Background Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RNO13) in several models of hypertension.Methods To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13(BN)) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13(LH)). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters.Results Compared with LH parents, LH-13(BN) rats showed decreased mean BP (up to -24mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13(LH) and BN rats were much smaller than those observed between LH-13(BN) and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RNO13, despite the significant BP differences.Conclusion The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13(BN) and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease. J Hypertens 27:1186-1193 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The metabolic syndrome (involving obesity, hypertension, dyslipidemia, insulin resistance, and a proinflammatory/prethrombotic state) is a major risk factor for cardiovascular disease. Its incidence continues to rise, in part because of the epidemic increase in obesity. The Lyon hypertensive (LH) rat is a model for hypertension and several other features of the metabolic syndrome, having high body weight, plasma cholesterol, and triglycerides, increased insulin-to-glucose ratio, and salt-sensitive hypertension. Previous genetic studies in LH/Mav rats and a normotensive control (LN/Mav) identified quantitative trait loci (QTLs) on rat chromosome (RNO) 17 for multiple features of the metabolic syndrome. To further evaluate the role of RNO17 in the LH rat, we generated a consomic strain (LH-17(BN)) by substituting LH RNO17 with that of the sequenced Brown Norway (BN/NHsdMcwi) rat. Male LH and BN rats and LH-17(BN) rats were characterized for blood pressure and metabolic and morphological parameters. Similar to the protective effect of LN alleles, the LH-17(BN) rat also showed decreased body weight, triglycerides, and blood pressure; however, there was no significant difference in cholesterol or insulin-to-glucose ratio. Therefore, the substitution of the LH chromosome 17 is sufficient to recapitulate some, but not all, of the traits previously mapped to this chromosome. This could be due to the lack of a susceptible LH genome background or due to the introgression of chromosome 17 from another strain. Regardless, this study provides a single-chromosome genetic model for further dissection of blood pressure and morphological and metabolic traits on this chromosome.

Le rat genetiquement hypertendu de souche lyonnaise (LH) presente une pression arterielle spontanement elevee et sensible au sel, et des signes qui evoquent un syndrome metabolique : surcroit ponderal, hyperlipidemie et augmentation du rapport insuline/glucose. L'analyse de cosegregation effectuee sur les hybrides de seconde generation issus du croisement entre rats genetiquement hypertendus LH et normotendus LN a montre l'existence, sur le chromosome 17, de deux agregats de loci d'interet quantitatif (QTLs). Le premier de ces QTLs est associe a des parametres morphologiques alors que le second influence a la fois le niveau de pression arterielle et celui des lipides plasmatiques. Afin de determiner l'importance fonctionnelle de ces QTLs, nous avons genere une souche de rats LH chez lesquels le chromosome 17 est remplace par celui de rats normotendus Brown Norway (BN) : rats consomiques LH-17 BN . Le phenotypage des rats mâles LH, BN et LH-17 BN comprend l'enregistrement, par radio-telemetrie de la pression arterielle dans des conditions d'apport alimentaire en NaCl normal puis eleve (1 % et ensuite 2 % da NaCl dans l'eau de boisson), et la mesure de differents parametres morphologiques, metaboliques (triglycerides, cholesterol) et fonctionnels renaux (clairance de la creatinine, proteinurie). Les rats LH-17BN, par rapport aux rats LH, presentent des diminutions du poids corporel et de la pression arterielle. Leurs fonctions renales sont ameliorees (diminution de la proteinurie). Au niveau metabolique, leur taux de cholesterol est identique alors que leur taux de triglycerides, tres abaisse, revient au niveau de celui observe chez les rats BN. Ce travail demontre que le chromosome 17 participe activement a la genese des troubles morphologiques, cardiovasculaires et metaboliques du rat LH. En particulier, il explique presque totalement l'hypertriglyceridemie observee spontanement chez le rat genetiquement hypertendu de souche lyonnaise.

Genetically hypertensive rats of the Lyon strain (LH) have both high blood pressure and a metabolic syndrome. Linkage studies have disclosed quantitative trait loci of interest on chromosomes 2, 13 and 17. In the present work we designed consomic rats, i.e. LH rats in which a full chromosome was replaced by the same chromosome originating from the Brown-Norway (BN) normotensive strain. Rats consomic for chromosome 17 (LH-17(BN)) exhibited slightly but significantly lower blood pressure, which remained sensitive to an oral salt load. The cholesterol level was unaffected, while the triglyceride level was markedly depressed. This consomic approach seems to be of value for studying polygenic diseases such as hypertension and the metabolic syndrome. In the case of LH rats, our results confirm the functional importance of the loci identified on chromosome 17.

Genetically hypertensive rats of the Lyon strain (LH) associate high blood pressure (BP), exaggerated salt-sensitivity, and a metabolic syndrome made of overweight together with increased plasma lipids and insulin/glucose ratio. A genetic mapping study in a large population of F2 rats derived from a cross between hypertensive (LH) and normotensive rats (LN) showed the existence, on chromosome 17, of two clusters of Quantitative Traits Loci (QTLs). The first one was associated to morphological parameters whereas the second influenced blood pressure and plasma lipids level.In order to determine the functional importance of this QTLs, we generated a consomic strain LH- 1 7BN in which the LH chromosome 17 has been fully substituted by a normotensive Brown Norway (BN) one. These LH- 17 BN, as well as LH and BN male rats of the parental strain were phenotyped. This included radio telemetric measurement of BP during normal and elevated salt intake (1% and then 2% in the drinking water) as well as the determination of morphological, metabolic (triglycerides, cholesterol) and renal (creatinine clearance, proteinuria) parameters.LH-17(BN), compared to LH rats, exhibited significant decreases in body weight and blood pressure. Renal functions are improved (decreased of proteinuria). Finally, plasma triglycerides were reduced and reach the level observed in BN rats.In conclusion, the present work demonstrates that, in our model, chromosome 17 contains genes which influence morphology, blood pressure, renal function, and lipid metabolism. Interestingly, chromosome 17 almost completely explains the spontaneous hypertriglyceridemia observed in Lyon Hypertensive rats.

Genetically hypertensive rats of the Lyon strain (LH) have both high blood pressure and a metabolic syndrome. Linkage studies have disclosed quantitative trait loci of interest on chromosomes 2, 13 and 17. In the present work we designed consomic rats, i.e. LH rats in which a full chromosome was replaced by the same chromosome originating from the Brown-Norway (BN) normotensive strain. Rats consomic for chromosome 17 (LH-17BN) exhibited slightly but significantly lower blood pressure, which remained sensitive to an oral salt load. The cholesterol level was unaffected, while the triglyceride level was markedly depressed. This consomic approach seems to be of value for studying polygenic diseases such as hypertension and the metabolic syndrome. In the case of LH rats, our results confirm the functional importance of the loci identified on chromosome 17.

Background Present developments in Nuclear Magnetic Resonance (NMR) imaging techniques strive for improved spatial and temporal resolution performances. However, trying to achieve the shortest gradient rising time with high intensity gradients has its drawbacks: It generates high amplitude noises that get superimposed on the simultaneously recorded electrophysiological signals, needed to synchronize moving organ images. Consequently, new strategies have to be developed for processing these collected signals during Magnetic Resonance Imaging (MRI) examinations. The aim of this work is to extract an efficient reference signal, from an electrocardiogram (ECG) that was contaminated by the NMR artefacts. This may be used for image triggering and/or cardiac rhythm monitoring. Methods Our method, based on sub-band decomposition using wavelet filters, is tested on various ECG signals recorded during three imaging sequences: Gradient Echo (GE), Fast Spin Echo (FSE) and Inversion Recovery with Spin Echo (IRSE). In order to define the most adapted wavelet functions to use according to the excitation protocols, noise generated by each imaging sequence is recorded and analysed. After exploring noise models along with information found in the literature, a group of 14 wavelets, members of three families (Daubechies, Coiflets, Symlets), is selected for the study. The extraction process is carried out by decomposing the contaminated ECG signals into 8 scales using a given wavelet function, then combining the sub-bands necessary for cardiac synchronization, i.e. those containing the essential part of the QRS energy, to construct a reference signal. Results The efficiency of the presented method has been tested on a group of quite representative signals containing: highly contaminated (mean SNR<-5 dB) simulated ECGs that replicate normal and pathological human heart beats, as well as some pathological and healthy rodents' actual ECG records. Despite the weak SNR of the contaminated ECG, the performances were quite satisfactory. When comparing the wavelet performances, one may notice that for a given sequence, some wavelets are more efficient for processing than others; for GE, FSE and IRSE sequence, good synchronisation condition is accomplished with coif5, sym8, and sym4 respectively. Conclusion Sub-band decomposition proved to be very suitable for extracting a reference signal from a corrupted ECG for MRI triggering. An appropriate choice of the wavelet function, in accordance with the image sequence type, could considerably improve the quality of the reference signal for better image synchronization.

The relationship between blood pressure (BP) and cardiovascular risk is clearly established; hypertension increases the rate of cardiovascular. High systolic blood pressure (SBP) may be the main parameter involved in cardiovascular morbidity and mortality. The benefit of lowering BP, particularly with diuretics has been proven in many outcome studies. Indapamide, a thiazide-type diuretic, was available for many years at a dosage of 2.5 mg in an immediate release formulation. A new sustained release (SR) formulation has been developed in order to allow the same antihypertensive efficacy with a better acceptability profile. This paper reviews the pharmacology of indapamide 1.5 mg SR from the bench to the bedside. Indapamide has a dual mechanism of action: diuretic effect at the level of the distal tubule in the kidney and a direct vascular effect. both of which contribute to the antihypertensive efficacy of the drug. The SR formulation contains a hydrophilic matrix, which delivers a smoother pharmacokinetic profile. This avoids unnecessary plasma peak concentrations, which may be associated with side effects. Indapamide SR has now been extensively used in hypertensive patients, including those at increased risk. for example elderly or diabetic patients. It has been shown to decrease BP, particularly SBP, with 24-h efficacy, allowing a once-daily dosage. Studies have demonstrated BP lowering to be at least as effective as all major therapeutic classes including the more recent anti hypertensive drugs. Beyond BP decrease, indapamide SR has also been shown to protect against hypertensive target-organ damage in the heart and the kidney and to have a favorable metabolic profile. A broad evidence-base has accumulated to support the benefit of indapamide 1.5 mg SR in hypertensive patients, alone or as part of combination therapy, as recommended by the majority of guidelines.

The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F-2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat.

Objective: In order to determine the influence of the lipid status on the ability of cholesteryl ester transfer protein (CETP) to modify the plasma lipoprotein profile, the effect of hypercholesterolemia versus hypertriglyceridemia were compared in wild-type and CETP-transgenic (CETPTg) rats expressing CETP at a constant level.Methods and results: Wild-type and CETPTg rats were fed either a chow diet, a high fat/high cholesterol (HF/HC) diet, or a sucrose diet. As compared to wild-type rats, CETPTg rats fed the standard chow exhibited lower high-density lipoproteins (HDL)-cholesterol concentration (-65%, p<0.01), but similar non-HDL-cholesterol concentrations. Both wild-type and CETPTg rats fed the HF/HC diet displayed pronounced increases in total and non-HDL-cholesterol levels, with no influence of CETP expression in this case. In contrast, the sucrose diet produced significant changes only in CETPTg rats which then exhibited a 82% increase in non-HDL-cholesterol in addition to a 80% reduction in HDL cholesterol when compared to sucrose-fed, wild-type rats (p<0.01 in both cases). The triglyceride to cholesterol ratio in very low-density lipoprotein (VLDL) was 10-fold lower in 'HF/HC' rats than in 'chow' and 'sucrose' rats (p<0.005 and p<0.01, respectively), and VLDL from 'HF/HC' animals were proven to constitute poor cholesteryl ester acceptors.Conclusions: CETP expression modified dramatically the lipoprotein phenotype in 'sucrose' rats but not in 'HF/HC' rats. These observations suggest that a CETP inhibitor treatment is susceptible to produce profound changes in hypertriglyceridemia or combined hyperlipidemia. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P < 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by. CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P < 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P < 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.

This chapter focused on rat models of genetic hypertension since (1) they are widely used and (2) they allow renal function and especially RBF to be measured with a relative accuracy. The various techniques used to obtain RBF (microspheres, pulsed Doppler, ultrasonic transit time, and laser Doppler methods) are presented with their major advantages and limitations. The most frequently used experimental conditions are described since they largely influence the data. Finally, the results obtained in various strains of genetically hypertensive rats are summarized with a special emphasis on the existence of preglomerular vasoconstriction in most of these strains, which makes them close to a “multiple, micro-Goldblatt renal hypertension”.

Abstract— The acetylcholinesterase inhibitor, soman, induces marked and sustained hypertension and tachycardia associated with a convulsive syndrome in rats. The aims of the present study were to distinguish between the cardiovascular and convulsant effects of soman and to determine whether the maintenance of the soman‐induced hypertension and tachycardia depends solely on a central muscarinic effect. To this end, using a computerised analysis of blood pressure (BP) in conscious freely moving rats, we examined the consequences on the increase in mean BP (MBP) and heart rate (HR) induced by soman (60 μg/kg, i.v.) of 1) a pre‐treatment with the anticonvulsant drug diazepam (3 mg/kg, i.v.) and 2) atropine sulphate (10 mg/kg, i.v.) administered 10 or 60 min after the intoxication. Pretreatment with diazepam prevented the convulsions, assessed by electroencephalogram (EEG) recording, but modified neither the magnitude nor the kinetics of the pressor and tachycardic effects of soman (Δ MBP = 74 ± 2 and 73 ± 5 mmHg, Δ HR = 69 ± 10 and 79 ± 7 bpm, maximum MBP = 186 ± 3 and 182 ± 6 mmHg, maximum HR = 545 ± 9 and 522 ± 16 bpm in solvent‐ (n = 8) and diazepam‐ (n = 8) pre‐treated rats, respectively). Whatever its time of administration, atropine sulphate fully and immediately reversed the rise in BP induced by soman. The soman‐induced tachycardia was also suppressed by atropine administered 10 min after soman whereas it persisted when atropine was injected 60 min after the intoxication. These results show that the cardiovascular effects of soman can occur independently of the convulsive syndrome and that the maintenance of the soman‐induced hypertension depends entirely on a permanent central muscarinic stimulation.

Indapamide is a thiazide-related diuretic drug with antihypertensive properties. Its blood pressure-lowering action has been repeatedly demonstrated in acute as well as chronic conditions in various genetically and nongenetically determined forms of hypertension. In rats, the maximally effective oral dose is 3 mg/kg/24h. The natriuretic effect of indapamide peaked at 3-fold at a dose of 1 mg/kg. In accordance with its antihypertensive properties, indapamide was shown to have excellent efficacy in protecting against target organ damage (heart, kidneys, brain).