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. Studies in collaboration with numerous colleagues have allowed us to describe a limited behavioral and neurochemical profile of WKHA rats. Their most prominent behaviors include hyperactivity in a novel environment, and a marked hyperreactivity to stress, both of which are also characteristic of SHRs. They differ from SHRs in other respects: WKHA are less aggressive, habituate more readily to a novel environment, and are less exploratory in a familiar environment than the SHR. Neurochemical studies have revealed changes in brain monoamine function in WKHA rats, particularly in frontal cortical norepinephrine and dopamine uptake, and they show marked changes in neuroendocrine responses in the hypothalamic/pituitary/adrenal axis, as well as altered POMC peptides in the pituitary anterior and posterior lobes. Molecular genetic studies by colleagues in Bordeaux have identified a quantitative trait locus for the hyperactivity/hyperreactivity trait of WKHA rats.

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. To increase usefulness of these strains, we characterized them by use of genetic methods, including DNA finger-printing and simple sequence length polymorphism (SSLP) analyses. We found that these two novel strains are more closely related genetically to either SHR or WKY rats than the degree to which the latter two strains are related to one another; heterozygosities of SSLP marker alleles were extremely rare in WKHA and WKHT, indicating that these strains can be considered as truly inbred (in contrast to WKY rats from two sources); and it was almost always possible to match the SSLP marker alleles found in WKHA and WKHT rats with similarly sized alleles in the parental SHR and WKY alleles, indicating that the WKHA and WKHT strains constitute true mixes of the genomes of SHR and WKY rats. Furthermore, immunogenetic analyses indicated that WKY and WKHT rats belonged to the RT1 l haplotype, whereas SHR and WKHA rats belonged to the k haplotype. These results extend the usefulness of WKHA and WKHT rats for further genetic and physiologic studies.

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. Hippocampal neurons, which are particularly vulnerable to damage in stroke, were shown to be more susceptible to ischemic damage in SHRSP than in either SHR or normotensive, stroke-resistant controls. The association of a mutated trkB gene with the stroke-prone genotype found in this study suggests that the trkB gene merits further study as a promising candidate gene for stroke.

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. Studies using brain lesions, neuropharmacology and gene knock-out strategies have shown that specific elements of the brain dopaminergic system can subserve hyperactivity. Evidence of a genetic contribution comes from family and twin studies but also from the ability to select divergent animal lines on the basis of their differential activity. The Wistar-Kyoto (WKY) and Wistar-Kyoto hyperactive (WKHA) rats are such strains--distinct for their low and high activity scores in a novel environment, respectively. Here, we report the detection of a major hyperactivity-related QTL on chromosome 8, explaining 29% of the variance of an intercross between these strains. This study represents the first behavioural QTL analysis in rat and provides a new starting point for biologically categorizing different forms of hyper-activity.

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). The plasma levels of prolactin, ACTH, corticosterone, glucose and renin activity were determined after a 10-min exposure to novelty. Our results showed that WKHA rats, compared to WKYs, were more active in a familiar as well as in novel environments. They exhibited also less anxiety-related behaviors and lower neuroendocrine responses. A principal component analysis performed on the behavioral F2 results defined three independent factors: general activity, anxiety and defecation, none of them being correlated with the neuroendocrine measures. Thus this study suggests that these different responses to stress are independent components that may have distinct molecular bases.

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. Systolic tail BP was monitored with a plethysmograph. AAA size was measured directly with a micrometer on postoperative days 7 and 14. All data are expressed as the mean +/- standard deviation (SD). BP (mmHg) was significantly higher in hypertensive rats: 164 +/- 15 versus 119 +/- 7 (p < 0.001). AAA were also significantly larger in hypertensive rats with a mean expansion rate (mm/day) nearly twice that of normotensive animals: 0.13 +/- 0.09 versus 0.07 +/- 0.03. In a second series of animals, propranolol treatment was compared to placebo. In those animals, hypertensive propranolol-treated rats had significantly smaller AAA than placebo-treated controls (p < 0.05). There was no difference in normotensive animals but these rats had an unexplained paradoxical rise in BP with treatment. In this model, hypertension increases the expansion rate of AAA. Propranolol reduced the size of AAA in hypertensive animals, at least in part because of a decrease in BP. Other possible mechanisms of propranolol's action may be operative and require further study.

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. Four groups of animals of both sexes were studied: (1) WKY, n = 101, (2) WKHA, n = 33, (3) WKHT, n = 91, and (4) SHR, n = 28. Blood pressure (BP) was determined by tail plethysmography as well as direct intraarterial monitoring under anesthesia. Fixed specimens were prepared for histologic analysis and the wall thickness determined morphometrically. Quantification of soluble tissue protein, elastin, and collagen in the aortic tissue was determined by measuring leucine (leu), hydroxyproline (HP/leu), and desmosine (DES/leu). The hypertensive strains (SHR and WKHT) had significantly higher tail BP than the normotensive strains (WKY and WKHA)-WKY: 128.7 +/- 22.3; WKHA: 126.7 +/- 14.6; WKHT: 162.8 +/- 21.2; SHR: 164.2 +/- 36.1 (p < 0.0001). Additionally, intraaortic diastolic BP and mean BP were higher in SHR rats than in WKHT. Morphometric studies showed the media thickness in the SHR rats was significantly greater than in the WKY and WKHA rats and no different than in the WKHT rats. Significantly less of the aortic wall protein was present as elastin in the hypertensive rats (SHR and WKHT), as well as the hyperactive rats (WKHA), compared to rats that had neither trait (WKY). These studies provide new information regarding aortic structure and function in genetic hypertension using inbred strains to control for the hyperactivity/hyperreactivity traits that coexist with hypertension in the SHR. They reveal that hypertensive aortas have altered matrix proteins that cannot be explained simply on the basis of blood pressure alone.

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. Because both WKHTs and SHRs show short circadian periods relative to their respective comparison strains, this trait may cosegregate genetically with hypertension. In contrast, because WKHAs and SHRs show similar photic entrainment and phase shifting, these circadian functions may cosegregate with open-field hyperactivity. Finally, because neither WKHAs nor WKHTs show the SHR's excessive levels of home-cage running wheel activity, this trait is not related to either hypertension or open-field activity. Further work would be required to elucidate specific genetic and/or physiological linkages among these variables.

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. Nucleotide sequence analysis of the LNGFR gene revealed that WKHT has the same mutation as SHR, whereas WKHA has the normal sequence, as seen in WKY. These results support our original hypothesis that the mutated LNGFR gene is linked to hypertension, since the mutation had co-segregated with the hypertensive trait, and not hyperactivity trait of SHR.

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. Animals of both strains were randomly allocated to control or MAB-treated groups (MAB, 5 microgram/100 gm body weight intraperitoneally, daily, beginning on the operative day for a total of four doses). The activity of the MAB against rat leukocytes had first been determined by in vitro immunofluorescence flow cytometry. Aortic size was directly measured initially and on day 14. At that time, a segment of aorta was stained with hematoxylin and eosin and mononuclear leukocytes and neutrophils were counted in each of 10 microscopic fields (400X). RESULTS: The initial aortic size in all animals was 1.11+/-0.15 mm. All groups developed aneurysms significantly larger than the initial aortic size (p<0.01). However, the MAB-treated animals had significantly smaller aneurysms than the untreated controls (mm): WKY: 3.63+/-1.26, WKY-MAB: 2.08+/-0.30, WKHT: 4.54+/-1.86, WKHT-MAB: 2.37+/-0.40, p<0.0001. There also were significantly fewer monocytes in the MAB-treated normotensive rats: WKY:35.5+/-29.9, WKHT:40.6+/-28.8, WKY-MAB: 8.9+/-8.5, WKHT-MAB: 32.3+/-25.7, p=0.03. Neutrophil counts did not differ significantly between the groups. CONCLUSIONS: Treatment with anti-CD18 monoclonal antibody slows the expansion of AAA in this experimental model. The associated inflammatory process at day 14, as indicated by monocyte infiltration, is reduced, but this effect may be opposed by the presence of hypertension. Further evaluation of the role of leukocytes and adhesion molecules in the expansion of AAA is warranted.

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. To determine whether the enhanced neuropeptide Y-immunoreactive vascular innervation is specifically associated with hypertension and/or these behavioral abnormalities, four genetically related, inbred rat strains were used: SHR, which are hypertensive and hyperactive; WKY rats, which are neither hypertensive nor hyperactive; WKHA, which are hyperactive but normotensive; and WKHT, which are hypertensive but not hyperactive. The present study demonstrated that whereas the hypertensive strains (SHR and WKHT) exhibited smooth muscle hypertrophy in both superior mesenteric and caudal arteries in adulthood (10 months) but not at a prehypertensive age (1 month), both arteries exhibited significantly increased neuropeptide Y-immunoreactive innervation at both ages. It was further observed that the mesenteric artery in WKHA, a normotensive strain, had significant smooth muscle hypertrophy at 10 months; however, neuropeptide Y innervation in this artery was no different from that of WKY controls. The findings indicate that there is a cosegregation of neuropeptide Y hyperinnervation of the vasculature with the hypertensive phenotype, evident as early as 1 month of life in the hypertensive strains, and this should be considered further as a contributory factor in genetic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

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. A propranolol dose-response was studied for each strain: (1) saline solution controls (n = 18); (2) propranolol, 10 mg/kg subcutaneously (n = 18); (3) propranolol, 30 mg/kg (n = 14). Systolic blood pressure was determined by tail plethysmography before operation and on day 14, as well as by direct recording at surgery and on day 14. Rats were killed at 14 days, and aneurysm diameter was measured. RESULTS: The initial tail BP was 129 +/- 22 mm Hg in WKY animals and 158 +/- 21 mm Hg in WKHT animals (p < 0.0001). Tail BP and intraaortic systolic, diastolic, and mean blood pressure (BP) were not significantly decreased by propranolol treatment in either strain of rats. However, BP tended to rise in WKY rats, whereas it fell slightly in WKHT rats. Initial aortic size in all animals was 1.06 +/- 0.12. The final aortic size in untreated, hypertensive rats was more than twice that of untreated normotensive controls: 1: WKHT, 3.0 +/- 0.73 mm, 1: WKY, 6.9 +/- 3.5 mm (p < 0.01). After treatment with both doses of propranolol, hypertensive aneurysms were significantly smaller than the untreated WKHT group (p < 0.05) and not significantly different from aneurysms in all groups of normotensive animals: 2: WKY, 3.1 +/- 1.13 mm, 2: WKHT, 4.0 +/- 1.81 mm; 3: WKY, 4.1 +/- 0.41 mm, 3: WKHT, 2.9 +/- 1.24 mm. There was no significant difference in aortic size between the three normotensive WKY groups. CONCLUSIONS: Hypertension increases the size of aortic aneurysms in this experimental model. Propranolol significantly reduces the size of experimental AAA in hypertensive animals independently of the dose and by a mechanism that may be unrelated to simple BP reduction.

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. The hyperactive strains exhibited significant neutrophilia and increased platelet count relative to the non-hyperactive strains. CONCLUSION: Not all of the differences in blood cells described originally in SHR versus WKY rats were associated with the inheritance of hypertension. The changes in the lymphocytes and in the erythrocytes should be examined as possible factors in the pathophysiology of hypertension.

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. Together with the SHR and WKY, these genetically related, homozygous strains permit a more definitive means of examining the neuroendocrine correlates of either hypertension or behavior. The adult (5-month-old) male anterior pituitary gland content of the POMC peptides beta-endorphin and ACTH was decreased approximately 50% in the SHR and WKHT strains compared to that in the WKY strain, whereas hormone levels in the WKHA strain were not significantly different from those in the WKY strain. Reduced POMC peptide levels were, therefore, specifically associated with the hypertensive trait. Hormone content in prehypertensive weanling (5- to 7-week-old) SHR and WKHT animals was also reduced approximately 35% compared to that in WKY animals. Northern blot analysis identified a 45% decrease in POMC mRNA expression in the hypertensive SHR and WKHT strains, which paralleled the changes in tissue hormone content. Using both immunocytochemistry and in situ hybridization histochemistry, the number of labeled cells per unit area of tissues section was reduced approximately 45% in anterior pituitary tissues from SHR and WKHT rats compared to that in WKY tissues. The levels of POMC mRNA per cell, determined by quantitative densitometry, were not statistically different in the anterior pituitaries of WKHT, SHR, and WKY rats. The decrease in hormone content and POMC mRNA levels may, thus, reflect decreased anterior pituitary gland corticotrope populations. Although POMC peptide levels in the anterior pituitaries of adult WKHA animals were not significantly different from those in WKY animals, the morphological studies demonstrated a 30% increase in the corticotrope population in the WKHA strain. In contrast, POMC mRNA levels in WKHA animals were decreased 30%, and the amount of POMC mRNA per corticotrope was decreased approximately 35% compared to that in WKY, SHR, and WKHT tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

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. The largest difference was found in the prolactin response. Post-open-field levels were much lower in the WKHA (27.11 +/- 4.69 ng/ml) than in the parent WKY strain (83.65 +/- 6.84 ng/ml), the hypertensive strains having intermediate levels (WKHT: 58.05 +/- 7.65 ng/ml; SHR: 64.13 +/- 7.19 ng/ml). Other differences were also found in the levels of aldosterone and renin activity. These results indicate that these strains are an excellent model to study neuroendocrine correlates of hypertension and hyperactivity, which are associated in the SHR strain and may be of interest for the study of the association between neuroendocrine and behavioral characteristics.

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. A fifth study used the Wistar-Kyoto, hyperactive (WKHA) strain developed by Hendley, and no differences were observed. Heart and adrenal weights; adrenal catecholamine synthetic enzymes; and heart, aortic, and kidney histology were measured and showed significant changes, which for the most part paralleled blood pressure changes. Social instability and the associated blood pressure changes were made more severe by periodic mixing of males from different colonies. This had no effect on the peaceable WKHA rats, some effect on the Sprague-Dawley rats, and a severe effect on the Long-Evans rats. The WKHA rats failed to show blood pressure changes despite stress-induced increases in heart and adrenal weights. Thus, different types of psychosocial stress and different genetics combine to induce a variety of neuroendocrine changes, not all of which necessarily lead to increased blood pressure.

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. Rats were killed at 7 or 14 days, aneurysm diameter was measured, and aneurysms were examined histologically. Systolic blood pressure was significantly higher in WKHT rats (164 +/- 15 mm Hg) compared to WKY animals (119 +/- 7 mm Hg, P < 0.001). Initial aortic size was 1.10 +/- 0.02 mm in the two groups. Aneurysms in the hypertensive animals were significantly larger at Day 7 (WKY, 2.31 +/- 0.09 mm; WKHT, 2.54 +/- 0.22 mm; P = 0.02) and Day 14 (WKY, 2.36 +/- 0.25; WKHT, 3.45 +/- 0.89; P = 0.001). Overall, the mean AAA growth rate of the WKYHT group was nearly twice that of the WKY group: 0.13 +/- 0.09 mm/day vs 0.07 +/- 0.03 mm/day, (P = 0.004). Growth rates were also positively correlated with sBP (r = 0.82, P < 0.0001). Both groups showed elastic lamellar disruption and inflammatory cell infiltration within the wall of the aorta. As demonstrated in this experimental model, hypertension does indeed increase the rate of growth of AAA.

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. Hyperactivity and hypertension are both expressed in the SHR. To determine if the DA-1 receptor coupling defect is associated with hyperactivity or hypertension, we studied the DA-1 receptor in the PCT of two new inbred rat strains derived from the SHR: the hyperactive WKHA and the hypertensive WKHT rat. Tail-cuff blood pressures taken at 4 weeks indicated that WKHT rats were not hypertensive (86 +/- 3 mm Hg, n = 6), whereas at 12 weeks systolic pressures in both SHR and WKHT rats exceeded 150 mm Hg. Hyperactivity, however, was noted in WKHA rats even at this early age. Basal AC activity was similar in WKHA and WKHT PCT in either age group. In the older rats, the DA-1 agonist fenoldopam (10(-7) mol/L) stimulated AC activity in WKHA (70.6 +/- 16.1 fmol per 3 mm PCT per 20 minutes, n = 3) but not in WKHT PCT (43.3 +/- 5.3 fmol per 3 mm PCT per 20 minutes, n = 4). Gpp(NH)p (10(-5) mol/L), a nonhydrolyzable GTP analogue, stimulated AC activity to a similar extent in WKHA and WKHT PCT.(ABSTRACT TRUNCATED AT 250 WORDS)

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. Significant increases in DA uptake Vmax in the frontal cortex were associated with the inheritance of hyperactivity among these strains. A limited study in SHRs indicated that DA uptake in the frontal cortex increased with age, and that males did not differ from females. No changes in DA uptake in the neostriatum were found with respect to either strain, or age or sex. These findings revealed changes in brain catecholamine neuronal function that are of relevance to both hypertension and hyperactivity. This was made possible by the availability of WKHA and WKHT, in addition to WKYs, as appropriate controls for the SHR.

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. Male SHR, WKY, WKHT, and WKHA were subjected to three protocols: 1) Two forced-exploration tests, where the results showed that both the SHR and the WKHA rats were hyperactive. 2) A free-exploration open field, where the SHR was more active than the other strains, showing shorter latencies to leave the home cage, spending more time in the field, ambulating and rearing more. Furthermore, the WKHT behavior was more similar to the SHR behavior than the WKHA behavior. 3) A two-component schedule of reinforcement, where one component (fixed-interval 2 min) was signaled by houselight on and the other (extinction, EXT) by houselight off. In this test, the SHR behavior was markedly different from that of the three other strains: the fixed-interval scallop, the accelerated responding towards the end of the interval, was steeper in SHR than in the other groups. The SHR emitted more responses during the extinction component of the schedule. The SHR hyperactivity was dependent upon the reinforcement value of the water deliveries and was increased even further by sensory-reinforcing respones feedback lights. Thus, the hyperactivity of the WKHA strain seems to be less pervasive than that of the SHR.(ABSTRACT TRUNCATED AT 250 WORDS)