Voluntary running improves glucose tolerance and insulin resistance in female spontaneously hypertensive rats

We evaluated the effects of voluntary exercise training on glucose metabolism and measures of insulin sensitivity in female spontaneously hypertensive rats (SHR). Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. Exercising SHR were housed in running wheels for 8 weeks (SHRx8) or 16 weeks (SHRx16). At 22 weeks of age, we measured systolic blood pressure, performed oral glucose tolerance tests, and determined hexokinase activity and glucose transporter (GLUT) 4 content in skeletal muscle to assess intracellular glucose metabolism. Blood pressure was lower in WKY (139 ± 12 mm Hg) than untrained SHR (216 ± 13 mm Hg). Exercise training caused a reduction in blood pressure (−18 mm Hg) for SHRx8. After a brief (5-h) fast, serum glucose was lower in SHR that exercised compared with sedentary SHR, whereas insulin concentrations were identical between all SHR and WKY. Corresponding free fatty acids (FFA) were twofold higher in SHR than in WKY. In response to glucose, SHR demonstrated higher glucose and FFA responses, with exercise decreasing the glucose values in a dose-dependent manner. Although the insulin response was comparable in all groups, the glucose-to-insulin ratio was higher in SHR, indicating a relative insulin resistance for both glucose disposal and suppression of free fatty acids. Hexokinase activity and GLUT4 content were elevated 1.4- and 2.8-fold, respectively, in plantaris muscle of SHRx16, suggesting an improvement in the capacity for glucose transport and phosphorylation with exercise. These results provide evidence that voluntary running in female SHR lowers blood pressure and selectively increases glucose uptake and insulin action, but not suppression of FFA.     

Brain corticotropin releasing factor in the spontaneously hypertensive rat

Corticotropin releasing factor and vasopressin were measured in major brain regions including the neurohypophysis in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) during development of hypertension. The highest concentration of corticotropin releasing factor was found in the hypothalamus in both strains. Corticotropin releasing factor was decreased in most major brain regions of SHR. In the hypothalamus, corticotropin releasing factor was lower in 3- and 6-week-old SHR than in age-matched WKY (p less than 0.01), but was similar at 12 and 24 weeks of age. The content of corticotropin releasing factor did not differ in the neurohypophysis in 3-week-old rats but began to decrease at 6 weeks of age (p less than 0.01) and continued to decrease during the development of hypertension (p less than 0.01). Brain vasopressin concentration did not differ between SHR and WKY except in the hypothalamus. The level of hypothalamic vasopressin was consistently lower in SHR than in WKY (p less than 0.01). These peptides are thought to be associated with autonomic nervous regulation, and our results may further strengthen the possibility that the deficit of the peptides may be involved in the development of spontaneous hypertension.     

Enhanced phospholipase C activity in the vascular wall of spontaneously hypertensive rats

To explore the roles of vascular phospholipase C activity in the development of hypertension, phospholipase C activity was examined in the aortic wall of spontaneously hypertensive rats (SHR). Phospholipase C activity was significantly enhanced (+87%, p less than 0.005) in 14-week-old SHR as compared with normotensive Wistar-Kyoto rats (WKY). The enzymatic activities were positively correlated with the levels of blood pressure in both of the rat strains (r = 0.62, p less than 0.003). Vascular phospholipase C was also significantly activated (+62%; p less than 0.006) in the aortic wall of 4-week-old prehypertensive SHR, as compared with age-matched WKY. In contrast, vascular phospholipase A2 activity was unaffected in the aortic wall of either adult or very young SHR. There was no difference in the cardiac phospholipase C activity between adult SHR and WKY. The vascular phospholipase C of SHR had a lower Michaelis constant (Km) value than that of WKY. Moreover, its pH profile and calcium requirement differed in part from those of WKY. These results indicate that the activation of vascular phospholipase C precedes the development of hypertension and that the enhancement may be induced by both quantitative and qualitative changes in phospholipase C in SHR.     

Adrenocorticotropin responses to corticotropin releasing factor and vasopressin in spontaneously hypertensive rats

The effects of exogenous corticotropin releasing factor and arginine vasopressin were evaluated in 6- and 11-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Basal adrenocorticotropic hormone (ACTH) and vasopressin levels did not differ between SHR and WKY, but basal corticosterone level was higher in 6-week-old SHR (p less than 0.01). To block endogenous corticotropin releasing factor secretion and nonspecific systemic responses, both groups were pretreated with chlorpromazine, morphine, and sodium pentobarbital anesthesia before measurement of ACTH responses to corticotropin releasing factor and vasopressin infusion. Basal ACTH level was lower in anesthetized 6-week-old SHR than in age-matched WKY (p less than 0.01), but no difference was seen between 11-week-old WKY and SHR. The ACTH response to corticotropin releasing factor in 6-week-old WKY was significantly greater than that in age-matched SHR (p less than 0.01), whereas in 11-week-old SHR and WKY the response was similar. Compared with responses in WKY, SHR showed an increased ACTH response to high doses of vasopressin (0.25 micrograms/100 g body weight) at both ages (p less than 0.05). These results indicate that the ACTH response to corticotropin releasing factor is blunted in the early stages of hypertension in SHR but later recovers. These abnormal responses to corticotropin releasing factor and vasopressin may be related to the development of spontaneous hypertension.     

Ouabain binding and Na+ content in resistance vessels and skeletal muscles of spontaneously hypertensive rats and K+-depleted rats

The possible role of Na+ in the development of hypertension in rats was explored in measurements of intracellular Na+, 22Na efflux, and 3H-ouabain binding sites in resistance vessels and skeletal muscles. In resistance vessels obtained from 13-week-old spontaneously hypertensive rats (SHR) or age-matched Wistar-Kyoto rats (WKY), (Na)i, total or ouabain-resistant 22Na efflux, and the concentration of 3H-ouabain binding sites showed no significant differences. Soleus muscles obtained from 6-week-old and 13-week-old SHR contained 5 to 11% more 3H-ouabain binding sites than those of WKY. The small difference in ouabain binding probably was related more to variations in growth rate and strain than to the hypertension. In SHR and WKY the Na+ and K+ contents of gastrocnemius muscles were almost identical at 6 and 13 weeks of age. By contrast, in Wistar rats in which the (Na)i of skeletal muscle was increased sixfold by K+ depletion, the systolic blood pressure was decreased by 10%. The K+ depletion was associated with a 35 to 55% decrease in the concentration of 3H-ouabain binding sites in both resistance vessels and skeletal muscles. The results provide no support for any simple cause-effect relationships between either elevated (Na)i or altered concentration of 3H-ouabain binding sites and hypertension in SHR.     

Age-related decrease of calcitonin gene-related peptide-containing vasodilator innervation in the mesenteric resistance vessel of the spontaneously hypertensive rat

We previously demonstrated that the mesenteric resistance blood vessels have nonadrenergic, noncholinergic vasodilator innervation in which calcitonin gene-related peptide (CGRP) is a possible neurotransmitter. The role of CGRP-containing vasodilator nerves in hypertension was investigated in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR). The adrenergic vasoconstrictor responses to perivascular nerve stimulation in both SHR (8-, 15-, and 30-week-old) and age-matched Wistar-Kyoto (WKY) rat preparations increased with aging, but the response was greater in SHR than in WKY rats at all ages. The preparation isolated from SHR and WKY rats was precontracted by continuous perfusion of Krebs' solution containing 7 x 10(-6) M methoxamine plus 5 x 10(-6) M guanethidine. In both SHR and WKY rats, perivascular nerve stimulation (1-8 Hz) produced frequency-dependent vasodilation, which was blocked by 1 x 10(-7) M tetrodotoxin, pretreatment with 5 x 10(-7) M capsaicin, and denervation by cold storage (4 degrees C for 72 hours). The vasodilation induced by perivascular nerve stimulation in SHR greatly decreased with age, whereas a slight decrease in the response with age was found in WKY rats. The neurogenic vasodilation in the young SHR preparation was similar in magnitude to the vasodilation in age-matched WKY rats, whereas the vasodilation in 15- and 30-week-old SHR was significantly smaller than that in age-matched WKY rats. In both SHR and WKY rats, perfusion of rat CGRP (1 x 10(-10) to 3 x 10(-8) M) produced marked vasodilation in a concentration-dependent manner. The CGRP-induced vasodilation in SHR increased with age, whereas an age-related decrease in vasodilation was found in WKY rats. Perivascular nerve stimulation (4 and 8 Hz) of the perfused mesenteric vascular bed evoked an increased release of CGRP-like immunoreactive substance in the perfusate, which was significantly less in 15-week-old SHR than in age-matched WKY rats. Immunohistochemical studies showed an age-related decrease in CGRP-like immunoreactive fibers in SHR but not in WKY rats. These results suggest that CGRP-containing vasodilator innervation is greatly decreased when SHR develop and maintain hypertension. It is also suggested that the decreased vasodilator mechanism by CGRP-containing nerves contributes to the development and maintenance of hypertension.     

Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats

The kappa-opioid receptor exerts a negative modulatory action on the beta-adrenoceptor and the action is blunted in adult spontaneously hypertensive rats (SHR). In order to determine whether the blunted negative modulation of the beta-adrenoceptor by the kappa-opioid receptor contributes to the development of hypertension, the electrically induced intracellular calcium ([Ca2+]i) transient was measured in single ventricular myocytes of SHR at 4, 6, 8 and 13-week-old and the age-matched Wistar Kyoto (WKY) rats. The electrically induced [Ca2+]i transients were augmented by norepinephrine (NE), a beta-adrenoceptor agonist, over four-fold in WKY rats of all ages studied and in SHR of 4 and 6 weeks of age. The enhancing effect of NE in 8- and 13-week-old SHR was, however, only approximately three-fold, significantly lower than the corresponding values in age-matched WKY rats. Similarly, the electrically induced [Ca2+]i transients were also augmented by forskolin, an activator of adenylate cyclase, by approximately two-fold in WKY rats of all ages and SHR aged 4 and 6 weeks. In SHR aged 8 and 13 weeks, the effect of forskolin was only 1.5-fold, significantly lower than the two-fold increase in the corresponding WKY rats. The enhancing effects of NE and forskolin were attenuated by U50,488H, a selective kappa-opioid agonist, by approximately 50 and 25%, respectively, in both types of rats of all ages studied, with the exception of 13-week-old rats. In rats of this age group, the attenuations by U50,488H on the enhancing effects of NE and forskolin were 17 and 9% in SHR, respectively, significantly less than the corresponding 54 and 29% in WKY. The fact that attenuation of U50,488H on the enhancing effects of NE and forskolin only occurs in 13-week-old SHR when hypertension has been fully developed indicates that the attenuated inhibitory modulation of kappa-opioid receptor stimulation does not contribute to the initiation of hypertension. Interestingly, the enhancing effects of NE and forskolin on the electrically induced [Ca2+]i transient was attenuated in SHR aged from 8 weeks when the blood pressure was rapidly increasing. The different time courses of altered responses to U50,488H, and NE and forskolin suggest that the attenuated negative modulation of kappa-receptor stimulation on the beta-adrenergic receptor is not due to the signal transduction pathway activated by beta-adrenergic stimulation. In 13-week-old SHR with the arterial blood pressure restored to normal by pharmacological manipulations, the blunted responses to NE, U50,488H and forskolin still occurred, indicating that the altered responses to activation of beta-adrenergic and kappa-opioid receptors and adenylate cyclase are not secondary to hypertension.     

Changes in vascular wall production of prostacyclin and thromboxane A2 in spontaneously hypertensive rats during maturation and the concomitant development of hypertension

The purpose of this study was to clarify how the metabolism of vascular prostacyclin (PGI2) and thromboxane (TX) A2 in spontaneously hypertensive rats (SHR) is involved in aging and development of hypertension. We removed the aortic walls from 5-week-old and 20 to 25-week-old SHR and age-matched Wistar Kyoto rats (WKY). At 5 weeks of age, there was no significant difference in basal and maximal (arachidonic acid 0.1 mM) 6-keto-PGF1 alpha production between SHR and WKY, but the TXB2 generation in the SHR aortic wall was markedly enhanced as compared with that in WKY. At 20 to 25 weeks of age, the SHR aortic wall synthesized about 1.5 times more 6-keto-PGF1 alpha in the basal condition and twice as much as in the maximal condition as did the WKY wall. However there was no significant difference in TXB2 production between SHR and WKY. Age-dependent increase of vascular 6-keto-PGF1 alpha was greater in SHR than in WKY. Moreover, the maximal/basal 6-keto-PGF1 alpha production ratio increased with age in SHR, but not in WKY. The synthesis of vascular TXB2 was enhanced with age in WKY, but did not change with age in SHR. These data suggest that not only the enhanced basal generation of vascular 6-keto PGF1 alpha but also a much greater reservoir of 6-keto-PGF 1 alpha synthesis in SHR was induced by both hypertension and maturity. The increased production of vascular TXB2 in young SHR may affect the development of hypertension.     

Renal kallikrein activity in spontaneously hypertensive rats

To assess possible roles of the renal kallikrein-kinin system in the development of spontaneous hypertension, we determined daily excretion of urinary total and active kallikrein in 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats for up to 2 weeks. We also evaluated the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension in the 6-week-old SHR on ordinary intakes of sodium or on sodium loading with 1% NaCl for up to 2 weeks. Active kallikrein was determined by its kininogenase activity, and the generated kinins were radio-immunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in 7-week-old SHR (1.5 +/- 0.2 microgram/day compared to 2.8 +/- 0.3 micrograms/day in WKY, P less than 0.05) and in 8-week-old SHR (1.6 +/- 0.2 microgram/day compared to 3.2 +/- 0.4 micrograms/day in WKY, P less than 0.01). Urinary total kallikrein excretion was also reduced in the 7- and 8-week-old SHR whereas the ratio of active to total kallikrein did not change. In addition, renal contents of total and active kallikrein were significantly lower in the 8-week-old SHR than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Norepinephrine overflow in perfused mesenteric arteries of spontaneously hypertensive rats

We examined the overflow of endogenous norepinephrine with electrical stimulation, the associated pressor response, and rate of initial neuronal uptake of [3H]norepinephrine in perfused mesenteric arteries of 7- and 13-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The tissues of two rats, a spontaneously hypertensive and a WKY control rat, were simultaneously processed and subjected to the same electrical stimulation. Both absolute and fractional overflow of endogenous norepinephrine during periarterial nerve stimulation (5 and 10 Hz for 1 minute) in the tissue of 7-week-old SHR was significantly greater whereas overflow of 13-week-old SHR was equivalent as compared with that of the age-matched WKY rats. The tissue content of norepinephrine was 20-25% higher in SHR of both ages. There was significantly enhanced [3H]norepinephrine uptake in the tissues of young SHR, but no difference was observed in the older SHR. The pressor response to periarterial nerve stimulation was significantly enhanced in 7-week-old SHR and much more so at the older age as compared with the WKY control rats. Exogenous norepinephrine dose-response curves in the tissues of 7-week-old SHR exhibited a parallel leftward shift, characteristic of a change in sensitivity, whereas that of 13-week-old SHR showed a much steeper slope as compared with the respective WKY control rats. This finding suggests that in addition to smooth muscle supersensitivity, structural alterations had occurred in vasculature of 13-week-old SHR. These data indicate that in SHR both the exocytotic release of norepinephrine and the responsiveness of the vascular smooth muscle cells are enhanced in the developmental stage of hypertension whereas smooth muscle supersensitivity to norepinephrine and nonspecific structural alterations primarily contribute to the maintenance of hypertension at 13 weeks of age.     

Activity of cyclic GMP-dependent protein kinase in aortae from spontaneously hypertensive rats

It has been suggested that various agents induce relaxation of vascular smooth muscles through guanosine 3',5'-cyclic monophosphate (cGMP) and cGMP-dependent protein kinase (cGMP-PK). In this work, the activity of cGMP-PK was studied in the 30,000 g supernatant from aortae of 4, 6, 8 and 12-week-old spontaneously hypertensive (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats and also of 4 and 12-week-old normotensive Wistar (W) and Sprague Dawley (SD) rats. At 4 weeks of age, both basal and cGMP-stimulated activity were not different in SHR and WKY rats. Nevertheless, a greater basal activity was measured in W (+50%) and SD (+20%) rats than in SHR, while no difference was observed between stimulated activities. In contrast with observations in the three normotensive rat strains, cGMP-PK activity did not decrease in the aortae supernatant of SHR rats aged 4-12 weeks. This resulted in mean increases of 45 and 30% in the basal and the cGMP-stimulated activity, respectively, in the 12-week-old SHR rats. The abnormal evolution of cGMP-PK activity in the hypertensive strain was already detectable at 4-6 weeks of age. In apparent agreement with observations on protein kinase activity, cGMP binding activity attributable to cGMP-PK was 25% greater in 12-week-old hypertensive rats compared with age-matched WKY rats. These results indicate that in aortae of SHR rats, control of cGMP-PK activity is abnormal early in life.     

Abnormal platelet and lymphocyte calcium handling in prehypertensive rats

We have reported that the basal and stimulated cytosolic free calcium concentrations [( Ca2+]i) are elevated in platelets isolated from 12-14-week-old spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto (WKY) rats. To determine whether altered cell calcium metabolism precedes the development of overt hypertension, we measured [Ca2+]i under resting and stimulated conditions in blood platelets and thymic lymphocytes isolated from 4-week-old prehypertensive SHR and WKY rats. Blood pressure was similar in both groups (SHR 95 +/- 8 versus WKY rats 92 +/- 7 mm Hg). Basal [Ca2+]i in platelets was higher in SHR than WKY rats (63.4 +/- 3.9 versus 54.8 +/- 3.1 nM, p less than 0.003). Also the [Ca2+]i response to thrombin was greater in SHR than WKY rats in both the presence and absence of extracellular calcium. For lymphocytes, although no difference was detected in basal [Ca2+]i, the concanavalin A-induced peak [Ca2+]i was higher for SHR than WKY rats in both calcium-containing and calcium-free media. These results suggest that agonist-stimulated calcium influx and calcium discharge from intracellular stores are enhanced in both platelets and lymphocytes of 4-week-old SHR. We conclude that abnormalities in calcium metabolism in two different cell types precede the development of overt hypertension in the SHR.     

Age-related variations in tissue angiotensin converting enzyme activities: comparison between spontaneously hypertensive and Wistar-Kyoto rats

Angiotensin converting enzyme (ACE) activity was measured by fluorimetry in the plasma, lung, heart, aorta and kidney (cortex and medulla) of 3-, 5-, 8- and 11-week-old spontaneously hypertensive rats (SHR) and compared with that of age-matched Wistar-Kyoto rats (WKY). In the plasma, lung and kidney (cortex and medulla), ACE activity was lower in SHR than in WKY. This was evident as early as the age of 3 weeks. In contrast, there were no differences between SHR and WKY in the aorta and the heart. Age-related variations in ACE activities differed in each tissue and in both groups of rats, but no major modifications were correlated with the development of hypertension. A binding assay was performed with [3H]ramiprilat; affinity (KD) and the maximum number of binding sites (Bmax) were determined in plasma and tissues of 3-week-old SHR and WKY. The KD values were identical in the two groups but Bmax was lower in all SHR tissues except in the heart; these results might be related to the decrease in ACE activity. Our results probably reflect genetic differences in ACE activity between SHR and WKY, and suggest that ACE regulatory mechanisms act differently in each tissue.     

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

Summary 1,2-Diacylglycerol (DAG) has been considered to play an important role as an activator of protein kinase C in the signal transduction of inositol phospholipid metabolism. To examine the relation of 1,2-DAG in heart tissues to cardiac hypertrophy associated with hypertension, we measured the amount of 1,2-DAG in spontaneously hypertensive rat (SHR) hearts at 4,10 and 20 weeks of age, and in age-matched normotensive Wistar-Kyoto (WKY) rat hearts using thin-layer chromatography with flame ionization detection (TLC-FID). Significant cardiac hypertrophy was found in 4-week-old SHR, while SHR did not yet have significant hypertension. Major phospholipids such as phosphatidylcholine and phosphatidylethanolamine increased from 4 to 20 weeks in the myocardium, but there was no difference between the two strains. The cholesterol levels of 4- and 20-week-old SHR were significantly higher than WKY rats. The 1,2-DAG contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA content was also observed in 4-week-old SHR hearts. However, analysis of the fatty acid composition of 1,2-DAG revealed no difference between the two strains. However, there was no significant difference in the 1,2-DAG content or in its fatty acid composition between SHR and WKY rat hearts at 10 and 20 weeks of age. It is suggested that an increase in the 1,2-DAG content of SHR hearts during the early stages appears related to the initiation of cardiac hypertrophy in SHR hearts before developed hypertension.     

Exaggerated natriuretic response to atrial natriuretic factor in rats developing spontaneous hypertension

The present study was designed to evaluate the renal response to atrial natriuretic factor (ANF) in young rats developing spontaneous hypertension (SHR) and compare this response to age-matched, normotensive controls (WKY) and adult animals. At 6 weeks of age, intravenous infusion of ANF (0.25 micrograms/kg min) in anesthetized, euvolemic rats produced a significantly larger natriuresis and diuresis in SHR compared with WKY rats; this strain difference was not observed in rats 11 weeks of age. SHR showed no age-related change in the natriuretic response to ANF, whereas adult WKY rats exhibited a greater response than young WKY rats. To determine the effect of renal perfusion pressure on the magnitude of the renal response to ANF, additional groups of 6- and 11-week-old SHR were studied while renal perfusion pressure was lowered acutely by aortic constriction (SHR-AC) to values similar to age-matched WKY rats. In young rats, the diuretic and natriuretic response to ANF was greatest in SHR, intermediate in SHR-AC, and lowest in WKY rats. In adult animals, the natriuretic and diuretic response was similar in SHR and WKY rats and tended to be less in SHR-AC. These results in both 6- and 11-week-old SHR are consistent with previous reports that the magnitude of the response to ANF is directly related to acute changes in renal perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular oxidative stress precedes high blood pressure in spontaneously hypertensive rats

This study examines whether longitudinal antioxidant treatment initiated in prehypertensive spontaneously hypertensive rats (SHR) can attenuate vascular oxidant stress and prevent blood pressure elevation during development. Male SHR and age-matched Wistar-Kyoto rats (WKY) were treated from 6 to 11 weeks of age with Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl) (1 mmol/l in drinking water), a membrane-permeable superoxide dismutase mimetic. Mean systolic blood pressures (SBPs) were measured by tail-cuff Agonist-induced and basal O2- production was measured in thoracic aortas of 6- and 11-week-old SHR and WKY by lucigenin-derived chemiluminescence and oxidative fluorescent microscopy, respectively. SBP of 6-week-old SHR (131 +/- 5 mmHg) and WKY (130 +/- 4 mmHg) were not different; however, 11-week-old SHR SBP (171 +/- 4 mmHg) was significantly greater (p = .0001) than 11-week-old WKY SBP (143 +/- 5 mmHg). Tempol treatment completely, but reversibly, prevented this age-related rise in SHR SBP (SHR + Tempol: 137 +/- 4 mmHg; p < .0001 versus untreated SHR). Agonist-induced vascular O2- was increased in 6- (p = .03) and 11-week-old SHR (p < .0001) and 11-week-old WKY (p = .03) but not in 6-week-old WKY. Long-term Tempol treatment significantly lowered O2- production in both strains. Basal O2- measurements in both 6- and 11-week-old SHR were qualitatively increased compared with age-matched WKY; this increase in SHR was inhibited with in vitro Tempol treatment. These data show that antioxidant treatment to reduce oxidative stress prevents the age-related development of high blood pressure in an animal model of genetic hypertension.     

A decrease in the amount and function of the stimulatory GTP-binding protein in the small resistance arteries of spontaneously hypertensive rats.

We investigated the concentration of stimulatory GTP-binding protein (Gs protein) in the peripheral resistance arteries of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and renovascular hypertensive rats (RHR). Changes in the function of Gs protein in SHR and WKY were also investigated by microcannulation techniques. The localization and abundance of Gs protein were determined immunohistochemically in 4-, 10- and 20-week-old SHR and age-matched WKY (control), as well as in RHR. Sections of the cremaster artery were stained with polyclonal antibodies to Gs protein. The concentration of Gs protein-like immunoreactivity in the cremaster artery was significantly lower in SHR at 4, 10, and 20 weeks of age, relative to that in age-matched WKY. In contrast, no significant differences were detected in the abundance of Gs between RHR and control rats. The dilatory response by isoproterenol in the presence of beta1-adrenoceptor blocker was lower in 4- and 10-week-old SHR than in age-matched WKY. The dilatory response by cholera toxin was also lower in SHR than in WKY for these two age groups. These results indicated that the amount and function of Gs protein in the peripheral resistance vessels in SHR was reduced. Since this change occurred before the onset of hypertension and no changes were seen in the secondary hypertensive rats, this change was not a secondary change due to hypertension. The impaired receptor-Gs protein-mediated signal transduction in the peripheral resistance arteries may be one of the possible mechanisms responsible for the pathogenesis of hypertension in SHR.     

Angiotensinogen levels in the brain and cerebrospinal fluid of the genetically hypertensive rat

The present experiments were designed to document changes in the regional distribution of angiotensinogen in the rat brain with the development of hypertension in spontaneously hypertensive rats (SHR) relative to age-matched normotensive Wistar-Kyoto rats (WKY). Levels of angiotensinogen were measured in discrete brain nuclei and cerebrospinal fluid from rats at 4, 7, and 16 weeks of age and in cerebrospinal fluid obtained by cisternal puncture at 7 and 16 weeks. Age-dependent changes in angiotensinogen were found, with levels higher in both strains at 4 weeks of age compared with 7 or 16 weeks. In contrast, plasma levels of angiotensinogen were essentially the inverse of the brain levels, low at 4 weeks and higher at 7 and 16 weeks. Levels in a number of regions adjacent to the rostral third ventricle from the 4-week-old SHR (prehypertensive phase) were significantly elevated relative to the WKY (p less than 0.05), while levels in the amygdala and posterior hypothalamus were significantly lower in the SHR (p less than 0.05). In 7-week-old rats (evolving phase), levels in nine brain regions were significantly elevated in the SHR relative to the WKY and included the nucleus tractus solitarii (p less than 0.01). Unlike the prehypertensive and evolving phases, in 16-week-old rats (maintenance phase) only two brain areas, the nucleus of the diagonal band and the lateral hypothalamus, had significantly elevated levels in the SHR (p less than 0.05). Cerebrospinal fluid levels of angiotensinogen did not correlate well with brain levels of angiotensinogen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered expression of BK channel beta1 subunit in vascular tissues from spontaneously hypertensive rats

Correlation of blood pressure (BP) with expression levels of large-conductance, voltage- and Ca2+-activated K+ (BK) channel beta1 subunit in vascular tissues from spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) at different ages was investigated. Systolic BP and BK beta1 expression in mesenteric arteries at either mRNA or protein levels were not different among 4-week-old SHR, WKY, and SD. With hypertension developed at 7 weeks and reached plateau at 12 weeks, expression levels of BK beta1 mRNA in mesenteric arteries and aortae from SHR during this period of time were significantly higher than in age-matched normotensive WKY. The BK beta1 protein expression was significantly higher in mesenteric arteries from 12-week-old but not 7-week-old SHR when compared with age-matched WKY and SD. The BK beta1 protein levels in aortae were not different among 7-week-old SHR, WKY, and SD but were significantly lower in 12-week-old WKY than in age-matched SHR and SD. Captopril treatment normalized BP of 12-week-old SHR. This treatment downregulated BK beta1 protein in mesenteric arteries but upregulated it in aortae. No significant difference in BK alpha subunit expression was detected in mesenteric arteries from three strains of rats as well as the captopril-treated SHR. It appears that expression patterns of BK beta1 in vascular tissues vary depending on tissue types, animal age, and animal strains. Expression of BK beta1 in mesenteric arteries is closely correlated with BP in SHR. Increased BK beta1 expression in mesenteric arteries may represent a compensatory reaction to limit the development of hypertension.