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.     

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.     

Altered responsiveness of proximal tubule fluid reabsorption of peritubular angiotensin II in spontaneously hypertensive rats

Stimulation of proximal tubular fluid reabsorption by peritubular angiotensin II (Ang II) was examined by split-drop micropuncture in 5- and 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). In WKY, the maximum stimulation occurred at 10(-11) mol/l and the response did not vary with age. In 5-week-old SHR, the dose-response relationship was similar in shape and in the extent of the maximum response but was shifted one half-logarithmic step to the right, indicating decreased sensitivity to Ang II. In contrast, the dose-response relationship was shifted one half-logarithmic step to the left in 12-week-old SHR compared with WKY. Alterations in the responsiveness of the proximal tubule to Ang II in young SHR could contribute to sodium retention observed during development of hypertension in these rats.     

Altered angiotensin II-induced small artery contraction during the development of hypertension in spontaneously hypertensive rats.

This study assessed whether the angiotensin-II (Ang II)-induced contractile responsiveness of resistance arteries is altered during the development of hypertension in spontaneously hypertensive rats (SHR). Structural parameters and Ang II-stimulated contraction were determined in small mesenteric arteries from 6-week-old (phase of developing hypertension) and 21-week-old SHR (phase of established hypertension), compared with age-matched Wistar-Kyoto rats (WKY). To ascertain whether effects were specific for Ang II, contractile responses to another vasoactive agonist, vasopressin (AVP), were also determined. Systolic blood pressure was measured in conscious rats by the tail-cuff method. Segments of third-order mesenteric arteries (approximately 200 microm in diameter and 2 mm in length) were mounted in a pressurized system with the intraluminal pressure maintained at 45 mm Hg. Blood pressure was significantly increased in SHR (P < .001) and was higher in adult than in young SHR (P < .001). Ang II dose-dependently increased contraction, with responses significantly greater (P < .05) in SHR than in age-matched WKY. SHR, in the early phase of hypertension, exhibited significantly augmented contractile responses (Emax = 70 +/- 5%), compared with SHR with established hypertension (Emax = 33 +/- 5%). These effects were not generalized, as responses to AVP were not significantly different between young and adult SHR. Functional Ang II-elicited alterations were associated with structural modifications: 6-week-old SHR had smaller media to lumen ratio compared with 21-week-old SHR (8.1% +/- 0.17% v 10.6% +/- 0.20%, P < .01). In young SHR vessels the media cross-sectional area was unchanged relative to age-matched WKY rats, suggesting eutrophic remodeling (remodeling index 101.4% v 93.3% young v adult), whereas the cross-sectional area of adult vessels was increased in comparison to WKY rats, suggesting mild hypertrophic remodeling (growth index -1.0% v 15.2%, young v adult). In conclusion, the present study demonstrates that in SHR with early hypertension and slight medial thickening, Ang II-mediated vascular contractile responsiveness is significantly augmented compared with SHR with established hypertension and more severe vascular structural changes. These findings indicate attenuation, as hypertension progresses, of the initially enhanced vascular reactivity to Ang II that is present during the development of 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.     

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.     

Impaired nitric oxide production and enhanced autoregulation of coronary circulation in young spontaneously hypertensive rats at prehypertensive stage.

In the current study, we investigated the NO-generation pathway in response to mechanical stimuli in SHR at the prehypertensive stage. To examine the role of NO in coronary autoregulation, we evaluated the effects of L-NAME on the coronary flow in SHR at both the prehypertensive and hypertensive stages. Isolated perfused hearts from 5- and 15-week-old SHR and from age-matched Wistar-Kyoto rats (WKY) were used. After stabilization at 60 mmHg, perfusion pressure was immediately raised to 90 mmHg to record the change in coronary flow for 10 min without (control) or with NO synthesis blockade by Nomega-nitro-L-arginine methyl ester (L-NAME). NOx- (nitrite/nitrate) was measured in coronary effluent. At 5 weeks of age, SHR did not have hypertension, while the coronary autoregulation was enhanced. L-NAME did not affect this enhanced autoregulation in 5-week-old SHR. At perfusion pressures of both 60 and 90 mmHg, 5-week-old SHR showed less coronary NOx- production than age-matched WKY. At 15 weeks, SHR showed a higher blood pressure than WKY. The coronary autoregulation in SHR remained higher than that in WKY, but was below that in 5-week-old SHR. NOx- production in 15-week-old SHR recovered to the level of age-matched WKY. These results indicate that NOx- production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the prehypertensive stage, which may have enhanced coronary autoregulation. An impaired nitric oxide production may precede the onset of hypertension in SHR.     

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct. Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR.     

High angiotensin converting enzyme (kininase II) activity in the cerebrospinal fluid of spontaneously hypertensive adult rats

Angiotensin converting enzyme (ACE, Kininase II, E.C. 3.4.15.1) activity was measured in the cerebrospinal fluid of 4- and 16-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensive controls. Adult SHR showed higher cerebrospinal fluid enzyme activity than normotensive age-matched WKY (19.6 +/- 1 and 32.3 +/- 5 nmol/h per ml in WKY and SHR, respectively, P less than 0.025). Conversely, there were no significant differences in enzyme activity in the cerebrospinal fluid of young animals. Our results support the hypothesis of enhanced activity of the central angiotensin system during the established phase of spontaneous hypertension in rats.     

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.     

Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats

The antihypertensive effect of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone has been reported in patients with diabetes or obesity. The correlation of PPARgamma expression with blood pressure and the therapeutic application of rosiglitazone in spontaneously hypertensive rats (SHR) were investigated in the present study. Systolic blood pressure of 21-week SHR was significantly higher than that of age-matched Wistar-Kyoto rats (WKY) (225 +/- 5 v 144 +/- 2 mm Hg, P <.05). Basal expression levels of PPARgamma proteins in vascular tissues of 21-week SHR were significantly lower than that of age-matched 21-week WKY (P <.05). This reduced expression of PPARgamma was not detected between 5- and 13- week SHR and age-matched WKY. Cardiac PPARgamma expression was also not different among different age groups between SHR and WKY. Chronic treatment with rosiglitazone, but not PPARalpha agonist Wy14643, significantly retarded hypertension development and reversed abnormally faster heart rate in young SHR. An unfavorable effect of rosiglitazone treatment was the increased heart-to-body weight ratio accompanied by left ventricular hypertrophy. In conclusion, vascular PPARgamma protein expression in adult SHR (21 weeks) is significantly decreased in comparison with the age-matched WKY. Chronic rosiglitazone treatment retards hypertension development, but the associated prohypertrophy effect calls for a cautious use of this thiazolidinedindione in the treatment of insulin resistance syndrome associated with hypertension.     

Increases in renal angiotensin II content and tubular angiotensin II receptors in prehypertensive spontaneously hypertensive rats

To examine the role of the intrarenal renin-angiotensin system in the development of hypertension in spontaneously hypertensive rats (SHR), we measured angiotensin II contents and tubular 125I-angiotensin II binding sites in the kidney of SHR and age-matched Wistar-Kyoto rats (WKY). In prehypertensive (4-week-old) SHR, not only the kidney angiotensin II content but also the angiotensin II receptor density in brush border membranes were significantly higher than in the WKY. In contrast, angiotensin II levels in the 20-week-old SHR kidneys were significantly lower than in the WKY. Acceleration of the intrarenal renin-angiotensin system and the increased density of tubular angiotensin II receptors in young SHR may therefore play an important role in the development of high blood pressure in SHR.     

高血压对大鼠血管平滑肌细胞结缔组织生长因子表达水平的影响及其意义

目的:探讨大鼠血管平滑肌细胞(VSMCs)结缔组织生长因子(CTGF)表达水平在高血压血管重构中的变化及其意义。方法:以4周龄及16周龄的自发性高血压大鼠(SHR)为模型,以相同周龄的Wistar-Kyoto(WKY)大鼠为正常对照,采用tail cuff法测量SHR及WKY大鼠尾动脉收缩压。开胸后分离胸主动脉,分别测量胸主动脉中层厚度(M)和管腔内径(L),并计算二者的比值(M/L)。应用免疫荧光技术结合激光共聚焦显微镜观察,对CTGF的表达进行定位及定量检测。采用Western blot分析和实时定量RT-PCR,检测不同周龄的SHR主动脉组织内CT-GF、III型胶原(Col III)蛋白及其mRNA的表达。结果:4周龄SHR主动脉M、L、M/L以及ColⅢ蛋白与mRNA表达水平较同龄的WKY相比,均无显著性差异;但CTGF蛋白及mRNA表达水平均明显增高(P<0.05)。16周龄的SHR与同龄的WKY大鼠相比,胸主动脉的M无明显变化;而L显著增高,M/L显著降低(P<0.01);CTGF和ColⅢ的表达亦显著升高(P<0.01)。结论:实验结果提示,异常的血流动力学因素可调节VSMCs中CTGF的表达,从而引起细胞外基质释放增加,导致血管重构的发生。     

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.     

自发性高血压大鼠心脏肥大过程中心肌细胞凋亡与增殖

目的　观察不同周龄自发性高血压大鼠 (SHR)左心室心肌细胞凋亡与增殖的变化 ,探讨心肌细胞凋亡与增殖在SHR心脏肥大过程中的作用。方法　心脏肥厚指数 (Cardiachypertrophicindex ,CHI)按心脏重量 (mg)与体重 (g)的比值计算 ;末端脱氧核苷酸转移酶介导的dUTP末端标记法 (TUNEL)和透射电镜技术检测SHR心肌细胞凋亡 ;免疫组化技术检测心肌细胞增殖核抗原 (proliferatingcellnuclearantigen ,PCNA)。结果　 (1)与同周龄组WKY相比 ,12w、2 4wSHR心脏肥厚指数显著升高 (P <0 0 1) ,SHR心脏肥厚指数随周龄增加表现出增大的趋势 (SHR16vsSHR12 ,P>0 0 5 ;SHR2 0 vsSHR12 ,P <0 0 1;SHR2 0 vsSHR16,0 0 5

0 1)。 (2 ) 12周龄SHR与同周龄WKY相比 ,左心室心肌细胞凋亡指数 (APOI)无显著增加 (P >0 0 5 ) ,2 4周龄SHR左心室心肌细胞凋亡指数显著低于同周龄WKY(P <0 0 5 ) ;从 12周龄到 2 0周龄 ,SHR左心室心肌细胞APOI逐渐增加 (SHR16vsSHR12 ,0 0 5

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Differential expression of melatonin receptors in spontaneously hypertensive rats.

Quantitative autoradiography was used to compare melatonin receptors in brain areas and arteries of young (4 weeks old) and adult (14 weeks old) spontaneously hypertensive rats (SHR) to those in age-matched normotensive controls, Wistar-Kyoto (WKY) rats. Age and strain influenced the number of melatonin receptors in an anatomically selective manner, and the most striking changes occurred in arterial receptors. Melatonin receptors were not detectable in the anterior cerebral arteries of adult SHR. In the caudal artery, melatonin receptors decreased with age in both strains, but the decrease was more pronounced in SHR. When compared to age-matched WKY rats, the number of caudal artery receptors was higher in young and lower in adult SHR. The number of melatonin receptors was higher in the area postrema of adult SHR when compared to adult WKY rats, but in the suprachiasmatic nucleus, no such differences between the two strains were present. Alterations in receptor density were not accompanied by changes in binding affinity. Our results indicate that in the rat melatonin receptors show different developmental patterns according to location and that the receptors may be expressed differentially in genetic hypertension.     

Prolonged QT Interval Is Associated with Blood Pressure Rather Than Left Ventricular Mass in Spontaneously Hypertensive Rats

QT interval is prolonged in hypertensive individuals, although the factors responsible for this increase are not completely understood. We questioned whether enhanced left ventricular mass (LVM) or increased systemic blood pressure represents the principal factor determining QT prolongation in the period of development of hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). In 12-and 20-week-old SHR (SHR12 and SHR20) and age-matched normotensive Wistar-Kyoto rats (WKY12 and WKY20), arterial systolic blood pressure (sBP) was measured using tail-cuff technique. Orthogonal Frank ECG was registered in anaesthetized animals in vivo, and bipolar ECG was measured in spontaneously beating isolated hearts in vitro. Progressive increase of sBP and LVM resulted in significant QT prolongation in SHR20 as compared to WKY12, WKY20, and also to SHR12 in vivo (WKY12: 82?±?9 ms, WKY20: 81?±?9 ms, SHR12: 88?±?15 and SHR20: 100?±?10, respectively; p?<?0.05) but not in isolated hearts (WKY20: 196?±?39 ms and SHR20: 220?±?55, respectively; NS). In whole animals, QT duration was positively related to sBP (r?=?0.6842; p?<?0.001) but not to LVM (r?=?0.1632, NS) in SHR20. The results suggest that QT prolongation in SHR developing hypertension and LVH depends on blood pressure rather than increase in LVM. In this period, myocardial hypertrophy is probably the predisposition for QT prolongation, but the significant change manifests only in the presence of elevated systemic factors.     

Cyclic GMP formation of resistance vessel in the development of hypertension in spontaneously hypertensive rats.

We investigated the basal levels and responses of cyclic GMP (cGMP) derived from perfused mesenteric arteries to acetylcholine (ACh) and sodium nitroprusside (SNP) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) at different ages, in order to evaluate the basal and stimulated release of endothelium-derived relaxing factor (EDRF) from the resistance vessel during the development of hypertension. The mesenteric arteries were removed from 8-, 12- and 20-week-old WKY and SHR, and were perfused with Krebs-Henseleit solution containing 0.2 mM isobutyl methyl xanthine. The effluents from the perfused arteries were corrected before and after infusions of graded doses of ACh or SNP, and the levels of cGMP were measured. The basal levels of cGMP from the mesenteric arteries in the 12- and 20-week-old SHR were significantly lower than those in age-matched WKY. A negative correlation was observed between the basal levels of cGMP and the systolic blood pressure in SHR, but not in WKY, among all ages. On the other hand, there were no differences in the responses of cGMP to infusion of ACh between the WKY and SHR at each age. Moreover, the responsiveness of cGMP to infusion of SNP in the 12-week-old SHR was much higher than that in age-matched WKY. These data suggest that the basal cGMP formation in the arteries which may reflect the basal release of EDRF is reduced in older SHR and is associated with the development of hypertension, and that the stimulated release of EDRF is not associated with the development of hypertension.     

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.     

Biomechanical properties and chemical composition of the aorta in genetic hypertensive rats.

OBJECTIVE: To study the alteration in the biomechanical properties of the thoracic aorta and its composition in young normotensive Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP). METHODS: The in-vitro biomechanical properties of the aorta in 4- and 12-week-old SHRSP were determined by means of a tensile testing machine and compared with those of the SHR and WKY rats; in addition, a biochemical analysis of collagen, elastin and advanced glycation endproducts was performed. RESULTS: The aortic biomechanical properties were altered in the 4- and 12-week-old SHRSP, compared with age-matched WKY rats and SHR. The maximum stress in the 12-week-old SHRSP was reduced by 27% compared with the normotensive WKY rats, and by 26% compared with the SHR. The maximum strain values in the 4- and 12-week-old SHRSP were lower than those in the age-matched WKY rats, by 12 and 9% respectively, whereas this value in the 12-week-old SHR was significantly increased (by 26%) compared with the age-matched WKY rats. No differences were observed in the aortic contents of collagen and elastin between the SHRSP and SHR. However, the extractability of collagen by pepsin digestion in the 12-week-old SHRSP was lower than that in the age-matched SHR and WKY rats, and a significantly larger accumulation of advanced glycation endproducts was observed in the 12-week-old SHRSP than in the age-matched SHR and WKY rats, suggesting a greater formation of collagen-derived cross-links in SHRSP. CONCLUSIONS: From these results, we conclude that decreased aortic distensibility and mechanical strength values are partly related to the greater formation of collagen-derived cross-links in 12-week-old SHRSP, and that the mechanical properties in SHRSP may be the result not only of the larger formation of collagen-derived cross-links but also of primary defects, since the aortic mechanical strength value was decreased even in 4-week-old SHRSP.