Differential metal content and gene expression in rat left ventricular hypertrophy due to hypertension and hyperactivity.

The spontaneously hypertensive rat (SHR) has been studied extensively as a model of left ventricular hypertrophy (LVH) and associated cardiac dysfunction due to hypertension (HT). The SHR also possesses a hyperactive trait (HA). Crossbreeding SHR with Wistar-Kyoto (WKY) control rats, which are nonHT and nonHA, followed by selected inbreeding produced two additional homozygous strains: WKHT and WKHA, in which the traits of HT and HA, respectively, are expressed separately.

Cardiomyocyte function associated with hyperactivity and/or hypertension in genetic models of LV hypertrophy.

We examined cardiomyocyte intracellular calcium ([Ca2+]i) dynamics and sarcomere shortening dynamics in genetic rat models of left ventricular (LV) hypertrophy associated with or without hypertension (HT) and with or without hyperactive (HA) behavior. Previous selective breeding of the spontaneously hypertensive rat (SHR) strain, which is HA and HT, with the Wistar-Kyoto (WKY) rat strain, which is not hyperactive (NA) and not hypertensive (NT), has led to two unique strains: the WKHA strain, selected for HA and NT, and the WKHT strain, selected for NA and HT. Cardiomyocytes were isolated from young adult males and females of each strain, paced at 2, 3, and 4 Hz in 1.

No involvement of the nerve growth factor gene locus in hypertension in spontaneously hypertensive rats.

Sympathetic hyper-innervation and increased levels of nerve growth factor (NGF), an essential neurotrophic factor for sympathetic neurons, have been observed in the vascular tissues of spontaneously hypertensive rats (SHRs). Such observations have suggested that the pathogenesis of hypertension might involve a qualitative or quantitative abnormality in the NGF protein, resulting from a significant mutation in the gene's promoter or coding region. In the present study, we analyzed the nucleotide sequences of the cis-element of the NGF gene in SHRs, stroke-prone SHRs (SHRSPs), and normotensive Wistar-Kyoto (WKY) rats.

Elevated renal cortical calmodulin-dependent protein kinase activity and blood pressure.

The spontaneously hypertensive rat (SHR) exhibits not only hypertension but also behavioral hyperactivity which are not genetically linked. Two strains of rats, one hypertensive but normoactive (WKHT) and another, hyperactive but normotensive (WKHA), have been generated from SHR. We have reported that in renal proximal tubules, the linkage between D1-like receptors an adenylyl cyclase was impaired in SHR and WKHT but intact in WKHA.

WKHA rats with genetic hyperactivity and hyperreactivity to stress: a review.

WKHA rats are a homozygous strain of hyperactive rats developed by successive selected inbreedings, starting from a cross of spontaneously hypertensive (SHR) rats with their normotensive control strain, WKY. WKHA express hyperactivity in a novel environment, as do SHRs, however their blood pressure is normotensive, thus they are potentially a more promising model of hyperactivity than the SHR. WKHA became homozygous in 1990 (20 strict brother/sister inbreedings), and they are currently in the F36 generation.

Impairment of the blood-brain barrier: a potential surrogate delineating the determinants of cerebral bleeding caused by fibrinolytic drugs.

Background: Intracranial bleeding is encountered in some patients with acute myocardial infarction treated with fibrinolytic drugs, and especially in patients with occult cerebral vasculopathy. In order to determine whether pharmacologically induced plasminemia is a determinant, and whether impairment of the blood-brain barrier can serve as a marker of risk, we studied spontaneously hypertensive stroke-prone rats (SHRSP) genetically disposed to cerebral vasculopathy.

Methods: In order to simulate the induction of plasminemia in patients treated with fibrinolytic drugs for acute myocardial infarction, three intravenous injections of human plasminogen and human tissue-type plasminogen activator (t-PA) were administered to the rats at 2-h intervals (12 mg plasminogen plus 60 micrograms t-PA, 6 mg plus 30 micrograms t-PA, and 0.

Genetic characterization of novel strains of rats derived from crosses between Wistar-Kyoto and spontaneously hypertensive rats, and comparisons with their parental strains.

Two novel strains of rats have recently been generated from hybrid crosses of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The breeding pairs chosen to create these strains were initially selected on the basis of two mutually exclusive phenotypic traits, so that the rats called WKHT are hypertensive but not hyperactive, whereas the rats called WKHA are hyperactive but not hypertensive. These strains have been refined by inbreeding on a strict brother-sister basis for more than 25 generations.

Mutation of the trkB gene encoding the high-affinity receptor for brain-derived neurotrophic factor in stroke-prone spontaneously hypertensive rats.

Brain-derived neurotrophic factor and its receptor, trkB, are thought to play a crucial role for protection against neuronal death induced by brain ischemia, such as in stroke. In the present study we found a missense mutation in the trkB gene from all of the five substrains of stroke-prone spontaneously hypertensive rats (SHRSP) that were examined. This mutation was not found in six out of seven hypertensive but stroke-resistant ancestral strains (SHR) of SHRSP, nor in any of seven strains of normotensive, non-stroke-prone strains.

Behavioral and neuroendocrine reactivity to stress in the WKHA/WKY inbred rat strains: a multifactorial and genetic analysis.

Genetic factors have been shown to influence the nature and the intensity of the stress responses. In order to understand better the genetic mechanisms involved, we have studied the behavioral and neuroendocrine responses to novel environments in the WKHA/WKY inbred strains and we have investigated the genetic relationships between these traits in a segregating F2 intercross. The animals were submitted to behavioral tests known to provide both indices of activity and fear (activity cages, open field and elevated plus-maze).

A major quantitative trait locus influences hyperactivity in the WKHA rat.

The syndrome of hyperactivity describes behavioural disorders existing mainly in children and characterized by increased levels of motor activity, inattention and impulsivity. Overall the aetiology is poorly understood due to the heterogeneity of the pathology although psychological, biological and social factors acting singly or in concert are generally thought to be involved. In animal studies the observed hyperactivity phenotype results from relative participation of exploration, emotionality and general activity.

Hemodynamic and biochemical characteristics of the aorta in the WKY, SHR, WKHT, and WKHA rat strains.

This study was designed to characterize the hemodynamic and biochemical properties of the abdominal aorta in four genetically related inbred rat strains that express genetic hypertension and hyperactive behavior in varying combinations. These include (1) the spontaneously hypertensive rat (SHR), which is hypertensive, hyperactive, and hyperreactive to stress; (2) Wistar-Kyoto (WKY) rats, which express none of these traits; (3) WKHT rats, which are hypertensive but not hyperactive; and (4) WKHA rats, which are hyperactive and hyperreactive to stress, but normotensive. Together, these four strains allowed us to examine the structural and functional changes in the aorta in the hypertensive SHR, the most widely used animal model of genetic hypertension, while controlling for the variables of hyperactivity and hyperreactivity that are also expressed in the SHR.

Effects of hypertension and propranolol upon aneurysm expansion in the Anidjar/Dobrin aneurysm model.

Propranolol has been suggested to slow aortic aneurysm (AAA) expansion by a mechanism independent of simple blood pressure (BP) reduction. To investigate this hypothesis, we designed a series of experiments to examine the effects of hypertension and propranolol upon AAA expansion. Using an established animal model, we induced AAA in normotensive and genetically hypertensive rats by perfusion of the isolated infrarenal aorta with elastase for two hours.

Circadian timekeeping in hyperactive and hypertensive inbred rat strains.

Inbred strains have been used to study genetic and physiological relationships among different aspects of circadian timekeeping, as well as relationships between circadian rhythmicity and other strain-specific traits. The present study characterized several features of circadian timekeeping in genetically hyperactive (WKHA) and genetically hypertensive (WKHT) inbred strains, derived from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. WKHAs and WKHTs differed in free-running period, steady-state entrainment to light-dark cycles, and photic phase shifting, and relationships among these measures were consistent with previous studies of species, strain, and individual differences.

Mutation of low affinity nerve growth factor receptor gene is associated with the hypertensive phenotype in spontaneously hypertensive inbred rat strains.

We previously reported a missense mutation in the low affinity nerve growth factor receptor (LNGFR) gene of spontaneously hypertensive rats (SHR), proposing this gene as a promising candidate in genetic hypertension. In this study we provide further support for implicating this gene in genetic hypertension using two new inbred strains, WKHT and WKHA rats. These strains originated from crossbreeding SHR rats with normotensive Wistar-Kyoto rats (WKY): WKHT rats are hypertensive but not hyperactive, and WKHA rats are hyperactive but not hypertensive.

Anti-CD 18 monoclonal antibody slows experimental aortic aneurysm expansion.

Purpose: Inflammation has been implicated as a contributing factor in the expansion of abdominal aortic aneurysms (AAA). To test this hypothesis, we examined the effects of a monoclonal antibody (MAB) to the leukocyte CD18 adhesion molecule on the expansion of experimental AAA.

Methods: Aneurysms were induced by perfusion of an isolated segment of the infrarenal aorta with elastase in 22 normotensive (WKY) and 17 genetically hypertensive (WKHT) rats.

Enhanced vascular neuropeptide Y-immunoreactive innervation in two hypertensive rat strains.

Considerable evidence indicates an enhanced sympathetic innervation of resistance arterial smooth muscle in the spontaneously hypertensive rat (SHR) compared with its normotensive Wistar-Kyoto (WKY) control. In addition to sympathetic hyperinnervation, an increased vascular innervation by neuropeptide Y-containing fibers, which are known to exert a vasoconstrictive and trophic action in vascular smooth muscle, has also been described. In addition to genetic hypertension, the SHR expresses hyperactive behavior and hyperreactivity to stress.

Expansion of aortic aneurysms is reduced by propranolol in a hypertensive rat model.

Purpose: It has been suggested that propranolol has unique effects that slow aneurysm expansion by remodeling the structural proteins of the aorta. These effects are believed to be independent of blood pressure reduction, a hypothesis we tested in this investigation with a rat model of abdominal aortic aneurysm (AAA).

Methods: With an established model, AAA were induced in normotensive Wistar-Kyoto (WKY) rats and genetically hypertensive Wistar-Kyoto (WKHT) rats by perfusing an isolated segment of the infrarenal aorta with elastase.

Blood cell changes in spontaneously hypertensive rats are not all associated with the hypertensive phenotype.

Objective: To search for cosegregation of a change in specific blood cells with either the hypertension or the hyperactivity phenotype in spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats and two new inbred strains.

Design And Methods: Standard hematological procedures were used to examine erythrocytes, leukocytes and platelets in blood drawn from adult SHR, WKY rats and the two new inbred strains of rats.

Results: The hypertensive strains exhibited significant erythrocytosis, microcytosis, lymphocytosis and monocytosis relative to the normotensive strains.

Anterior pituitary proopiomelanocortin expression is decreased in hypertensive rat strains.

Studies comparing neuroendocrine differences between the spontaneously hypertensive rat (SHR) and the normotensive Wistar-Kyoto (WKY) strains have suggested altered anterior pituitary corticotrope expression of POMC associated with the development of hypertension in SHR animals. One major difficulty in comparing the SHR and WKY strains is that the two strains exhibit genetic differences unrelated to blood pressure status, because inbred in the SHR genome is a profile of behavioral characteristics different from those in the WKY, including hyperactivity in a novel environment and hyperreactivity in responding to stress. The present studies examine two new inbred rat strains, the WKHT and WKHA, which independently express the hypertension and behavioral traits, respectively.

Psychoneuroendocrine profile associated with hypertension or hyperactivity in spontaneously hypertensive rats.

The behavioral and neuroendocrine reactivity to a novel environment (open field) and the adrenocorticotropic hormone (ACTH)/corticosterone response to a corticotropin-releasing factor (CRF) challenge were measured in 2-mo-old rats from four inbred strains derived from the Wistar-Kyoto rat: spontaneously hypertensive rats (SHRs), hypertensive and behaviorally hyperactive to novelty; WKY, neither hypertensive nor hyperactive; WKHA, hyperactive but normotensive; and WKHT, only hypertensive. The ACTH response to CRF was much lower in SHRs than WKYs, this reduced reactivity being clearly associated with the hyperactivity trait, since it was present in the WKHA and absent in the WKHT strain. On the other hand, the ACTH/corticosterone response to a psychological stimulus (open field) could not clearly discriminate the four strains.

Psychosocial stress can induce chronic hypertension in normotensive strains of rats.

We report on five 6-month experiments during which five colonies of four male and four female rats were exposed to psychosocial stress. Monthly blood pressure measurements by a tail-cuff method showed a modest (10 mm Hg) increase in two studies using Sprague-Dawley rats. In two further studies using the more aggressive Long-Evans strain, terminal direct carotid arterial pressures were taken as well, and in one study the differences exceeded 20 mm Hg.

Hypertension accelerates the growth of experimental aortic aneurysms.

Hypertension has long been suspected to increase the growth rate of abdominal aortic aneurysms (AAA), but there is little experimental evidence to support this hypothesis. Using an established model, aneurysms were induced in normotensive Wistar-Kyoto (WKY) rats and in a unique strain of genetically hypertensive Wistar-Kyoto (WKHT) rats by perfusing an isolated segment of the infrarenal aorta with elastase (n = 14, each group). Aortic diameter was measured with a micrometer and systolic blood pressure (sBP) determined by tail plethysmography.

Renal dopamine-1 receptors in hypertensive inbred rat strains with and without hyperactivity.

Renal dopamine-1 (DA-1) receptors are involved in the regulation of sodium transport in several nephron segments, including the proximal convoluted tubule (PCT). DA-1 receptors in the PCT and cortical collecting duct of normotensive rats are linked to the stimulation of adenylyl cyclase (AC). We have reported a defect in the DA-1 receptor/AC coupling in the PCT of the spontaneously hypertensive rat (SHR) of the Okamoto-Aoki strain.

Regional differences in brain norepinephrine and dopamine uptake kinetics in inbred rat strains with hypertension and/or hyperactivity.

High-affinity uptake of norepinephrine (NE) and dopamine (DA) were determined in synaptosomes of brain regions from four genetically related inbred rat strains, all derived from the Wistar-Kyoto rat: SHR, WKY, WKHA and WKHT strains. SHRs express hypertension and hyperactivity, WKHAs express hyperactivity alone, WKHTs express hypertension alone, and WKYs are neither hypertensive nor hyperactive. Significant increases in NE uptake, primarily in Vmax, in cerebral cortical areas and the cerebellum, were associated with the hypertensive trait.

Behavior of hypertensive and hyperactive rat strains: hyperactivity is not unitarily determined.

The spontaneously hypertensive rat (SHR) is behaviorally hyperactive relative to the Wistar-Kyoto rat (WKY). By breeding SHR with WKY, followed by inbreeding, two new strains have been developed in which hypertension seems to be separated from hyperactivity to novel stimuli: the WKHT and the WKHA strains. The main purpose of the present study was to determine which behavioral characteristics of SHR have been dissociated from the hypertensive trait in the WKHA strain.