Abstract-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. Key Words: genetics Ⅲ linkage analysis Ⅲ metabolism Ⅲ hypertension, genetic Ⅲ rats, inbred strains Ⅲ cardiovascular diseases H uman essential hypertension and associated cardiovascular diseases are multifactorial disorders with a complex etiology, resulting from the interaction between multiple genes and environmental factors. Despite development of new genetic and genomic technologies, the genetic determinants of multifactorial disorders remain unclear. The study of animal models in discovering pathophysologic and genetic determinants of polygenetic disorders such as hypertension provides a platform of reduced heterogeneity. Currently, there exist several different genetically hypertensive rat and mouse selection models. 1 Numerous linkage studies in rats have shown that each rat chromosome contains at least 1 blood pressure (BP) quantitative trait locus (QTL; http://rgd.mcw.edu/qtls).The Lyon hypertensive (LH) rat has many features common to the human metabolic syndrome, a group of metabolic risk factors including central obesity, atherogenic dyslipidemia, elevated BP, insulin resistance or glucose intolerance, and prothrombotic and proinflamatory states. 2 Interestingly, a control strain, the Lyon normotensive (LN) rat, has been simultaneously derived from a common ancestor of the LH; the LN is genetically quite similar to the LH (85% identical based on characterization of 4328 microsatellite markers; data not shown) but phenotypically very distinct. Compared with the LN, LH rats have mild salt-sensitive hypertension and reduced life ...

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 saltsensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia and elevated insulin-to-glucose ratio. Previous genetic mapping identified Quantitative Trait Loci (QTL) influencing blood pressure on chromosome 13 (RNO13) in several models of hypertension. 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 blood pressure, metabolic and morphological parameters. Compared to LH parents, LH-13 BN rats showed decreased mean blood pressure (up to −24 mmHg on 2%NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13 LH and BN rats are 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 is not affected by the substitution of RNO13, despite the significant blood pressure differences.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.

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.

1. In order to determine whether the antihypertensive effect of neonatal thymectomy in genetically hypertensive rats could be mediated through altered adrenal function, systolic blood pressure (SBP) and urinary excretion of deoxycorticosterone (DOC), corticosterone (B) and aldosterone were measured in thymectomized hypertensive (LH), normotensive (LN) and low-blood pressure (LL) rats of the Lyon strain. Sham-operated animals served as controls. 2. Neonatal thymectomy prevented the spontaneous increase of SBP in LH rats while it slightly decreased the SBP of LN and did not change that of LL rats. 3. Five week old sham-operated LH rats exhibited an increased urinary excretion of DOC and a decreased excretion of B compared with both LN and LL controls. Thymectomy did not alter the urinary excretion of adrenal steroids in LN and LL rats. The urinary excretion of B was markedly enhanced in thymectomized LH rats whereas that of DOC remained unmodified. 4. These data suggested that the thymus could be involved in the development of hypertension in LH rats. 5. The antihypertensive effect of thymectomy did not seem to be mediated by a decreased mineralocorticoid production in the genetically hypertensive rat of the Lyon strain.

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 antihypertensive 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.