS through its characteristics, the brain structures involved, and learning.

Arterial stiffness is associated with left atrial size in hypertensive patients.

BACKGROUND: Arterial stiffness is a strong predictor of cardiovascular events and particularly of stroke. A likely explanation is the development of atherosclerotic lesions at the carotid level, favored by increased local stiffness. Another possibility involves cardiac consequences of aortic stiffness and particularly left atrial dilatation with its subsequent risk of atrial fibrillation (AF) and cerebral embolism. AIMS: The present study investigated the link between arterial stiffness, pulse pressure and left atrial size, a determinant of AF risk. METHODS: Arterial stiffness was determined from pulse wave velocity (PWV) and pulse pressure (PP). Left atrial size was also measured. Several potential confounders were taken into account including indices of ventricular remodeling and diastolic function (estimated by NT-Pro brain natriuretic peptide (NT-proBNP) levels). RESULTS: Three-hundred and ten hypertensive patients, aged 53 +/- 13 years, were included. Mean 24-h blood pressure (BP) was 154 +/- 20 over 93 +/- 13 mmHg. Significant relationships were found between left atrial diameter (LAD) and PWV (r=0.27, P<0.001) and between LAD and 24-h PP (r=0.32, P<0.001). LAD was also correlated significantly, although not always tightly, with left ventricular dimensions, geometry and NT-proBNP. In two different multivariate models, LAD remained significantly correlated with PWV or with 24-h PP, independently of classical determinants like age, gender, body mass index, ventricular remodeling (i.e. dimensions and geometry) and filling pressure. CONCLUSION: These results led us to propose AF as a new possible pathophysiological link between arterial stiffness and stroke. These results also emphasize the cardiac consequences of arterial stiffness which can fuel a new approach to AF prevention.

Role of selenium in heart lesions produced by neuroleptics in the rabbit.

Organic and/or functional heart lesions sometimes resulting in sudden death have been described in psychiatric patients treated with neuroleptics. As selenium has been suggested previously to play a role in the development of such lesions, the present study was undertaken to determine whether a correlation could be found between heart lesions induced by neuroleptics and changes in blood selenium as well as myocardial tissue concentrations in the rabbit. Twelve NZW adult rabbits were treated intramuscularly with both levomepromazine (3 mg kg(-1) day(-1)) and risperidone (1 mg kg(-1) once every other week) for 3 months, and compared with 12 saline-treated controls. Blood samples were drawn before and at the end of the study. Tissue samples from the heart, liver and kidneys were obtained at the end of treatment, and the hearts were examined histologically. Heart lesions including disorganization of cardiac fibers, myolysis, interstitial and endocardial fibrosis, and necrosis were noted in treated animals, but not in controls. There was a 20% decrease in selenium blood levels and a 50% decrease in selenium myocardial tissue levels in treated animals compared with controls (P < 0.001). In contrast, no differences in selenium levels in liver and kidneys were found across the experimental groups. These results suggest a possible correlation between selenium depletion and neuroleptics-induced heart lesions.

Experimental assessment of new stent technologies: validation of a comparative paired rabbit iliac artery study model.

Preventing coronary in-stent restenosis is a major challenge for physicians and industry. To assess new stent technologies, a comparative paired iliac artery model in rabbits is proposed. One tubular stent was implanted in each external iliac artery in 12 rabbits (i.e., 24 stents). An artery overdilatation level of 20% was strictly observed. Restenosis was examined at 30 days by angiography, intravascular ultrasound (IVUS) examination, and histomorphometry. On quantitative angiography, the mean loss of angiographic diameter was 9.8 +/- 4.4% in the right as compared to 9.3 +/- 55% in the left artery (p = 0.75). On IVUS, the volume of intrastent neointimal proliferation was 26.6 +/- 4.9 mm(3) in the right and 25.8 +/- 3.5 mm(3) in the left artery (p = 0.58). In histomorphometry, the neointimal proliferation area was 0.78 +/- 17 mm(2) in the right and 0.76 +/- 0.17 mm(2) in the left artery (p = 0.87). Intrastent neointimal proliferation was comparable between the left and right arteries of all rabbits. The model has three main advantages: (1) arterial dilatation and thus arterial wall aggression are controlled, (2) pairing makes each animal its own control subject, and (3) the statistical power for comparative testing is maximized. The model enables the effect of a new drug-delivery device to be assessed.

Thioredoxin reductase 1 is upregulated in atherosclerotic plaques: specific induction of the promoter in human macrophages by oxidized low-density lipoproteins.

Uptake of modified low-density lipoproteins (LDLs) by macrophages in the arterial wall is an important event in atherogenesis. Indeed, oxidatively modified LDLs (oxLDLs) are known to affect various cellular processes by modulating oxidation-sensitive signaling pathways. Here we found that the ubiquitous 55 kDa selenoprotein thioredoxin reductase 1 (TrxR1), which is a key enzyme for cellular redox control and antioxidant defense, was upregulated in human atherosclerotic plaques and expressed in foam cells. Using reverse transcription polymerase chain reaction analysis, we also found that oxLDLs, but not native LDLs (nLDLs), dose-dependently increased TrxR1 mRNA in human monocyte-derived macrophages (HMDMs). This stimulating effect was specific for oxLDLs, as pro-inflammatory factors, such as lipopolysaccharides (LPSs), interleukin-1beta (IL-1beta), interleukin-6 (Il-6), and tumor necrosis factor alpha (TNFalpha), under the same conditions, failed to induce TrxR1 mRNA levels to the same extent. Moreover, phorbol ester-differentiated THP-1 cells or HMDMs transiently transfected with TrxR1 promoter fragments linked to a luciferase reporter gene allowed identification of a defined promoter region as specifically responding to the phospholipid component of oxLDLs (p <.05 vs. phospholipid component of nLDLs). Gel mobility shift analyses identified a short 40-nucleotide stretch of the promoter carrying AP-1 and HoxA5 consensus motifs that responded with an altered shift pattern in THP-1 cells treated with oxLDLs, however, without evident involvement of either the Fos, Jun, Nrf2 or HoxA5 transcription factors.

[Markers of cardiovascular remodeling in hypertension]. / Marqueurs du remodelage cardiovascularire structural et fonctionnel dans l'hypertension.

UNLABELLED: Our goal was to study the relative influence of systolic blood pressure (SBP) and plasmatic markers of sympathetic and renin-aldosterone systems (RAS) activities to left atrial diameter (LAD), left ventricular posterior wall thickness (LVPWT) and pulse wave velocity (PWV), which reflect cardiovascular remodeling in hypertension. METHODS: In 227 consecutive patients with hypertension (mean age +/- SD: 53.3 years +/- 13.4, 126 men), we measured: PWV, LAD, LVPWT, mean 24-hours SBP, plasma renin activity, and plasma aldosterone and catecholamine levels. Multiples linear regression analyses were performed to test statistical associations between hemodynamic and neurohumoral factors, and cardiovascular remodeling parameters, after adjustment for age, gender and body mass index. RESULTS: LVPWT was positively correlated to SBP as well as to plasma aldosterone and meta-noradrenaline (p < 0.001). LAD and PWV were related to SBP but not to any of the biological variables. Moreover, LAD correlated to PWV independently of SBP (p < 0.05), whereas after SBP inclusion in the model, there was not significant correlation between LAD and LVPWT nor between LVPWT and PWV. CONCLUSION: In hypertension, the development of cardiac hypertrophy depends on SBP and the sympathetic and renin-aldosterone systems activities. The RAS is not involved in the PWV nor LAD modifications. Strong association between LAD and PWV suggest that left atrial enlargement, that may be considered as a marker of diastolic function, may results more from arterial stiffness than from ventricular hypertrophy.

[Expression of cytokines and their receptors in left ventricular hypertrophy in TGR(mRen2)27 rats]. / Expression des cytokines et de leurs récepteurs dans le ventricule gauche hypertrophique du rat TGR(mRen2)27.

Variations in the expression of cytokines from the interleukin-6 (IL-6) family: ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), and cardiotrophin 1 (CT-1) were studied during cardiac remodelling leading to left ventricular hypertrophy (LVH) in TGR(mRen2)27 rats at the age of 8 and 20 weeks. The cytokines mRNA levels within the free wall of the left ventricle were measured by semi-quantitative RT-PCR standardised with 18S. They were compared between heterozygous rats for the mRen2 transgene (TG+/-) and control rats (TG-/-). No significant difference was observed between results obtained at 8 and 20 weeks of age. At 20 weeks of age, TGR(mRen2)27 rats showed higher levels of mRNA LIF and IL-6 respectively by 52 and 55% compared to the control rats [LIF TG+/-: 3.17 +/- 0.21, TG-/-: 2.09 +/- 0.03; p < 0.001; n = 5; and IL-6 TG+/-: 1.53 +/- 0.13; TG-/-: 0.99 +/- 0.17; p < 0.05; n = 5]. By contrast, no variation of mRNAs levels of CT-1 and gp 130 genes was observed between control and transgenic rats. Concerning the cytokine receptors, the levels of mRNA for IL-6R did not vary while those of receptor subunits LIFR and CNTFR were decreased respectively by 48 and 42% in transgenic rats vs controls [LIFR TG+/-: 0.48 +/- 0.01; TG-/-: 0.92 +/- 0.08 p < 0.001; n = 5; and CNTFR TG+/-: 1.07 +/- 0.08; TG-/-: 1.85 +/- 0.18; p < 0.01; n = 5]. Therefore, these results show a specific pattern of activation of the cytokines pathway in the LVH of the TGR(mRen2)27 rat.

[Cardiotoxicity of 5-fluorouracil: report of 6 cases]. / Cardiotoxicité du 5-fluorouracil: à propos de 6 nouveaux cas.

5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite, is widely used in the treatment of cancers of the digestive tract and breast. The clinical cardiotoxicity of 5-FU was first reported in 1975. Adverse cardiac effects include coronary disorders, heart failure and sudden death of suspected cardiac origin. Six new cases are reported, including 5 cases of angina and one of heart failure. The patients, 4 males and 2 females, were 26 to 71 years of age (mean: 56.2). They had no medical history of heart failure, myocardial ischemia or electrocardiographic anomalies prior to 5-FU treatment. Three patients had hypertension of whom one had had type-II diabetes mellitus for the past 20 years. Clinical symptoms included chest pain in 4 patients and heart failure in one, whereas the last patient had ECG changes with no associated clinical symptoms. Clinical symptoms of angina totally disappeared after the cessation of 5-FU administration, but heart failure was alleviated only after the introduction of digitalis, a converting-enzyme inhibitor and a diuretic. It has been estimated that 1.6% of patients treated with 5-FU develop adverse cardiac effects. Patients at greater risk are those with a history of ischemic cardiac disease, thoracic radiotherapy or high-dose 5-FU therapy. The mechanism involved is not clearly elucidated. Spasms of the coronary arteries or toxic inflammation of the myocardium have been suspected. These 6 new cases confirm the potential for cardiotoxicity of 5-FU and the need for careful cardiac monitoring of treated patients.

Alterations in blood pressure and heart rate variability in transgenic rats with low brain angiotensinogen.

To study whether the brain renin-angiotensin system plays a role in the long-term and short-term control of blood pressure and heart rate variability, we examined in transgenic rats [TGR(ASrAOGEN)] with low brain angiotensinogen levels the 24-hour variation of blood pressure and heart rate. Telemetry recordings were made during basal and hypertensive conditions induced by a low-dose subcutaneous infusion of angiotensin II for 7 days. Short-term blood pressure and heart rate variability were evaluated by spectral analysis, and as a measure of baroreflex sensitivity, the average transfer gain between the pressure and heart rate variations was calculated. During the angiotensin II infusion in control but not TGR(ASrAOGEN) rats, the 24-hour rhythm of blood pressure was inverted (5.8+/-2 versus -0.4+/-1.8 mm Hg/group of day-night differences of blood pressure, P<0.05, respectively). In both the control and TGR(ASrAOGEN) rats, the 24-hour heart rate rhythms remained unaltered and paralleled those of locomotor activity. The transfer gain between 0.3 to 0.6 Hz was significantly higher in TGR(ASrAOGEN) than in control rats during control (0.71+/-0.1 versus 0.35+/-0.06, P<0.05) but not during angiotensin II infusion (0.6+/-0.07 versus 0.4+/-0.1, P>0.05). These results demonstrate that the brain renin-angiotensin system plays an important role in mediating the effects of angiotensin II on the circadian variation of blood pressure. Furthermore, these data indicate that a permanent deficiency in the brain renin-angiotensin system alters the reflex control of heart rate in rats.

Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN).

TGR(ASrAOGEN)680, a newly developed transgenic rat line with specific downregulation of astroglial synthesis of angiotensinogen, exhibits decreased brain angiotensinogen content associated with a mild diabetes insipidus and lower blood pressure. Autoradiographic experiments were performed on TGR(ASrAOGEN) (TG) and Sprague-Dawley (SD) control rats to quantify AT(1) and AT(2) receptor-binding sites in different brain nuclei and circumventricular organs. Dose-response curves for drinking response to intracerebroventricular injections of ANG II were compared between SD and TG rats. In most of the regions inside the blood-brain barrier [paraventricular nucleus (PVN), piriform cortex, lateral olfactory tract (LOT), and lateral preoptic area (LPO)], AT(1) receptor binding (sensitive to CV-11974) was significantly higher in TG compared with SD. In contrast, in the circumventricular organs investigated [subfornical organ (SFO) and area postrema], AT(1) receptor binding was significantly lower in TG. AT(2) receptors (binding sensitive to PD-123319) were detected at similar levels in the inferior olive (IO) of both strains. Angiotensin-binding sites sensitive to both CV-11974 and PD-123319 were detected in the LPO of SD rats and specifically upregulated in LOT, IO, and most notably PVN and SFO of TG. The dose-response curve for water intake after intracerebroventricular injections showed a higher sensitivity to ANG II of TG (EC(50) = 3.1 ng) compared with SD (EC(50) = 11.2 ng), strongly suggesting that the upregulation of AT(1) receptors inside the blood-brain barrier of TG rats is functional. Finally, we showed that downregulation of angiotensinogen synthesized by astroglial cells differentially regulates angiotensin receptor subtypes inside the brain and in circumventricular organs.

ICAM-1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE(-/-)/ICAM-1(-/-)) fed a fat or a chow diet.

Intercellular adhesion molecule (ICAM)-1, a major adhesion molecule, plays a critical role in the homing of leukocytes to sites of atherosclerotic lesions. However, very little is known on the role of ICAM-1 in initiating and perpetuating vascular lesions in ApoE(-/-) mice fed a chow or a fat diet. This study has investigated the mean aortic lesions in mice (C57BL6 background) with a single-knockout (ApoE(-/-)) or double-knockout (DKO; ApoE(-/-), ICAM-1(-/-)) fed a chow or a fat diet over a period of 3, 6, 15, and 20 weeks. A 3-fold reduction in lesion size was observed at all time points in DKO mice fed a chow diet. However, in DKO mice fed a fat diet, a marked reduction in the aortic lesion was observed at 3 and 15 weeks, which did not reach a significant level at 6 and 20 weeks. This study shows in essence that DKO mice are protected from developing significant lesions for up to 6 weeks when fed a chow diet and from 3 to 6 weeks when fed a fat diet. After 6 weeks, the lesion size of the DKO mice follows that of the single-knockout mice when fed a chow diet and gets to the same level in mice fed a fat diet. Plasma cholesterol levels were not altered as a result of ICAM-1 deficiency. These studies show that ICAM-1 is implicated in the formation and progression of atherosclerotic lesions.

Hypertension in transgenic (mREN2)27 rats is not associated with the presence of B1 receptors.

B1 receptors are inducible receptors expressed only in stressful conditions. The aim of this study was to determine if, in (mREN2)27 transgenic rats, hypertension is associated with the presence of B1 receptors in the cardiovascular system and if a heat stress inducible effect is preserved during hypertension. Age-matched (16 weeks old) heterozygous hypertensive transgenic (mREN2)27 rats (HT rats) and the normotensive control animals (homozygous Sprague-Dawley rats, NT rats) were used. The study was conducted in two parts: in the first part the responsiveness of B1 receptors was studied in rats submitted to heat stress (42 degrees C rectal temperature, 20 min) or sham anaesthesia 24 h before, by recording changes in isometric tension in aortic rings in response to [des-Arg9]-bradykinin, a B1 receptor agonist. In the second part, we studied whether B1 receptor mRNA was present in aorta, heart and kidneys, using a semi-quantitative RT-PCR technique. [des-Arg9]-Bradykinin induced a concentration-dependent relaxation of aortic rings only from animals submitted to prior heat stress. This response was significantly higher in aortic rings from heat stressed HT rats than from heat stressed NT ones. B1 receptor mRNA was undetectable in organs from rats not submitted to heat stress but they were present 5 h after heat stress in aorta, heart and kidneys from both NT and HT rats. In conclusion, arterial hypertension observed in (mREN2)27 rats is not associated with the presence of B1 receptors. However, after heat stress, we observed an increase in responsiveness from HT rat aortas compared to NT ones.

Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen.

Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.