Kinetic properties of the Na+/H+ antiporter of lymphocytes from the spontaneously hypertensive rat: role of intracellular pH.

Enhanced activity of the Na+/H+ antiporter is increasingly reported as a feature of cells from hypertensive subjects but the intracellular pH (ipH) dependency of its activity has not been examined. This study was designed to characterize the kinetic properties of the Na+/H+ antiporter in lymphocytes from adult spontaneously hypertensive rats (SHR) and in those from age-matched normotensive Wistar-Kyoto (WKY) controls. Steady-state ipH, estimated from the measurement of BCECF fluorescence, was significantly lower in lymphocytes from the SHR than in those from WKY rats (7.09 +/- 0.02, n = 17 and 7.17 +/- 0.03, n = 19, respectively, P less than 0.025). The velocity of the antiporter determined from the product of the change in intracellular hydrogen ion concentration (i[H+]) by the buffering power measured concurrently at each starting ipH exhibited similar kinetic parameters in SHR and WKY cells: Vmax, 72 +/- 18 vs. 79 +/- 24 mM H+/30 s; pKH, 10.04 +/- 0.87 vs. 8.49 +/- 0.80; and Hill coefficient, 1.67 +/- 0.12 vs. 1.44 +/- 0.10, respectively. Likewise, no significant differences were observed between SHR and WKY cells in either the Km (29 +/- 5 and 32 +/- 8 mM, respectively) or the Vmax (6.0 +/- 1.0 and 5.53 +/- 1.0 mM H+/30 s, respectively) of the sodium activation curve. We conclude that while the ipH of SHR lymphocytes is reduced, the kinetic properties of the Na+/H+ antiporter are virtually identical in SHR and WKY lymphocytes. Consequently, a primary abnormality in the activity of this antiporter is not an inherent feature of lymphocytes from the SHR model of genetic hypertension. We propose that the activity of the Na+/H+ antiporter in SHR cells is apt to be increased as a result of reduction in ipH which dictates a higher set point in its steady-state activity.

Differences in striatal spiny neuron action potentials between the spontaneously hypertensive and Wistar-Kyoto rat strains.

The spontaneously hypertensive rat (SHR) and the Wistar-Kyoto (WKY) inbred rat strains display behavioral differences characterized by relative increases and decreases in levels of activity. Both strains have subsequently been utilized as animal models of hyperactive and hypoactive behavioral traits. The etiology of these behavioral characteristics is poorly understood, but may stem from alterations in the physiology of selected neural circuits or catecholamine systems. This study investigated the cellular properties of neurons from three genetically related strains: the SHR; WKY; and Wistar (WI). In vivo intracellular recordings were made under urethane anesthesia from spiny projection neurons in the striatum, a brain area involved in behavioral activation. Results obtained from 71 spiny projection neurons indicate that most cellular properties of these neurons were very similar across the three strains. However, the amplitude and half-duration of both spontaneously occurring and current-evoked action potentials were found to be significantly different between the SHR and WKY strains with neurons from the SHR firing action potentials of relatively greater amplitude and shorter duration. Action potential parameters measured from the WI rats were intermediate between the two other strains. These differences in action potentials between two behaviorally distinct strains may reflect altered functioning of particular membrane conductances.

Antidepressant drug induced alterations in binding to central dopamine transporter sites in the Wistar Kyoto rat strain.

The Wistar Kyoto (WKY) rat has been proposed as an animal model of depressive behavior. Exposing WKY rats to stress stimulation produces symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias. Given the role of the mesolimbic dopamine (DA) system in cognitive, emotional and motivational behaviors, we previously examined the distribution of DA transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and Sprague-Dawley (S-D) rats. WKY rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas compared to the other strains. It was reasoned that these differences may lead to altered synaptic levels of DA in specific brain regions thus contributing to the behavioral differences observed in this rat strain. Thus, the present study examined whether repeated treatment with antidepressant drugs that block the uptake of DA (nomifensine and bupropion) would modify [3H]-GBR12935 binding to DAT sites in WKY rats compared to WIS and S-D rats. The results indicate that while nomifensine and bupropion increased the binding of [3H]-GBR12935 to DAT sites in the mesocorticolimbic regions in WKY rats, these drugs increased the binding of [3H]-GBR12935 to DAT sites in the cell body areas in WIS rats but not in S-D and WKY rats. The data from this study suggest that antidepressant induced alterations in DAT sites in the mesocorticolimbic brain regions may play a role in the behavioral improvement seen in WKY rats, as measured by the Open Field Test (OFT) and the Porsolt Forced Swim Test (FST).

Enhancement of experimental gastric carcinogenesis induced in spontaneously hypertensive rats by N-methyl-N'-nitro-N-nitrosoguanidine.

The incidence, number, and histological types of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine and the tissue norepinephrine concentration of the gastric wall were investigated in spontaneously hypertensive rats and in control Wistar Kyoto rats and Wistar rats. All rats were given drinking water containing 25 micrograms/ml of N-methyl-N'-nitro-N-nitrosoguanidine for 25 weeks. During Week 52, the incidence and number per rat of gastric cancers were significantly greater in spontaneously hypertensive rats than in Wistar Kyoto and Wistar rats. All tumors induced in the glandular stomach were adenocarcinomas, but no significant difference was found in the histological types of adenocarcinoma in the three strains of rats. At Weeks 15, 30, and 52, norepinephrine concentrations in the fundic and antral portion of the gastric walls and labeling indices in the antral and fundic mucosa were significantly higher in spontaneously hypertensive rats than in Wistar Kyoto and/or Wistar rats. These findings indicate that increased sympathetic nervous system activity enhances the development of gastric cancers, but immunological dysfunction in spontaneously hypertensive rats may contribute to the increased susceptibility to gastric cancer.

Glial fibrillary acidic protein (GFAP) immunoreactivity correlates with cortical perfusion parameters determined by bolus tracking arterial spin labelling (bt-ASL) magnetic resonance (MR) imaging in the Wistar Kyoto rat.

Alterations in astrocyte number and function have been implicated in the pathophysiology of a number of psychiatric disorders. The development of magnetic resonance imaging (MRI) as a tool in the animal laboratory has enabled an investigation of the relationship between pathological and neuroimaging markers in animal models. However the physiological processes which underlie these markers and their role in mediating behavioural deficits is still poorly understood. Rodent models have provided us with important insights into physiological and cellular mechanisms which may mediate anxiety and depression-related behaviours. The Wistar-Kyoto (WKY) rat is a strain which endogenously expresses highly anxious and depressive-like behaviours and has previously been reported to exhibit alterations in immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP) in brain sub-regions relative to more stress resilient out-bred strains. Here we report that the depressive and anxiety-like behaviours exhibited by the WKY rat strain are associated with alterations in brain morphology including a decrease in hippocampal volume, coupled with reduced resting state frontal cortical perfusion as assessed by MR bolus tracking arterial spin labelling (bt-ASL) relative to the out-bred Wistar strain. Pre-limbic cortical GFAP immunoreactivity and astrocyte cell number were positively correlated with cortical blood perfusion in the WKY strain. These experiments provide a link between pathological and neuroimaging markers of aberrant astrocytic function and add validity to the WKY rat as a model for co-morbid anxiety and depression.

Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains.

Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences.

Enhanced glucose tolerance in spontaneously hypertensive rats. Pancreatic beta-cell hyperfunction with normal insulin sensitivity.

We used intravenous glucose tolerance tests in vivo and 3-O-methylglucose transport into skeletal muscle in vitro to assess glucose tolerance, pancreatic beta-cell function, and insulin action in 9- to 11-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Body weight was slightly higher in the WKY (P less than 0.001), while blood pressure was elevated in the SHR (P less than 0.001). Insulin responses to intravenous glucose after 4 or 12 h of fasting in SHR were 2-3 times the responses of WKY rats (P less than 0.001). The greater insulin responses in SHR were associated with accelerated glucose disappearance P less than 0.001 vs. WKY rats). A direct correlation (r = 0.49, P less than 0.05) between the peak plasma insulin responses to glucose and Kg values in SHR suggested that the exaggerated insulin responses contributed to the accelerated glucose disappearance in that group. 3-O-methylglucose transport rates into epitrochlearis muscles in vitro did not differ significantly between SHR and WKY groups in the absence of insulin (P less than 0.2) or in the presence of insulin at physiological (600 pM, P greater than 0.4) or pharmacological (120,000 pM, P greater than 0.9) concentrations. Thus, compared with WKY rats, SHR had exaggerated insulin responses to glucose, similar insulin-mediated glucose transport into skeletal muscle, and enhanced glucose tolerance. Our findings indicate that young, hypertensive SHR have hyperfunction of pancreatic beta-cells that is unrelated to insulin resistance. The resultant nutrient-stimulated hyperinsulinemia could play a role in the development or maintenance of elevated blood pressure in SHR.

Stimulus processing and associative learning in Wistar and WKHA rats.

This study assessed basic learning and attention abilities in Wistar-Kyoto hyperactive (WKHA) rats using appetitive conditioning preparations. Two measures of conditioned responding to a visual stimulus, orienting behavior (rearing on the hind legs), and food cup behavior (placing the head inside the recessed food cup) were measured. In Experiment 1, simple conditioning, but not extinction, was impaired in WKHA rats compared with Wistar rats. In Experiment 2, nonreinforced presentations of the visual cue preceded the conditioning sessions. WKHA rats displayed less orienting behavior than Wistar rats but comparable levels of food cup behavior. These data suggest that WKHA rats exhibit specific abnormalities in attentional processing as well as in learning stimulus-reward relationships.

The effects of chlorpyrifos on blood pressure and temperature regulation in spontaneously hypertensive rats.

Using radiotelemetry to monitor blood pressure and core temperature, studies in our laboratory have shown that a prolonged hypertensive response is elicited in rats exposed to chlorpyrifos, an organophosphate-based insecticide. Chlorpyrifos inhibits acetylcholinesterase activity, resulting in central and peripheral stimulation of central cholinergic pathways involved in blood pressure regulation. The spontaneously hypertensive rat has been shown to be more sensitive to central cholinergic stimulation. Therefore, we hypothesized that these rats would be more susceptible and sustain a greater hypertensive response when exposed to chlorpyrifos. Heart rate, cardiac contractility, core temperature, and blood pressure were monitored by radiotelemetry in SHRs and their Wistar Kyoto (WKY) normotensive controls following exposure to chlorpyrifos (10 mg/kg or 25 mg/kg, orally). Baseline blood pressure of SHRs was approximately 35 mmHg above that of WKYs prior to dosing. SHRs exhibited a greater and more sustained elevation in diastolic, mean and systolic blood pressure following exposure to 25 mg/kg of chlorpyrifos. The rise in blood pressure lasted for approximately 56 hours in SHRs compared to approximately 32 hours in WKYs. Chlorpyrifos also led to a prolonged elevation in daytime heart rate in both strains. There was a transient elevation in cardiac contractility in both strains lasting approximately 7 hr after exposure to chlorpyrifos. The hypothermic response to chlorpyrifos was similar in magnitude and duration for both strains. Plasma cholinesterase activity measured 4 hr after exposure to 25 mg/kg chlorpyrifos was inhibited to approximately 40% of control levels in both strains. Using the SHR strain as a model to study susceptible populations, the data suggest that individuals with a genetic predisposition to hypertension may be more susceptible from exposure to organophosphate-based insecticide, as manifested by an exacerbated hypertensive response.

Brown Norway rats, a putative schizophrenia model, show increased electroencephalographic activity at rest and decreased event-related potential amplitude, power, and coherence in the auditory sensory gating paradigm.

In recent schizophrenia clinical research, electroencephalographic (EEG) oscillatory activities induced by a sensory stimulus or behavioral tasks have gained considerable interest as functional and pathophysiological biomarkers. The Brown Norway (BN) rat is a putative schizophrenia model that shows naturally low sensorimotor gating and deficits in cognitive performance, although other phenotypes have not been studied. The present study aimed to investigate the neurophysiological features of BN rats, particularly EEG/event-related potential (ERP). EEG activity was recorded at rest and during the auditory sensory gating paradigm under an awake, freely moving condition. Frequency and ERP analysis were performed along with time-frequency analysis of evoked power and intertrial coherence. Compared with Wistar-Kyoto rats, a well-documented control line, BN rats showed increased EEG power at rest, particularly in the theta and gamma ranges. In ERP analysis, BN rats showed reduced N40-P20 amplitude but normal sensory gating. The rats also showed reduced evoked power and intertrial coherence against auditory stimuli. These results suggest that BN rats show features of EEG/ERP measures clinically relevant to schizophrenia and may provide additional opportunities for translational research.

Comparison of the validity of the use of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder in males and females.

The spontaneously hypertensive rat (SHR) is a commonly used and well-studied rodent model of attention deficit hyperactivity disorder (ADHD). Sex differences in the cognitive symptoms of ADHD are reported. However, the female SHR rat is much less studied than its male counterpart. The goal of the current study was to assess the validity of the SHR rodent model of ADHD by examining attentional performance, inhibitory control, and hyperactivity in both male and female SHR rats. Adult SHR and control Wistar-Kyoto rats were trained on the 5-choice serial reaction time task, a self-paced test of attention and inhibitory control. This task requires animals to identify the location of a brief light stimulus among five possible locations under several challenging conditions. Analyses of percent correct revealed that attentional performance in SHR females was not significantly different from control females, whereas attentional performance in SHR males was significantly different from control males. Analyses of the number of premature responses revealed that SHR rats made more inhibitory control errors than did control rats and that this decrease in inhibitory control was present in both SHR males and females. Analyses of activity in the open field revealed that SHR rats were more hyperactive than were control rats and that this increased hyperactivity was present in both SHR males and females. The current findings have implications for the study of sex differences in ADHD and for the use of SHR rats as a model of ADHD in females.

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats during development of hypertension.

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats (SHR) during development of hypertension were investigated using in vivo and in vitro methods. Plasma ACTH responses to hemorrhage and ether stress were significantly smaller in 7-week-old SHR than in age-matched Wistar-Kyoto rats (WKY), while plasma corticosterone baseline levels and its response to stress were greater in SHR than in WKY. There was no significant difference in the plasma ACTH response to ether stress between bilaterally adrenalectomized SHR and WKY replaced with a 25% corticosterone pellet for 6 days. Adrenalectomy prevented the development of hypertension in SHR; however, corticosterone replacement restored hypertension. Plasma ACTH showed a smaller response to iv CRH injection in SHR than in WKY, while the ACTH response to arginine vasopressin was not different between SHR and WKY. CRH concentrations in the median eminence, posterior pituitary, and cerebral cortex were lower in SHR than in WKY, while the CRH concentration in the median eminence was not different in SHR and WKY when they were adrenalectomized with or without corticosterone replacement. Basal in vitro CRH release from hypothalamic tissue was reduced in SHR, while CRH release in response to 56 mM KCl was not different in SHR and WKY. These results suggest that adrenocortical function is enhanced in young SHR, that reduced ACTH response to stress and exogenous CRH in SHR may be ascribed to higher plasma corticosterone levels, and that corticosterone is essential for the development of hypertension in SHR.

Activation of the humoral antihypertensive system of the kidney increases diuresis.

Isolated kidneys taken from normotensive Wistar-Kyoto rats were cross-perfused extracorporeally by normotensive strain-matched donor rats. The extracorporeal perfusion circuit was arranged so that the perfusion pressure to the normotensive recipient kidney could be varied from 90 to 200 mm Hg without any change in total flow through this circuit. This setup avoided hemodynamic or mechanical interferences with reflexogenic circulatory control in the normotensive donor rat when the recipient kidney was manipulated. Diuresis and natriuresis were measured in the normotensive donor rat and the normotensive recipient kidney. A few minutes after normotensive recipient kidney perfusion pressure had been raised, mean arterial pressure (MAP) and heart rate started to decline rapidly in the normotensive donor rat, and circulatory collapse ensued within 15 to 100 minutes. During the control period at 90 mm Hg normotensive recipient kidney perfusion pressure, urinary flow, MAP and heart rate were stable in the normotensive donor rat and the normotensive recipient kidney. When perfusion pressure was raised to 200 mm Hg in the recipient kidney, the urinary flow in the donor rat increased 62% on average in the first 10 minutes over values recorded before the pressure rise (p less than 0.05) while MAP simultaneously fell by 16% and HR remained unchanged. During the subsequent period, the urinary flow of the donor rat declined together with MAP and heart rate. In the extracorporeally high-pressure perfused recipient kidneys, an eightfold to ninefold increase in diuresis and natriuresis occurred during the first 45 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal cortical and papillary blood flow in spontaneously hypertensive rats.

The present study examined whether an alteration in renal medullary hemodynamics is associated with the development of hypertension in the spontaneously hypertensive rat (SHR). The relationships between whole kidney, cortical and papillary blood flows, and renal perfusion pressure were compared in 3- to 5-, 6- to 9-, and 12- to 16-week-old SHR and Wistar-Kyoto rats (WKY). Cortical and papillary blood flows were similar in the different age groups of SHR and WKY over most of the range of perfusion pressure studied. Control papillary blood flows, determined at a renal perfusion pressure equal to the mean arterial pressure of each animal, were not significantly different in the 3- to 5- and 12- to 16-week-old SHR in comparison to values observed in age-matched WKY. In contrast, the control papillary blood flow was 30% lower in 6- to 9-week-old SHR in comparison to the value observed in WKY. Papillary blood flows were significantly less in all age groups of SHR than the corresponding flows measured in WKY when they were compared at equivalent renal perfusion pressures. These findings indicate that medullary vascular resistance is elevated even in very young SHR and suggest that alterations in vasa recta hemodynamics may participate in the development of hypertension by shifting the pressure-natriuresis relationship toward higher pressures.

Potassium depletion ameliorates hypertension in spontaneously hypertensive rats.

The hemodynamic effect of moderate K+ depletion in hypertension is unknown. Since severe K+ depletion reduces systemic vascular resistance in normotensive rats, we determined the effect of K+ depletion on the natural history of hypertension in spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) and SHR were fed a K+-replete, a moderately K+-depleted, or a severely K+-depleted diet. After 6 weeks, systemic vascular resistance was reduced by 25% in WKY on the severely K+-depleted diet while mean arterial pressure and systemic vascular resistance were comparable in WKY on the other two diets. In SHR on the severely K+-depleted diet for 6 weeks, muscle K+ was reduced by 23% and growth rate by 65%. In SHR on the moderately K+-depleted diet, growth rate was reduced by 23% after 3 weeks. By 6 weeks, however, muscle K+ was reduced by 5 to 6% and growth rate was comparable to that in SHR receiving the K+-replete diet. The administration of either K+-depleted diet prevented the development of hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 122 +/- 3; K+-replete, 155 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups) and reversed established hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 128 +/- 3; K+-replete, 171 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups). The protective effect of K+ depletion was mediated by a 40% reduction in systemic vascular resistance. These results suggest that K+ depletion has a potent antihypertensive effect in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral glucose utilization and blood flow in adult spontaneously hypertensive rats.

Not only blood pressure but also behavioral activity, brain morphology, and cerebral ventricular size differ between young spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. This suggests that cerebral blood flow and cerebral metabolism may vary between these two rat strains. To test this hypothesis, we measured local cerebral glucose utilization in 31 brain areas of 26-30-week-old rats. Local cerebral blood flow was also assessed in these same areas. Cerebral glucose utilization was measured by the 2-deoxyglucose method; cerebral blood flow was determined by the iodoantipyrene method. In virtually all gray matter structures, the apparent rate of glucose utilization was lower in SHR than in normotensive WKY rats; the interstrain differences varied significantly among structures and were statistically significant (uncorrected t tests) in 14 of 28 gray matter areas. Local cerebral blood flow was fairly similar in the two rat strains. The coupling of blood flow to glucose utilization varied significantly among brain areas in normotensive WKY rats as well as in SHR. In a number of gray matter structures, the coupling of flow to metabolism differed between hypertensive and normotensive animals. These data suggest that for many brain areas, either glucose utilization or glucose partitioning differs between WKY rats and SHR.

Is the hypertensive rat really hyperreactive?

This study investigated the behavior of hypertensive-prone and nonhypertensive-prone rat strains to see whether there are differences in behavioral reactivity to environmental stimulation. Of primary interest was general activity, because investigators have assumed it to be an index of reactivity to environmental stimulation and to be correlated with the elevation of blood pressure in spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto (WKY) rats. Therefore, general activity was assessed in SHRs and WKYs as a function of walking and rearing in an open field (Experiments 1 and 2) and crossings in a shuttlebox test (Experiments 3, 4, and 5). Activity was assessed under a constant level of environmental stimulation in the open field (Experiment 1) and shuttlebox (Experiment 3) or under varying degrees of stimulation in the open field (Experiment 2) and shuttlebox (Experiments 4 and 5). In the open field and the shuttlebox, SHR activity was above WKY activity when the degree of environmental stimulation was constant. However, when stimulation was manipulated, the SHR activity level was similar for all intensity levels, while the WKY activity was inversely related to stimulus intensity. These results suggest that while the SHRs may generally be more active than WKYs, WKYs display a greater behavioral reactivity to environmental stimulation than SHRs.

Biological variability in Wistar-Kyoto rats. Implications for research with the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) initially bred in Kyoto is the most widely studied animal model of essential hypertension. As controls for the SHR, most workers have used normotensive descendants of Wistar rats from the colony in Kyoto from which the SHR strain was derived (Wistar-Kyoto rats, WKY). But the presumption that WKY are serviceable controls for SHR rests on the tacit assumption that all WKY constitute a single inbred strain. It appears, however, that whereas the National Institutes of Health distributed breeding stocks of SHR after they had been fully inbred (i.e., after 20 generations of brother-sister mating), the breeding stocks of WKY were distributed before they had been fully inbred. Accordingly, the biological variability of WKY may be greater than that of SHR. To investigate this possibility, we obtained SHR and WKY from two of the largest commercial suppliers in the United States and systematically measured the growth rate and blood pressure of these rats under identical physical and metabolic conditions. We found that WKY from one source differed from those of the other in both growth rate and blood pressure. In contrast, the SHR from the two suppliers were not different with respect to either growth rate or blood pressure. Because the National Institutes of Health may have distributed breeding stocks of WKY as early as the F6 generation, it is possible that rats currently designated as WKY do not constitute a single inbred strain. Thus, interpretation of studies employing "the Wistar-Kyoto rat strain" as a control for the SHR may be much more problematic than has previously been recognized.

Excitatory sympathetic reflex in NaCl-sensitive spontaneously hypertensive rats.

We have previously demonstrated blunted reflex responses of lumbar sympathetic nerve activity during volume expansion in NaCl-sensitive spontaneously hypertensive rats maintained on basal (1% NaCl) diets compared with NaCl-resistant spontaneously hypertensive rats, Wistar-Kyoto rats, and Sprague-Dawley rats. The current study tested the hypothesis that chronic ingestion of a high (8%) NaCl diet further blunts cardiopulmonary reflex function in the NaCl-sensitive spontaneously hypertensive rat. After 3 weeks of a 1% or 8% NaCl diet, male rats of all four strains were instrumented with femoral arterial and venous cannulas and lumbar nerve recording electrodes at 10 weeks of age. Two days later, conscious rats were infused with whole blood to expand blood volume. NaCl-sensitive spontaneously hypertensive rats maintained on a 1% NaCl diet had blunted responses of nerve activity to acute volume expansion compared with control strains. NaCl-sensitive spontaneously hypertensive rats maintained on an 8% NaCl diet had increases in nerve activity responses to volume expansion. In a second experiment, the volume expansion protocol was repeated in anesthetized NaCl-sensitive spontaneously hypertensive rats that had been subjected to sinoaortic denervation after 3 weeks of a 1% or 8% NaCl diet. After sinoaortic denervation, an increase in nerve activity was again observed during volume expansion in animals fed the 8% NaCl diet. In animals fed the 1% NaCl diet, changes in nerve activity were variable. The excitatory response was significantly reduced after bilateral vagotomy. These studies suggest that blood pressure regulation in NaCl-sensitive spontaneously hypertensive rats is a complex interaction of excitatory and inhibitory sympathetic reflex systems that is altered by high dietary NaCl exposure.

Characteristics of pressor response to endothelin in spontaneously hypertensive and Wistar-Kyoto rats.

Endothelin, an endothelium-derived vasoconstrictor peptide, and angiotensin II were intravenously injected into the femoral vein of normotensive Wistar-Kyoto (WKY) rats that had been anesthetized with urethane. Blood pressure and heart rate were recorded from a cannula inserted into the carotid artery. All experiments were carried out after treatment with adrenergic and cholinergic antagonists. Endothelin showed a potent, dose-dependent pressor action. The dose-response relations for the increase in blood pressure of rats receiving endothelin were comparable with those of rats receiving angiotensin II. However, endothelin showed far more long-lasting effects. Endothelin-induced responses consisted of three phases: a rapid and transient depressor phase and then two phases of pressor (transient and long-lasting) response. Nicardipine (0.1 mg/kg), a dihydropyridine Ca2+ channel blocker, markedly attenuated the slow phase of the pressor response but only slightly attenuated the rapid one. The pressor action of endothelin was not inhibited by continuous infusions of saralasin, which almost abolished the angiotensin II-induced pressor response. Endothelin-induced pressor response was also not attenuated by indomethacin, a prostaglandin synthesis inhibitor. These data provide evidence that endothelin produces a unique, potent, and long-lasting pressor response, which appears to be in part related to the activation of Ca2+ channels. In 12-week-old spontaneously hypertensive rats (SHR), the maximal pressor response to endothelin was slightly but significantly greater than that in age-matched WKY rats, but the dose dependency of the response was approximately consistent with that in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)