Pharmacodynamic effects of chronic cigarette smoke exposure in spontaneously hypertensive rats

In investigating the influence of chronic cigarette smoke exposure on hypertension, we compared the pharmacodynamic effects of enforced exposure to smoke on spontaneously hypertensive rats (SHR) with those on Wistar-Kyoto (WKY) rats. Chronic cigarette smoke exposure for 8 weeks decreased the elevated heart rate of mature male SHR to approximately the rate in WKY rats 24 h after smoke exposure. Both systolic and diastolic blood pressures also decreased slightly. However, WKY rats showed a marked rise in heart rate soon after exposure to cigarette smoke began, with no change in blood pressure, while the heart rate of SHR in the early stage remained similar to that of animals without exposure, although their blood pressure was clearly reduced. The body weight of both strains tended to decrease during smoke exposure, but the effect was more severe in SHR. Moreover, the effects of chronic smoke exposure were observed using retired, aged female SHR breeders. A decrease in body weight and heart rate, but not in blood pressure, was also recognized even in these mature animals. These effects gradually recovered after withdrawal from exposure. On the basis of these results, a profile of chronic cigarette smoke exposure under hypertension is discussed in this study.     

Effects of intravenous diltiazem on cardiocirculatory dynamics and cardiac output distribution in conscious spontaneously hypertensive rats

The effects of the calcium channel blocker, diltiazem hydrochloride (DZ), on conscious, resting spontaneously hypertensive rats (SHR) were evaluated and compared with results from parallel studies on Wistar-Kyoto (WKY) controls. DZ was administered as a continuous, cumulative infusion at rates equal to 0.40, 2.00, and 10.00 mg/kg/h (each dose was administered for 15 min). Parallel volume infusion (saline) controls were simultaneously conducted using volume infusion rates identical to those used in DZ studies (0.015, 0.100, and 0.500 ml/min). Three hours prior to study, animals were instrumented under halothane anesthesia for measurement of left ventricular, arterial, and central venous pressures; heart rate and arterial blood gases; and for injection of radioactive microspheres and subsequent determination of cardiac output, regional blood flows, and cardiac output distribution. All data were collected at control (C) before initiation of infusion, and at the end of each 15-min infusion period in each animal. At C and compared with WKY, SHR had increased heart rate (392 vs. 280 beats/min), mean arterial pressure (155 vs. 100 mm Hg), left ventricular peak systolic pressure (200 vs. 132 mm Hg), and systemic vascular resistance (0.3 vs. 0.2 mm Hg/ml/min/kg), and reduced stroke volume (1.8 vs. 2.2 ml/beat/kg); but no difference in cardiac output, left ventricular end diastolic pressure, or central venous pressure was found. At C, SHR tended to have increased blood flow and reduced vascular resistance in the coronary circulation and increased vascular resistance in the cutaneous, renal, bronchial arterial, hepatic arterial, testicular, and cerebral circulations. Infusion of DZ increased cardiac output and stroke volume and decreased heart rate, left ventricular and arterial pressures, and systemic vascular resistance in SHR. Similar changes of substantially smaller magnitude were observed in WKY. DZ increased flow and reduced resistance in the coronary and skeletal muscle circulations of SHR to a greater extent than in WKY. DZ also normalized vascular resistance in previously elevated regions. These results suggest that acute intravenous infusion of DZ at doses ranging between 2 and 5 mg/kg is capable of normalizing cardiovascular hemodynamics and regional blood flow distribution in SHR.     

Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats

1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.     

Down-regulation of brain and spinal cord K-opiate receptors in spontaneously hypertensive, Wistar-Kyoto normotensive, and Sprague-Dawley rats by chronic treatment with U-50, 488H.

The effects of chronic administration of U-50,488H, a K-opiate receptor agonist, on the binding of [3H]ethylketocyclazocine ([3H]EKC) to K-opiate receptors on the cerebral cortical and spinal cord membranes of spontaneously hypertensive (SHR), Wistar-Kyoto normotensive (WKY), and Sprague-Dawley (SD) rats were determined. Age-matched (10 weeks old) male rats of each strain were injected twice daily for 7 days with either U-50,488H (25 mg/kg, i.p.) or its vehicle. On day 8, the rats were killed. The cerebral cortex and the spinal cord were isolated for binding studies. The systolic blood pressure and heart rate of SD and WKY rats did not differ but the blood pressure of SHR rats were higher than that of SD and WKY rats. The receptor density (Bmax) and apparent dissociation constant (Kd) values of [3H]EKC binding to the spinal cord of WKY and SHR rats did not differ. However, the spinal cord of SD rats had higher Bmax and Kd values than WKY or SHR rats. The cortex of the SD rats had a lower Bmax value than the other two strains. Treatment with U-50,488H decreased the Bmax value of [3H]EKC in spinal cord of SD rats, increased the Kd value in SHR rats, and had no effect in WKY rats. Decreases in the Bmax value were produced in the cortex of all strains of rats, but a greater effect was observed in WKY and SHR rats than in SD rats.     

Blood pressure and alpha-vascular reactivity in hypertensive rats treated with amlodipine and dietary Ca

It has been suggested that the combination of dietary Ca and Ca2+ channel antagonists could have a synergic antihypertensive effect. In this study, 3-week-old male spontaneously hypertensive rats (SHR) were randomized into four groups of animals. Two of these groups were fed on a normal Ca diet (Ca 1%) and the other two groups were fed on a Ca-enriched diet (Ca 2.5%). One of the groups fed on each diet also received amlodipine (1 mg/kg/day) in their drinking water. Systolic and diastolic arterial blood pressure were measured weekly in the rats, from the 6th week of life until the 25th week of life, by the tail-cuff method, and we also calculated the corresponding pulse pressure values (systolic blood pressure-diastolic blood pressure). Determination of plasma Ca levels by colourimetric methods, and measurement in pithed rats of the pressor responses to the alpha-adrenoceptor agonists methoxamine and B-HT 920 (5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)-acepin-dihydrochloride, talixepole) were also performed using 16- and 23-week-old animals from the different groups. The Ca-enriched diet decreased systolic and diastolic blood pressure in SHR. Almodipine also decreased systolic and diastolic blood pressure in SHR, and this drug intensified the antihypertensive effect of the Ca 2.5% diet in the SHR between weeks 13 and 18. Nevertheless, in the 19- to 25-week-old SHR amlodipine antagonized the effect of dietary Ca on arterial blood pressure. A decrease in the pulse pressure was seen only in the 15- to 20-week-old SHR which had been simultaneously treated with dietary Ca and amlodipine. All the treatments used increased calcaemia, and the highest plasma Ca levels were obtained in the animals which had received the combined treatment with Ca and amlodipine. The responses to methoxamine and to B-HT 920 in the pithed 16-week-old SHR were similar in the four groups of animals. The responses to these agonists in the pithed 23-week-old SHR fed on the Ca-enriched diet were smaller than the corresponding responses in 23-week-old SHR of the untreated group. By contrast, the responses to these agonists were slightly higher in the pithed 23-week-old SHR which were treated with amlodipine than in the pithed 23-week-old SHR in the untreated group. Moreover, amlodipine partially reversed the effect of dietary Ca on alpha-vascular reactivity. According to our results, it would seem inadvisable to use dietary Ca with a Ca2+ channel antagonist with the aim of controlling arterial blood pressure.     

Adrenomedullary and beta-adrenergic participation in enhanced sympathetic pressor responses of spontaneously hypertensive rats

The beta-adrenergic and adrenomedullary components of pressor responses to sympathetic nerve stimulation were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The effects of electrical stimulation of the entire spinal cord of pithed rats pretreated with tubocurarine and atropine were studied on systolic blood pressure, heart rate and plasma cyclic AMP levels. The heart rate increase upon low frequency stimulation (1 Hz) and the blood pressure elevation upon stimulation at higher frequencies (3 and 5 Hz) were higher in SHR than in WKY whereas the increase in circulating cyclic AMP level was not different in the two strains. Pretreatment with propranolol (2.5 mg X kg-1) further enhanced the pressor responses in SHR but not in WKY, although it inhibited the heart rate acceleration and decreased the circulating level of cyclic AMP similarly in the two strains. After acute adrenalectomy, the elevations of blood pressure and circulating cyclic AMP levels were reduced to an identical level in SHR and WKY. These results show that the marked enhancement of the pressor response observed in SHR upon stimulation of the entire sympathetic outflow is mostly of adrenomedullary origin and includes a hypotensive component due to beta-adrenoceptor stimulation which is not present in WKY.     

Atrial natriuretic factor and volume expansion-induced natriuresis in the spontaneously hypertensive rat.

The implication of atrial natriuretic factor (ANF) during acute volume expansion in the spontaneously hypertensive rat (SHR) was evaluated. The effect of short-term afterload relief was also investigated. Fourteen- to 15-week-old SHR and Wistar-Kyoto (WKY) rats were treated with hydralazine for 5 days. The systolic blood pressure (BP) of SHR decreased to normotensive levels but cardiac hypertrophy was not reduced. Isotonic, iso-oncotic volume expansion (equivalent to 10% of total blood volume) was performed 3 times at 15-min intervals on conscious animals. The effect of volume expansion on central venous pressure was identical among the groups. Changes in left ventricular end-diastolic pressure (LVEDP) induced by volume expansion were greater in SHR than in WKY rats and were not affected by treatment. The increases in plasma N-terminal ANF (ANF-(1-98)) concentrations were larger in both treated and untreated SHR verses WKY rats. Despite enhanced ANF release in SHR, the overall magnitude of the diuretic and natriuretic responses to volume expansion was similar in all groups. The natriuretic response was strongly correlated with plasma ANF in WKY rats, this relationship was weak in control SHR, and restored by treatment. It is suggested that ANF release is not impaired in SHR at a 10% volume load; however, there seems to be a lower renal responsiveness to ANF in SHR.     

口服螺内酯对SHR心肌组织TNF-α表达的影响

目的:观察口服小剂量螺内酯对自发性高血压大鼠(SHR)心肌组织TNF-α表达水平的影响.方法:20只8周龄雄性SHR随机分为螺内酯组和安慰剂组,每组10只,另设对照组(Wistar-kyoto,n=7).螺内酯组螺内酯双蒸水溶解,20 mg/(kg·d)灌胃,安慰剂组和对照组等容积双蒸水灌胃,持续16周,24周龄大鼠称取体质量,颈动脉插管检测动脉血压.摘取心脏,心尖部横断为两片,分别投入液氮罐中和10％中性甲醛固定液中,用ELASA方法检测心肌组织匀浆上清液TNF-α水平,免疫组化观察TNF-α表达.结果:螺内酯组与安慰剂组比较,收缩压、舒张压、平均动脉压水平无明显变化(P＞0.05),但两组的收缩压、舒张压、平均动脉压均明显高于对照组,差异有统计学意义(P＜0.05).安慰剂组与对照组比较,心肌组织TNF-α水平明显升高,螺内酯组与安慰剂组比较心肌组织TNF-α水平降低,差异有统计学意义(P＜0.01),但未达对照组水平(P＞0.05).结论:SHR大鼠心肌组织TNF-α高表达,口服小剂量螺内酯可降低SHR大鼠心肌组织TNF-α水平.     

Effect of nebivolol on beat-to-beat and short-term blood pressure variability in spontaneously hypertensive rats

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.     

VALIDATION OF INDIRECT SYSTOLIC BLOOD PRESSURE MEASUREMENT IN ETHER ANAESTHETISED RATS

• 1 Systolic blood pressures and plasma catecholamine concentrations were determined in conscious and ether-anaesthetised male spontaneously hypertensive (SHR), Wistar-Kyoto normotensive (WKY/N), Wistar (W) and Sprague-Dawley (SD) rats.
• 2 When compared to conscious animals, plasma noradrenaline concentrations were significantly higher in all four strains of ether-anaesthetised rats.
• 3 Only the SHR rats did not show an elevation in plasma adrenaline concentration when anaesthetised with ether.
• 4 A good correlation was obtained between systolic blood pressures measured indirectly, using a tailcuff method with two different sensors, in ether-anaesthetised rats and pressures measured directly, via an indwelling carotid catheter, in conscious unrestrained animals.
• 5 It is concluded that, while ether anaesthesia elevates plasma catecholamine concentrations in rats, the increase in plasma catecholamines has little, if any, effect on indirect systolic blood pressure measurements.

     

Cardiovascular effects of leukotriene D4 in SHR and WKY rats

Leukotriene D4 (LTD4, 0.8-4 micrograms/kg i.a.) increased blood pressure and heart rate of conscious SHR and WKY rats. LTD4, 20 micrograms/kg (i.a.), caused a short lasting increase in blood pressure and heart rate in WKY. In SHR, LTD4, 20 micrograms/kg (i.a.) caused a triphasic effect: hypotension and bradycardia (0.5-1 min), hypertension and tachycardia (2-5 min) and prolonged hypotension and bradycardia (5-180 min). Leukopenia was observed after LTD4, 20 micrograms/kg in both groups of rats but platelets count was unaffected. These results show that SHR are mor sensitive than WKY to the hypotension-bradycardia effect of LTD4.     

Effect of clonidine on renal sodium handling in spontaneously hypertensive rats

Up-regulation of kidney α2-adrenoceptor expression has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). This study was carried out to evaluate renal sodium excretion in response to clonidine administration in SHR and control normotensive Wistar-Kyoto (WKY) rats. SHR and WKY rats (12-week-old) were placed in metabolic cages for 4 days: the first 2 days in control conditions and the following 2 days under oral clonidine treatment (100 μg/kg body weight). Clonidine produced a similar reduction in systolic blood pressure values in SHR and WKY rats, although SHR remained hypertensive. At the end of the study SHR and WKY rats presented similar noradrenaline plasma levels. However, noradrenaline kidney tissue levels were significantly higher in SHR compared to WKY rats. Under control conditions, SHR presented lower urine flow compared to WKY rats. Clonidine produced a significant decrease in urine flow in WKY rats but not in SHR. Furthermore, clonidine also produced a significant reduction in urinary sodium, potassium, and creatinine excretion in WKY rats, but had no effect in SHR. In conclusion, in SHR the reduction in systolic blood pressure and sympathetic activity produced by clonidine was not accompanied by a decrease in urine volume and sodium excretion.     

巴马小型猪植入式遥测动物模型的建立及应用

目的 基于遥测技术建立适用于监测清醒自由活动状态下巴马小型猪心电、血压、体温等生理指标的动物模型,为其在安全药理学研究中的应用提供支持。方法 8只巴马小型猪（雌雄各半）经手术植入植入子,手术后恢复3~4周,经体格检查确认已完全恢复后,采用EMKA遥测系统连续监测至少24 h心电图、血压等生理指标,包括心率、PR间期、QRS间期、QT间期、校正QT （QTcv）间期、体温、收缩压（SBP）、舒张压（DBP）、平均动脉压（MBP）,并于次周重复监测1次。对巴马小型猪的24 h指标变化进行分析,并与Beagle犬和食蟹猴数据进行种属间比对分析。结果 巴马小型猪的心电数据和血压数据昼夜节律均不明显;体温呈现明显的昼夜节律,白天体温高,夜间体温低;动物的心率、血压和体温均受外界影响比较大,与动物的活动呈现明显的相关性;与Beagle犬和食蟹猴比较,巴马小型猪的心率和人类最为相似,SBP仅稍高于人类。结论 通过体内植入植入子,成功建立了巴马小型猪植入式遥测动物模型;与Beagle犬和食蟹猴比较,巴马小型猪更适合用于药物对心血管系统影响的评价。     

Influence of gender on oxidative stress, lipid peroxidation, protein damage and apoptosis in hearts and brains from spontaneously hypertensive rats

1. Hypertension leads to oxidative stress, lipid and protein damage, apoptosis and impaired cardiac contractile function. However, impact of gender on these hypertension-associated abnormalities has not been elucidated. 2. The present study evaluated the oxidative stress, lipid/protein damage, apoptosis in heart and brain tissues as well as cardiomyocyte contractile function in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) of both genders. Oxidative stress, lipid peroxidation, protein damage and apoptosis were assessed by glutathione (GSH) : reduced glutathione (GSSG) ratio, malondialdehyde (MDA) levels, protein carbonyl levels and caspase-3 activity, respectively. Cardiomyocyte contractile function was examined including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/-dL/dt). The SHR cardiomyocytes displayed reduced PS and +/-dL/dt compared with gender-matched WKY counterparts. Male but not female SHR cardiomyocytes possessed longer resting cell length, normal TPS and prolonged TR90. All mechanical parameters were comparable between male and female WKY rats with the exception of a higher TR90 in females. Hypertension did not significantly affect the GSH : GSSG ratio in the heart and brain tissues of either gender. Brain from female WKY rats displayed a reduced GSH : GSSG ratio. The MDA levels were unchanged and elevated, respectively, in SHR heart and SHR brain tissues from both genders. Protein carbonyl formation and caspase-3 activity were elevated in male but not female SHR hearts. Nonetheless, brain protein carbonyl level and caspase-3 activity were unaffected by hypertension or gender. 3. In summary, these results suggest that gender affects hypertension-associated oxidative stress, lipid and protein damage, apoptosis in heart and brain tissues and cardiomyocyte contractile function.     

Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12 weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity.     

Changes in autonomic activity and baroreflex sensitivity with the hypertension process and age in rats

1. Autonomic activity and baroreflex sensitivity (BRS) were compared in age-matched conscious groups of Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. Male WKY rats, SHR and SHRSP aged 4-30 weeks were used. Autonomic activity and BRS were estimated by power spectral and cross-spectral analysis of systolic blood pressure (SBP) and SBP-SBP (SS) interval fluctuations, respectively. 3. The time-course of heart rate (HR), SBP, the amplitude of the low-frequency component of SBP fluctuation (SBP-LF; prazosin-sensitive index) and the amplitude of the high-frequency component of the SS interval fluctuation (SS-HF; atropine-sensitive index) consisted of two periods. In the first period (up to 10 or 15 weeks of age), BP, SBP-LF and SS-HF increased with age. The order of SBP-LF was SHRSP > SHR > WKY rats throughout this period. During the second period, BP was sustained at certain levels in all strains, but changes in SBP-LF and SS-HF with age were different among strains. In particular, in SHRSP, SBP-LF markedly decreased with age after 10 weeks. Baroreflex sensitivity in WKY rats increased gradually with age, whereas the BRS in SHR and SHRSP decreased before 6 weeks of age and remained lower than that in WKY rats. 4. In conclusion, the present study shows that both prazosin-sensitive and atropine-sensitive indices are associated with the elevation of BP in all strains studied. However, hypertension after 15 weeks of age in SHRSP is sustained despite a paradoxical reduction in sympathetic activity with an abnormal control of BRS. Therefore, the contribution of autonomic activity to hypertension may be discussed separately as a developmental period and a sustained period.     

TOTAL BODY SODIUM IN IMMATURE SPONTANEOUSLY HYPERTENSIVE AND WISTAR KYOTO RATS

Total body sodium of male and female spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats was estimated weekly during the first 8 weeks of life by measuring exchangeable sodium (ENa). Blood pressure and sodium intake was measured from weeks 4 to 8. SHR had significantly higher blood pressure and sodium intake than WKY from 4 to 8 weeks of age. ENa was higher in SHR than WKY throughout the first 8 weeks of life. Relative sodium retention was observed in SHR during weeks 5 to 8 despite a significant rise in SHR blood pressure and fall in sodium intake. These findings suggest a change in the renal pressure/natriuresis relationship at this age in the SHR.     

CGP12177-induced haemodynamic and vascular effects in normotensive and hypertensive rats

CGP12177 is a non-conventional partial agonist, known to have cardiostimulating and vasorelaxant properties related to its agonist action on the low affinity state of the beta(1)-adrenoceptor (beta(1LA)-adrenoceptor). In normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), CGP12177-induced vasorelaxant effects were analysed in hindquarter vessels to assess modifications in hind limb vascular resistance, and in femoral artery rings. The global haemodynamic effects induced by CGP12177 were also investigated using telemetry in conscious animals. In hindquarters vasculature precontracted with 5-hydroxytryptamine, CGP12177 (0.16 to 475 microg) produced a similar dose-dependent decrease in hindquarters perfusion pressure in both strains. Vasorelaxation was not modified by nadolol, a beta(1) and beta(2)-adrenoreceptor antagonist, nor by L748337, a beta(3)-adrenoceptor antagonist, but was concentration dependently inhibited by bupranolol, a beta(1LA)-adrenoceptor antagonist at high concentrations. In femoral artery rings from WKY rats and SHR, CGP12177 produced a concentration-dependent relaxation, which was unaffected by nitric oxide synthases inhibition but was significantly reduced in the presence of bupranolol. With double cardiac autonomic blockade (atropine plus atenolol) in conscious WKY rats and SHR, CGP12177 greatly increased heart rate with minor changes in mean arterial pressure in both strains. Conversely, in the absence of double cardiac autonomic blockade, the amplitude of CGP12177-induced heart rate increase was less pronounced and had an hypotensive effect. The reduction in tachycardia and the hypotension were significantly greater in SHR compared to WKY rats. In conclusion, in both strains, CGP12177 produced vasodilating effects in hindquarter vessels and femoral arteries that can be attributed to a beta(1LA)-adrenoceptor stimulation. In conscious WKY rats and SHR, CGP12177-induced cardiostimulation and hypotension were not significantly different after baroreflex blockade, but were decreased and increased respectively, in the presence of baroreflex activity.     

Effect of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the blood pressure in rats (author's transl)]

The effects of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the systolic blood pressure and heart rate were investigated in conscious Kyoto Wistar normotensive rats (WKY), spontaneously hypertensive rats (SHR) and DOCA-NaCl hypertensive rats (DOCA rats) and the results compared with those of propranolol and practolol. In WKY and DOCA rats, the intraperitoneal administration of acebutolol, propranolol and practolol (0.5 approximately 20 mg/kg) produced a hypotensive action, however, these effects were observed only with restricted doses and there was no evidence of a dose-dependency. The heart rate was decreased by acebutolol and propranolol, but was increased by practolol which possesses an intrinsic sympathomimetic activity. In SHR, propranolol produced a dual action, a slight rise followed by a slight fall, the change not being significant, while practolol induced a slight hypertension. On the other hand, acebutolol in high doses induced a dose-dependent hypotensive action. The heart rate was markedly and dose-dependently decreased by these three agents. Thus, while propranolol and practolol produced hypotensive effects in WKY and DOCA rats, acebutolol produced hypotensive effects in WKY, SHR and DOCA rats. These results suggest that acebutolol is a beta-adrenoceptor blocking agent which possesses hypotensive activity in hypertensive rats.     

Characterization of cardiac size and function in SHRSP.Z-Lepr(fa)/IzmDmcr rats, a new animal model of metabolic syndrome

Cardiac structural and functional abnormalities are observed in metabolic syndrome. However, such changes have not been investigated in the SHRSP.Z-Lepr(fa)/IzmDmcr rat (SHRSP-fatty) model of metabolic syndrome. Here we compare cardiac size and hemodynamic function in these rats with their lean littermates (SHRSP) and normotensive control Wistar-Kyoto rats (WKY). In male 16-week-old SHRSP-fatty, we determined heart rate and systolic blood pressure (SBP) by tail-cuff, cardiac output (CO), subcutaneous peripheral blood flow (BF) and stroke volume (SV) by plethysmography, and systolic and diastolic functions by echocardiography. We also assessed weight and collagen type I expression by Western blot in isolated atrium and ventricle, and beat rate in isolated atrial preparation by myography. Heart rate was lower in conscious SHRSP-fatty than SHRSP, and the beat rate of isolated atria was lower in SHRSP-fatty and SHRSP than that of WKY. Atrial weight was larger in SHRSP-fatty than others. Ventricular weight of SHRSP-fatty and SHRSP was larger than WKY. There were significant inverse correlations between atrial weight and heart rate or beat rate in SHRSP-fatty. SBP, CO, BF and SV were increased in SHRSP-fatty similarly to SHRSP. Increased deceleration time and decreased E/A ratio, and preserved fractional shortening were observed in SHRSP-fatty. Expressions of collagen type I were increased in atria and ventricle of SHRSP-fatty. SHRSP-fatty with metabolic syndrome exhibit cardiac changes, including slowed heart rate, ventricular diastolic dysfunction, and fibrosis, and atrial enlargement. SHRSP-fatty may be a useful rat model to study on cardiac abnormalities in metabolic syndrome.