Role of a molecular variant of rat atrial natriuretic Peptide gene in vascular remodeling.

Previous studies in a hypertensive animal model of stroke and in humans showed that mutations of the atrial natriuretic peptide (ANP) gene are associated with increased risk of stroke. To elucidate the vascular disease mechanisms that result from structural modifications of the ANP gene, we investigated a coding mutation of the ANP gene in stroke-prone spontaneously hypertensive rats (SHRsp). This mutation leads to a Gly/Ser transposition in the prosegment of ANP.

A transgenic rat expressing human APP with the Swedish Alzheimer's disease mutation.

In recent years, transgenic mice have become valuable tools for studying mechanisms of Alzheimer's disease (AD). With the aim of developing an animal model better for memory and neurobehavioural testing, we have generated a transgenic rat model of AD. These animals express human amyloid precursor protein (APP) containing the Swedish AD mutation.

Reciprocal congenic lines for a major stroke QTL on rat chromosome 1.

We previously identified a quantitative trait locus (QTL) for stroke proneness between the kallikrein (Klk) and Mt1pa markers on rat chromosome 1. To gain functional insights, we constructed congenic strains by introgressing either the whole or selected chromosomal segments from the stroke-prone (SHRsp) onto the stroke-resistant (SHRsr) spontaneously hypertensive rat genome and vice versa. The phenotype was the latency to develop stroke under a Japanese high-salt, low-potassium diet for 3 mo [known as Japanese diet (JD)].

Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes.

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation.

Augmentation of BNP gene expression in atria by pressure overload in transgenic rats harbouring human renin and angiotensinogen genes.

We studied the role of angiotensin II in pressure overload-induced B-type natriuretic peptide (BNP) gene expression by using a double transgenic rat (dTGR) model, in which transgenic rats for the human angiotensinogen and renin genes are crossed. Pressure overload produced by [Arg8]-vasopressin (AVP) infusion (i.v.

Differential brain atrial natriuretic peptide expression co-segregates with occurrence of early stroke in the stroke-prone phenotype of the spontaneously hypertensive rat.

Objective: To determine how the downregulation of atrial natriuretic peptide (ANP) gene expression, previously demonstrated to occur only in the brain of the stroke-prone spontaneously hypertensive rat (SHRsp), in contrast to the stroke-resistant SHR (SHRsr), co-segregates with stroke occurrence in SHRsp/SHRsr F2 descendants in order to study the 'protective' role towards stroke previously demonstrated in SHRsp for the quantitative trait locus STR2 that also carries the ANP gene.

Design And Methods: Eight male SHRsp, eight male SHRsr and 16 male SHRsp/SHRsr F2-intercross animals (progeny of brother/sister mated F1 hybrids from an original cross between F0 SHRsp and SHRsr) were selected for this study. All rats were exposed to a stroke-permissive Japanese-style diet starting at the age of 6 weeks.

Analysis of the genetic basis of the endothelium-dependent impaired vasorelaxation in the stroke-prone spontaneously hypertensive rat: a candidate gene approach.

Objective: To investigate the role of potential candidate genes in the pathogenesis of the endothelium-dependent impaired vasorelaxation that associates and co-segregates with stroke in the stroke-prone spontaneously hypertensive rat (SHRsp) compared with the stroke-resistant SHR (SHRsr).

Design And Methods: An SHRsp/SHRsr F2-intercross (n = 137; 64 males, 73 females) was obtained and, at the age of 6 weeks, it was placed under a stroke permissive Japanese-style diet for 4 weeks. At the end of the treatment the vascular function of each rat was characterized.

Hemodynamics and metabolism in stroke-prone spontaneously hypertensive rats before manifestation of brain infarcts.

Genomic screening of hybrids from stroke-prone (SHR-SP) and stroke-resistant spontaneously hypertensive rats (SHR) identified a STR1 locus on the rat chromosome 1, which correlates with the susceptibility to cerebral stroke but not with hypertension. The authors examined whether this genetic abnormality is associated with hemodynamic or metabolic alterations in the brain that can be detected before the manifestation of brain infarction. Starting at 6 weeks of age, SHR-SP were fed with a salt-rich diet to accelerate arterial hypertension.

Overexpression of the sarcolemmal calcium pump in the myocardium of transgenic rats.

The plasma membrane calmodulin-dependent calcium ATPase (PMCA) is a calcium-extruding enzyme controlling Ca2+ homeostasis in nonexcitable cells. However, its function in the myocardium is unclear because of the presence of the Na+/Ca2+ exchanger. We approached the question of the physiological function of the calcium pump using a transgenic "gain of function" model.

Expression of smooth muscle myosin heavy chain B in cardiac vessels of normotensive and hypertensive rats.

We investigated expression of the 5'-spliced isoform of smooth muscle myosin heavy chain (SM-MHC-B) in smooth muscle cells of cardiac vessels of the left ventricle of normotensive (Wistar-Kyoto) and spontaneously hypertensive rats of the stroke-prone strain by immunofluorescence microscopy. In parallel, liver and bladder were studied for characterization of the nature of vessels expressing SM-MHC-B and for semiquantitative evaluation of its abundance. Smooth muscle cells were detected by staining with a monoclonal antibody specific for alpha-smooth muscle actin.

Increased potency of neuropeptide Y to antagonize alpha2-adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat.

The regulation by neuropeptide Y of alpha2-adrenoceptors in the nucleus tractus solitarii was evaluated in the adult normotensive Wistar Kyoto rat and the adult spontaneously hypertensive rat. The microinjection of a submaximal dose of l-noradrenaline (800 pmol in 50 nl) alone into the nucleus tractus solitarii produced a significant reduction in the mean arterial blood pressure in either strain. The threshold dose (1 pmol in 50 nl) of neuropeptide Y(1-36) for the vasodepressor response in the Wistar Kyoto rat was five times higher than that (0.

Lifelong angiotensin-converting enzyme inhibition, pressure natriuresis, and renin-angiotensin system gene expression in transgenic (mRen-2)27 rats.

The transgenic rat (TGR) (mRen-2)27 is said to have low circulating active renin values in plasma and little or no renin gene expression in the kidney. Nevertheless, intrarenal angiotensin II-related effects appear to be responsible for the rightward shift in pressure-natriuresis curves of TGR. To clarify the role of the intrarenal renin-angiotensin system in modulating TGR pressure-natriuresis, TGR were given lifelong lisinopril by treating TGR and their mothers before conception.

Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.

Stroke is a complex disorder with a poorly understood multifactorial and polygenic aetiology. We used the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genome-wide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder) segregated. We identified three major quantitative trait loci, STR1-3, with lod scores of 7.

Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats.

While hypertension is a major risk factor for stroke, it is not its sole determinant. Despite similar blood pressures, spontaneously hypertensive rats (SHR) do not share the predisposition to cerebrovascular disease typical of stroke-prone spontaneously hypertensive rats (SHRSP). We investigated vascular function in male SHR and SHRSP as well as in SHRSP/SHR-F2 hybrid animals.

Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27.

Transgenic techniques represent powerful tools for the study of gene-related mechanisms of diseases such as hypertension, which results from a complex interaction between genetic and environmental factors. The renin-angiotensin system, a biochemical cascade in which renin functions as the key enzyme in the formation of the effector peptide angiotensin II, plays a major role in the regulation of blood pressure. The renin gene, therefore, represents an important candidate gene for hypertension.

The renin-angiotensin system and renal function in transgenic (mRen2)27 rats.

The transgenic rat (TGR)(mRen2)27 was the first hypertensive transgenic rat model developed. The model is unique in that it allows studying the effects of a single gene, namely the mouse salivary gland renin gene (mRen2), in the rat. The transgene is expressed in various rat tissues, including the central nervous system, adrenal gland, and the kidney.

Evidence for a differential modulation of the alpha-2 adrenoceptors by angiotensin II in the nucleus tractus solitarii of the spontaneously hypertensive and the Wistar-Kyoto normotensive rats.

An interaction between angiotensin II (Ang II) receptors and alpha 2-adrenoceptors was evaluated in the nucleus tractus solitarii (NTS) of the normotensive Wistar-Kyoto rat (WKY) and of the spontaneously hypertensive rat (SHR) using quantitative receptor autoradiography and cardiovascular analysis. In the WKY rat, Ang II promoted a dose-dependent increase in the IC50 value of l-noradrenaline when competing for ([3H]p-aminoclonidine ([3H]PAC) binding sites, which reached a maximum of 400% with 10 nM of Ang II and was associated with a small decrease in the B0 value (20%). In the SHR Ang II (0.

Ontogenetic regulation of mouse Ren-2d renin gene in transgenic hypertensive rats, TGR(mREN2)27.

TGR(mREN2)27 is a new monogenetic rat model with fulminant hypertension, low kidney renin, and high extrarenal renin gene expression. This study characterizes and compares expression of the Ren-2 gene in TGR(mREN2)27 with that in DBA/2 mice and with renin gene expression in rats. Except in the submandibular gland, the tissue-specific expression of Ren-2 is similar in TGR(mREN2)27 and DBA/2.

Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.

Objective: Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP.

Design: We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed.

Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes.

The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure. We report here the development of transgenic rats carrying the human angiotensinogen TGR-(hAOGEN) and human renin TGR(hREN) genes. The plasma levels and tissue distribution of the transcription and translation products from both genes are described.

Effects of nifedipine and moxonidine on cardiac structure in spontaneously hypertensive rats. Stereological studies on myocytes, capillaries, arteries, and cardiac interstitium.

Light and electron microscopic stereological studies were performed on the myocardium of spontaneously hypertensive rats (SHR-SP) before and after treatment with nifedipine (27 mg/kg body weight/day) and the antisympathotonic agent moxonidine (8 mg/kg body weight/day). The treated groups were compared with nontreated SHR-SP and normotensive WKY (n = 10 in each group). At the beginning of therapy (when the male SHR-SP were 6 months old), blood pressure was increased and left ventricular hypertrophy had developed whereas pathologic changes of myocardial structure were not observed.

The influence of cold stress on the myosin heavy chain expression of cardiac and smooth muscle in normotensive and spontaneously hypertensive female rats.

Cold exposure (6 weeks at 4 degrees C) of normotensive (Wistar-Kyoto) and stroke-prone spontaneously hypertensive female rats led to cardiac hypertrophy (in stroke-prone spontaneously hypertensive rats), increased the level of plasma thyroxine, and increased the alpha-myosin heavy chain expression in the left ventricle. In contrast, myosin heavy chain expression of both main mesenteric artery and uterus was not affected by cold stress and chronic hypertension, suggesting different regulation of myosin heavy chain expression in smooth and cardiac muscle in vivo.

Differences in rat kidney morphology between males, females and testosterone-treated females.

Kidneys of normal female and male Wistar-Kyoto rats were studied by standard morphological techniques and morphometry in order to evaluate possible differences in the overall kidney morphology between both sexes. Furthermore, we investigated the role of testosterone (DHT) on kidney morphology by treating females with daily DHT injections. Kidney weight and volume in relation to body weight were not significantly different between males and females and were not affected by DHT.

Regulation of calcitonin gene-related peptide mRNA expression in the hearts of spontaneously hypertensive rats by testosterone.

Previous studies have demonstrated the existence of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibres and nerve cell bodies in the rat heart. Using polymerase chain reaction we have investigated whether CGRP messenger RNA (mRNA) could be detected in heart tissue of spontaneously hypertensive rats, and whether CGRP-mRNA levels are affected by gonadectomy and testosterone substitution. Two weeks after castration CGRP-mRNA levels decreased to 65.