Increased pressor responses to physostigmine in spontaneously hypertensive rats

Summary Intravenous injection of physostigmine evoked a pressor response in unanaesthetized rats. Spontaneously hypertensive rats (SHR) showed increased pressor responses, but the responses were within normal limits in renal hypertensive and DOCA-saline hypertensive rats. The pressor effect in SHR was abolished by the i.v. injection of atropine sulphate but not by the i.v. injection of atropine methyl bromide. After inhibition of the peripheral muscarinic receptors by atropine methyl bromide, oxotremorine also produced a pressor response in unanaesthetized rats. In contrast to the pressor effect of physostigmine, there was no difference between the oxotremorine-induced pressor response of SHR and that of normotensive Wistar-Kyoto rats. The pressor effect of oxotremorine in SHR was blocked by the i.v. injection of atropine sulphate.     

Emotional hyperthermia in spontaneously hypertensive rats

Basal body temperature of spontaneously hypertensive rats (SHR) was found to be significantly elevated compared to normotensive Wistar Kyoto rats (WKR). The hypothermic response to low doses of the alpha₂-receptor agonist clonidine was significantly smaller in SHR compared to WKR. In contrast, the thermoregulatory response of SHR to a non-noxious stressor was heightened.We propose that the elevated basal temperature observed in SHR is not due to an impaired thermolysis but the result of a noradrenaline-mediated hyperreactivity to environmental stress, e.g. handling of the animals during the temperature measurement procedure.     

Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 μg) was significantly lower and the non-renal clearance (5.78 versus 3·94 ml min^?1 kg^?1) was significantly faster in SHRs of 16 weeks of age than in age-matched control Wistar rats. This suggested that the nonrenal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age-matched control Wistar rats, and this could be supported by the significantly greater amount of 4-chloro-5-sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11·1 versus 4·79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50μg of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40·4 versus 43·7μg) in SHRs of 16 weeks of age than in age-matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P-450 (0·7013 versus 0·5186 nmol/mg protein) and the weights of liver (3·52 versus 2·93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age-matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9·93 versus 16·5 ml) and 8 h urinary excretion of sodium (1·21 versus 2·05 mmol) and chloride (1·37 versus 2·17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age-matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA-salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA-salt rats. On the other hand, the 8 h urinary excretion of furosemide and non-renal clearance were not significantly different between SHRs of six weeks of age and age-matched control Wistar rats after i.v. administration of furosemide. Since the non-renal metabolism of furosemide was not faster in either DOCA-salt rats of 16 weeks of age or SHRs of six weeks of age than that in the respective age-matched control group, the faster non-renal metabolism of furosemide in SHRs of 16 weeks of age could be due to the physiological factor from the chronic phase of hypertension in SHRs, and could not be due solely to the heredity of SHRs or the hypertensive state itself.     

Evaluation of the direct systemic and cardiopulmonary effects of diesel particles in spontaneously hypertensive rats

Recent data suggest that ultrafine pollutant particles (diameter <0.1 μm) may pass from the lung into the systemic circulation. However, the systemic and cardiorespiratory effects of translocated particles are not well known. In this study, we determined the direct acute (24 h) effect of the systemic administration of 0.01 mg/kg and 0.02 mg/kg diesel exhaust particles (DEP) on systolic blood pressure, heart rate, and both systemic and pulmonary inflammation in spontaneously hypertensive rats (SHR). Compared to the blood pressure in control group, rats exposed to DEP exhibited a dose-dependent increase in systolic blood pressure, at 0.01 mg/kg (P < 0.05) and 0.02 mg/kg (P < 0.01). Likewise, the heart rate was also dose-dependently increased at 0.01 mg/kg (P:NS) and 0.02 mg/kg (P < 0.01) compared to control SHR. DEP exposure (0.02 mg/kg) significantly elevated the number of leukocytes in blood (P < 0.05), interleukin-6 (IL-6, P < 0.005), tumor necrosis factor alpha (P < 0.05) and leukotriene B4 (LTB4, P < 0.005) concentrations in plasma. Moreover, in SHR given 0.02 mg/kg, the number of platelet was significantly reduced (P < 0.05), whereas the tail bleeding time was prolonged (P < 0.05). Pulmonary inflammations were confirmed by the presence of a significant increase in the number of macrophages (0.02 mg/kg) and neutrophils (0.01 and 0.02 mg/kg) and protein contents (0.02 mg/kg) in bronchoalveolar lavage (BAL) compared to saline-treated SHR. Also, IL-6 (0.01 mg/kg; P < 0.05 and 0.02 mg/kg; P < 0.01), LTB4 (0.02 mg/kg; P < 0.05) concentrations in BAL and the superoxide dismutase activity (0.02 mg/kg; P = 0.01) were significantly elevated compared to control group. We conclude that, in SHR, the presence of DEP in the systemic circulation leads not only to cardiac and systemic changes, but also triggers pulmonary inflammatory reaction involving IL-6, LTB4 and oxidative stress.     

Chronic propranolol treatment decreases cardiac beta-adrenoceptors in spontaneously hypertensive rats

Spontaneously hypertensive (SHR) rats were treated for 6 months with 41.6 or 94.6 mg/kg per day of (+/-)-propranolol. Compared to untreated SHR rats, the heart rate and blood pressure in both treated groups were decreased. The cardiac beta-adrenoceptor concentration was similar in the untreated and low dose (+/-)-propranolol-treated group but was decreased by 30% after treatment with the high (+/-)-propranolol dose. The results suggest that high dose (+/-)-propranolol treatment reduces the cardiac beta-adrenoceptor concentration.     

奈比洛尔对自发性高血压大鼠循环和主动脉肾素-血管紧张素系统的影响

目的：探讨奈比洛尔（Nebivolol）对自发性高血压大鼠循环和主动脉肾素-血管紧张素系统（RAS）的影响。方法：18只自发性高血压大鼠（SHR）和6只同源正常血压大鼠Wistar-Kyoto（WKY）随机分为：（1）奈比洛尔组（n=6）：SHR给予奈比洛尔5mg·kg-1·d-1;（2）卡托普利组（n=6）：SHR给予卡托普利15mg·kg-1·d-1;（3）SHR对照组（n=6）;（4）WKY对照组（n=6）。奈比洛尔、卡托普利溶于蒸馏水中灌胃,对照组给予等体积蒸馏水灌胃。给药8周后测定血浆肾素活性（PRA）,血浆和主动脉血管紧张素Ⅱ（AngⅡ）、一氧化氮（NO）浓度,NO/AngⅡ和血管紧张素转化酶（ACE）活性。结果：与WKY比较,SHR血浆和主动脉NO含量降低,AngⅡ水平显著增加,NO/AngⅡ降低;主动脉ACE活性明显增加,而血浆ACE活性则降低;但PRA在两组间无显著性差异。奈比洛尔治疗对SHR血浆AngⅡ含量和ACE活性无影响,但可降低主动脉AngⅡ水平,抑制主动脉ACE活性,从而增加血浆及主动脉NO含量和NO/AngⅡ。结论：奈比洛尔抑制肾素-血管紧张素系统,可能是其降低血压的机制之一。     

Properties of cardiac alpha- and beta-adrenoceptors in spontaneously hypertensive rats

Summary The effects of isoprenaline, Ca²⁺ and phenylephrine (in the presence of propranolol) on force of contraction were studied in isolated electrically driven papillary muscles of spontaneously hypertensive rats (SHR) and age-matched (14–18 weeks) Wistar Kyoto control rats (WK). Cardiac alpha- and beta-adrenoceptors were characterized by radioligand binding studies. The positive inotropic effect of isoprenaline in SHR was less effective than in control rats. The EC₅₀ values did not differ in both groups. In SHR, isoprenaline was less effective than Ca²⁺ to increase force of contraction whereas in WK it had the same effectiveness as Ca²⁺. The positive inotropic effect of phenylephrine in the presence of propranolol was similar in SHR and WK. In SHR, both the densities of cardiac alpha- and betaadrenoceptors were reduced. In beta-adrenoceptor binding experiments, the nonhydrolysable GTP analog Gpp(NH)p caused a rightward shift of agonist competition curves of isoprenaline. Biphasic competition curves revealed a similar percentage of low and high affinity sites in SHR and WK, respectively. In alpha-adrenoceptor binding experiments, Gpp(NH)p caused no detectable shift of agonist competition curves with norepinephrine. It is suggested that cardiac beta-adrenoceptor down-regulation is involved in the reduced positive inotropic effect of isoprenaline in SHR. Functional uncoupling of beta-adrenoceptors does not appear to be involved in the reduced beta-adrenoceptor-mediated positive inotropism in SHR. Binding studies do not show evidence for a large number of alpha-adrenoceptors coupling to a guanine-nucleotide binding protein in the rat heart. Finally, in ventricular myocardium of SHR, cardiac alpha-adrenoceptors do not serve as a reserve mechanism during impaired beta-adrenergic stimulation. Instead, it is assumed that in SHR not only beta- but also alpha-adrenoceptors are subject to receptor down-regulation.Send of fprint requests to M. Böhm at the above address     

Effect of hypothalamic stimulation in spontaneously hypertensive and Wistar-Kyoto rats

This study was undertaken to determine if central nervous system differences in blood pressure regulation exist between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls. Central control mechanisms were examined by observing the effects of posterior hypothalamic (PH) stimulation upon preganglionic sympathetic activity in 14–18 week old SHR and WKY rats. A bipolar, concentric electrode was stereotaxically placed in the PH. Stimulation was delivered at 20, 60 and 100 Hz (3-sec duration, 0.1 msec pulse width) at a voltage twice that producing an increase in blood pressure (? 5 mm Hg) at 60 Hz. Sympathetic activity was recorded from a portion of the splanchnic nerve just distal to the diaphragm. Blood pressure was measuredfrom a femoral artery catherer. SHR responded with greater increases in symphathetic activity than WKY; the differences were statistically significant at 60 and 100 Hz. SHR also responded with significantly greater increases in blood pressure at all frequencies of stimulation. To determine if the enhanced sympathetic response to PH stimulation seen in adult SHR is an intrinsic difference rather than secondary to sustained hypertension, we maintained SHR normotensive from four weeks of age with antihypertensive drug therapy (clonidine or hydralazine). Chronically treated animals were then tested at 14–18 weeks of age while on antihypertensives of four days after drug discontinuance. Sympathetic and blood pressure responses to PH stimulation were significantly greater in SHR maintained normotensive than untreated or chronically treated WKY. These data support the concept that a central factor is involved in the etiology of hypertension in the SHR.     

Effect of intracerebroventricular 5,6-dihydroxytryptamine on blood pressure of spontaneously hypertensive rats.

The effects of intracerebroventricular injections of 5,6-DHT on the development and maintenance of hypertension in spontaneously hypertensive rats has been investigated. 5,6-DHT, injected into 6 week old rats, retarded the development of hypertension for at least 6 weeks; this effect was not accompanied by inhibition of the pressor response produced by stimulation of the total peripheral sympathetic outflow. 5,6-DHT, injected into 14-15 week old rats with established hypertension, produced a short-lived fall in blood pressure. These findings suggest that central 5-HT neurones are involved in the development of hypertension in spontaneously hypertensive rats.     

The symptoms of unilateral inflammation in spontaneously hypertensive,renal hypertensive and normotensive wistar kyoto and wistar rats

Widy-Tyszkiewicz E, Kohutnicka M, Mierzejewski P, Czlonkowski A. The symptoms of unilateral inflammation in spontaneously hypertensive, renal hypertensive and normotensive Wistar Kyoto and Wistar rats. Inflammopharmacology. 1994;2:337-343. Spontaneously hypertensive (SHR) and renal hypertensive (RHR), Wistar (NR) and Sham or Wistar Kyoto (WKY) rats were tested for clinical symptoms following inoculation with Freund’s adjuvant in the unilateral hind paw. In the present study, body weight change (during weeks 1–11) was examined once a week and inflammatory score of hindpaw twice a week. The body weight gain was increased in the WKY compared with NR/Sham, SHR and RHR groups. Inflammatory changes were also most profoundly exhibited in the NR/Sham, the SHR and the RHR, compared with the WKY rats. The data may reflect a genetic difference not necessarily related to elevated blood pressure.     

Effects of clonidine and guanfacine on drinking and ambulation in spontaneously hypertensive rats

Present experiment was undertaken to compare the effects of clonidine and guanfacine on water drinking behavior and ambulatory activity in spontaneously hypertensive rats (SHR). Equipotent hypotensive doses of clonidine and guanfacine, 150 micrograms/kg and 1500 micrograms/kg, respectively, given twice a day at 8:00 and 20:00, produced a triphasic pattern of behavioral changes; initial increase in water drinking and ambulation during the light period, decrease in water intake and ambulation at the beginning of the dark period, and a second increase in water drinking and ambulation at the end of the dark period. Guanfacine treated SHR showed less change in water drinking behavior and ambulation than the clonidine treated SHR.     

Evidence that nitric oxide mediates the blood pressure lowering effect of a polyphenol-rich cocoa powder in spontaneously hypertensive rats

The involvement of endothelial-relaxing factors on the antihypertensive effect of a polyphenol-rich cocoa powder named CocoanOX (CCX) was studied. Thirty 17–20-week-old male spontaneously hypertensive rats (SHR), weighing 314 ± 3 g were used. They were divided into two groups of 15 animals, that were respectively administered by gastric intubation distilled water or 300 mg/kg CCX dissolved in distilled water, between 9 am and 10 am. 2 h after the oral administration, 5 of the animals in each group were intraperitoneally administered 1 ml saline. The remaining rats in both groups were divided into another two groups of 5 animals that were respectively administered 30 mg/kg Nw-nitro-l-arginine methyl ester (l-NAME) dissolved in 1 ml of saline or 5 mg/kg indomethacin also dissolved in 1 ml of saline by the same procedure. Systolic blood pressure (SBP) was recorded in the rats by the tail cuff method before the initial oral administration and also 4 h after this administration. CCX caused a significant decrease in SBP (−49.5 ± 4.9 mm Hg; p < 0.05). l-NAME caused a clear increase in SBP in the rats (+16.2 ± 4.3 mm Hg; p < 0.05), and the effect of CCX was not observed in the SHR that were treated with l-NAME (+4.1 ± 1.7 mm Hg; p < 0.05). Nevertheless, indomethacin treatment did not modify SBP in the SHR and this compound failed to modify the antihypertensive effect of CCX in these animals. In conclusion, this study proves the participation of NO in the antihypertensive effect of CCX in the SHR strain. When CCX is administered, the synthesis, or the bioavailability, of this endothelial factor could increase, but other mechanisms may also participate in the antihypertensive effect of this cocoa powder. In any case, further investigation should be carried out to characterize the signalling pathways involved in the antihypertensive effect of CCX.     

Cerebral neuronal activity in spontaneously hypertensive rats as demonstrated by the 14C-deoxyglucose method

Summary The ¹⁴C-deoxy-d-glucose technique was used to examine glucose utilization, as a measure of neuronal activity, in 100 cerebral nuclei by means of radiodensitometry of autoradiographs of serial brain sections. Three groups of rats were studied, namely young spontaneously hypertensive rats (SHR), adult SHR and normal Wistar-Kyoto rats whose blood pressure was acutely increased by injection of angiotensin II.In all three groups as compared to corresponding normotensive controls, glucose utilization was consistently increased in the caudal part of the nucleus (n.) tractus solitarii, medullary related nuclei (n. commissuralis, area postrema and n. dorsalis nervi vagi), n. centromedianus, n. habenulae lateralis, n. supraopticus, n. paraventricularis, n. suprachiasmaticus, n. periventricularis, n. amygdaloideus centralis, and area amygdaloidea anterior. The increase in glucose utilization in these areas is probably due to facilitation of baroreceptor afferent impulses.In young SHR at 4 weeks of age (but not in other groups), increased glucose utilization was found in limbic areas such as the n. interpeduncularis, n. dorso-and ventro-medialis thalami, area anterior and n. dorsomedialis hypothalami, fasciculus medialis telencephali (caudal), n. amygdaloideus lateralis and intercalatus, stria terminalis nuclei, n. dorsalis and intermedius septi, and n. caudatus.In adult SHR at 20 weeks of age (but not in other groups), there was an increase in glucose utilization in the n. intercalatus, n. originis nervi hypoglossi, n. olivaris superior, n. parabrachialis dorsalis and ventralis, substantia grisea centralis, n. paramedianus, reticular formation areas such as n. centralis superior, n. reticulotegmentalis pontis, n. reticularis lateralis and n. tegmentalis pedunculopontinus and substantia reticularis mesencephali, n. corporis mamillaris medialis, n. arcuatus, infundibulum, fasciculus longitudinalis dorsalis and hippocampus ventralis.In SHR at both ages, there was an increase in glucose utilization in most of the sensory trigeminal nuclei, which might indicate enhanced perception of sensory inputs, probably leading to peripheral vasoconstriction. Also in SHR at both ages, increased glucose utilization was found in the substantia nigra pars compacta, n. tegmenti dorsalis and ventralis, fasciculus medialis telencephali (rostral), n. amygdaloideus medialis, n. tractus olfactorii lateralis and n. lateralis septi.In conclusion, baroreceptor-independent neuronal activation in the limbic area in young SHR and in the reticular formation, periventricular fibers and arcuate-infundibular system in adult SHR, in addition to the sensory trigeminal nuclei and tegmental tract at both ages, might be involved in the development and maintenance of hypertension in SHR.     

The cardiovascular effects of propranolol in adrenalectomized spontaneously hypertensive rats and the opposing influence of rauwolscine

In conscious adrenalectomized spontaneously hypertensive rats (SHR) propranolol (5 mg/kg s.c.) induced an acute and profound decrease in blood pressure and heart rate, the maximum effect occurring 15–30 min after propranolol administration. The decrease was associated with a fall in cardiac output. Rauwolscine pretreatment abolished the propranolol-induced hypotension but not the bradycardia. The fall in cardiac output was significantly reduced. These results suggest that in adrenalectomized SHR the hypotensive effect of propranolol is due to the modulation of catecholamine release from nerve terminals.     

超声评价瑞舒伐他汀对自发性高血压大鼠血压及左心室重构的影响

目的应用超声观察、评价单独或联合应用瑞舒伐他汀对自发性高血压大鼠左心室重构的影响,为临床应用提供理论依据。方法32只16周自发性高血压大鼠（SHR）,随机分成两组,每组16只：（1）瑞舒伐他汀组（R组）应用瑞舒伐他汀10mg／（kg·d）加2ml蒸馏水每天灌胃1次;（2）对照组2ml蒸馏水每天灌胃1次。分别于给药前及给药后2、4、6周测量大鼠尾动脉收缩压;给药前和给药6周后进行超声测量;进行左心重量及左室重量指数（LVMI）测定。结果（1）2、4、6周对照组大鼠血压较基础值显著升高,R组大鼠血压较基础值显著降低（P〈0.05或P〈0.01）。（2）治疗后,左心重量及LVMI,R组显著低于对照组（P〈0.05或P〈0.01）。与基础值比较,治疗后对照组LVEDD显著降低,IVSD、IVSS、LVPWD和LVPWS显著增加（P〈0.05或P〈0.01）;R组LVEDD显著增加（P〈0.05或P〈0.01）,IVSD、IVSS、LVPWD和LVPWS显著降低（P〈0.05或P〈0.01）。R组LVEDD显著高于对照组（P〈0.01）IVSD、IVSS、LVPWD和LVPWS显著低于对照组（P〈0.05或P〈0.01）。结论使用瑞舒伐他汀可改善自发性高血压大鼠左心室重构。     

Enhanced thromboxane A2 biosynthesis in the kidney of spontaneously hypertensive rats during development of hypertension

Arachidonic acid (AA)-induced pressor response and production of thromboxane YXB₂, the stable metabolite of TXA₂, prostaglandin (PG)-like substance (PLS) and 6-keto-PGF_1α the stable metabolite of prostacyclin (PGI₂), were studied using isolated, perfused kidneys of 6- and 18-week old spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), two-kidney, one clip hpertensive rats (RHR) and DOCA/salt hypertensive rats (DOCA/salt HR). The AA-induced pressor response and release of TXB₂ were highest in the 6-week old SHR, whereas, the release of PLS and 6-keto-PGF_1α was marked in the 18-week old SHR and the established hypertensive stages of both RHR and DOCA/salt HR. In the kidneys of SHR and WKY, exogenous TXA₂ induced a severe vasoconstriction and there was a positive correlation between the AA-induced pressor response and the release of TXB₂ or PLS. Thus, the initiation of hypertension in SHR may follow an accelerated synthesis of TXA₂ against PGI₂ in response to stimuli which induce a release of AA.     

Age-related changes of in vivo beta-adrenergic responsiveness in normotensive and spontaneously hypertensive rats

The variations of plasma cyclic AMP concentration caused by propranolol and isoproterenol were studied in order to investigate endogenous stimulation and responsiveness of the beta-adrenoceptor-cyclic AMP system in vivo, in 7 and 18 week old unanaesthetized male SHR and WKY. In both age groups, the basal cyclic AMP level was higher in SHR than in controls but was significantly reduced to a comparable value in the two strains after intraperitoneal injection of 2.5 mg X kg-1 propranolol, a dose which markedly depressed or even abolished the effect of isoproterenol. Cumulative dose-response curves of plasma cyclic AMP concentration obtained in another group of rats after successive subcutaneous injections of isoproterenol showed that the ED50 value of this drug was higher in SHR than in WKY and increased in a parallel manner in the two strains between 7 and 18 weeks of age (respectively from 0.21 +/- 0.01 to 0.34 +/- 0.02 mumol X kg-1 in WKY and from 0.32 +/- 0.02 to 0.52 +/- 0.03 mumol X kg-1 in SHR). At the same time blood pressure increased much less markedly in WKY (from 115 +/- 4 to 119 +/- 2 mm Hg) than in SHR (from 134 +/- 3 to 179 +/- 3 mm Hg). Altogether these results show that endogenous beta-adrenergic stimulation of the cyclic AMP system was higher in SHR of both ages in spite of a diminished responsiveness of this system to exogenous isoproterenol.     

Differential effects of selected dopaminergic agents on locomotor activity in normotensive and spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) exhibit a significantly higher level of spontaneous locomotor activity than age-matched normotensive controls (WKY). The direct-acting dopamine agonists, apomorphine and pergolide, produced a biphasic effect on locomotor activity levels in normotensive controls. Low doses of these agonists decreased activity levels, while higher doses of these agonists dramatically stimulated activity. In marked contrast to these results was the effect observed in the SHR, in which these agonists at all doses tested decreased activity. Amphetamine, a dopamine releaser, stimulated activity levels in both the WKY and SHR; however, the magnitude of the increase was somewhat attenuated in the SHR.