Mechanisms underlying systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) beat-to-beat variability were investigated using spectral analysis in conscious genetically normotensive (LN) and hypertensive (LH) adult rats from the Lyon strains. In LN rats, basal SBP, DBP, and HR spectra exhibited peaks in low (LF: 0.38-0.45 Hz) and high (HF: 1.04-1.13 Hz) frequencies. The LF peak of SBP, and even more of DBP, could be attributed to the influence of the sympathetic nervous system as it disappeared after destruction of the sympathetic nerves or a combined alpha- and beta-adrenoceptor blockade, whereas it was higher after blockade of the parasympathetic system. The HF peak of HR, linked to the respiratory rate, was abolished by the parasympathetic system blockade, whereas those of SBP and DBP were enhanced. In LH rats, which exhibit a lower sympathetic activity, the LF peaks of SBP and DBP were less distinct compared with LN controls. We conclude that the LF peak of DBP and the HF peak of HR are likely to represent useful estimates of the sympathetic vascular control and of the parasympathetic cardiac control, respectively.

Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for "candidate hypertension loci in humans" based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics.

The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that a recently identified gene of yet unknown function, termed SA, which is differentially expressed in the kidney of the spontaneously hypertensive rat, cosegregates with an increase in blood pressure in F2 rats derived from a cross of the spontaneously hypertensive rat with normotensive Wistar-Kyoto rats, accounting for 28 and 21% of the genetic variability in systolic and diastolic blood pressures, respectively. Further, the genotype at this locus appears to determine the level of expression of the gene in the kidney. The findings provide strong evidence for a primary genetic involvement of the kidney in hypertension. (J. Clin. Invest. 1993.

Angiotensin II recognizes two receptor subtypes, AT, and AT2, both of them having been recently cloned. Although AT2 receptors represent 5-10% of angiotensin II receptors in the kidneys of adult rats, their function remains unknown. In the present work, we examined the possible contribution of AT2 receptors to the regulation of pressurenatriuresis in anesthetized rats infused either with the specific AT2 antagonist PD 123319, or with CGP 42112B, an AT2 ligand with agonistic properties. The effects of PD 123319 were examined in a preparation with stable levels of angiotensin II, and in which AT1 receptors were blocked by the specific antagonist losartan. The effects of CGP 42112B were studied in rats deprived of endogenous angiotensin II. AT2 receptor blockade with PD 123319 did not change the renal blood flow while it increased the diuresis and natriuresis. These effects persisted even after full AT1 receptor blockade with losartan. CGP 42112B did not modify the renal blood flow, but dose-dependently decreased urine flow and natriuresis. These results show that, contrary to AT1 receptors, renal AT2 receptors have no effect on total renal blood flow, but blunt the pressure-natriuresis, thus demonstrating that this receptor subtype is involved in a function of importance for body fluid and blood pressure regulation. (J. Clin. Invest. 1995. 95:1394-1397

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 ...

Abstract-It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed to large transient blood pressure (BP) fluctuations such as those occurring spontaneously in conscious sinoaortic baroreceptordenervated (SAD) rats. In this study, BP and RBF were simultaneously recorded in 8 SAD rats (2 weeks before study) and 8 baroreceptor-intact rats during Ϸ3 hours of spontaneous activity. The kidney used for RBF recordings was denervated to prevent the interference of changes in renal sympathetic tone with autoregulatory mechanisms. In intact rats, RBF variability (coefficient of variation 9.1Ϯ0.8%) was larger (PϽ0.02) than BP variability (5.9Ϯ0.2%). This was mainly because of slow changes in RBF that were unrelated to BP and also to a prominent oscillation of RBF of Ϸ0.25-Hz frequency. Autoregulatory patterns were identified at frequencies Ͻ0. Key Words: autoregulation Ⅲ blood pressure Ⅲ rats Ⅲ denervation A lthough hemodynamic factors are likely to play a role in the progression of renal failure, 1,2 the possible deleterious effects of an exaggerated blood pressure (BP) variability on the kidney have not yet been established. It is often proposed that autoregulatory mechanisms prevent acute changes in systemic BP from being transmitted to the glomerular capillary circulation. 3 Most studies on renal blood flow (RBF) autoregulation have been performed in anesthetized rats, with the use of either induced 4 or spontaneous 5 changes in BP. In the conscious rat, RBF autoregulation has been described by measuring RBF responses to steady-state changes in renal perfusion pressure induced by reversible constrictions of the abdominal aorta above or below the renal arteries. 6,7 This technique suffers from 2 major limitations. First, it is difficult to determine the higher limit of autoregulation because it is impossible to raise renal perfusion pressure by Ͼ20% to 25% with the use of an aortic cuff. Second, the technique overlooks the essentially dynamic nature of autoregulation. 8 Spontaneous autoregulatory patterns have been reported in the renal circulation of conscious rats. 9,10 However, in normal rats with intact baroreceptors, BP varies within a relatively narrow range 10 -12 ; therefore, it is not known whether the kidney is able to cope with transient large fluctuations of BP, such as those occurring spontaneously in the sinoaortic baroreceptor-denervated (SAD) rat. [11][12][13][14] In the present study, RBF and BP were simultaneously recorded during long periods of spontaneous activity in conscious SAD rats. Rats were studied 2 weeks after surgery, ie, in the early chronic phase of denervation, when mean levels of BP are nearly normal and BP variability is markedly increased. 11,14 Sympathetic nerves play a major role in promoting behaviorally coupled changes in RBF 15 and are probably also involved in generating BP fluctuations in SAD rats, at least the acute pressor episodes. 16 To avoid the interference of sympathetically mediated vasoconstriction with autoregulatory responses, t...

Several genetic loci involved in blood pressure regulation have recently been localized in experimental models of hypertension, but the manner in which they influence blood pressure remains unknown. Here, we report a study of the Lyon hypertensive rat strain showing that different loci are involved in the regulation of steady-state (diastolic pressure) and pulsatile (systolic-diastolic, or pulse pressure) components of blood pressure. Significant linkage was established between diastolic blood pressure and a microsatellite marker of the renin gene (REN) on rat chromosome 13, and between pulse pressure and the carboxypeptidase B gene (CPB) on chromosome 2. These findings show that two independent loci influence different haemodynamic components of blood pressure, and that pulse pressure has a specific genetic determination.

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