Acarbose attenuates Basal and postprandial insulin concentrations but fails to lower blood pressure in the spontaneously hypertensive rat

Background: Patients with essential hypertension and the spontaneously hypertensive rat (SHR) are insulin-resistant and hyperinsulinemic. These findings suggest the possibility that insulin resistance and hyperinsulinemia may play a pivotal role in blood pressure regulation. Acarbose, an oral antihyperglycemic drug, decreases hyperinsulinemia and hyperglycemia. The purpose of this study was to assess the influence of acarbose on basal and postprandial insulin and glucose levels and whether changes in beta-cell function result in a change in blood pressure measurements. Methods: SHRs were fed custom diets ad libitum, six with and six without acarbose (40mg/100g of chow). Fasting and postprandial glucose and insulin levels were analyzed following glucose administration (1.75 g/kg body weight). Blood pressure was determined by the tail cuff method. Results: Fasting glucose values were similar, but fasting insulin levels declined 23% in the acarbose treated group (P < .05). Postprandial glucose and insulin levels decreased 18% and 20%, respectively (P < .01), in the acarbose group vs the control animals. Despite the decrease in fasting and postprandial insulin concentrations, systolic, mean, and calculated diastolic blood pressures were insignificantly different in the acarbose group after six weeks of treatment compared to control animals. Conclusion: Acarbose decreases fasting insulin levels and postprandial glucose and insulin levels without effectively lowering blood pressure in the SHR. The ability of acarbose to attenuate the hyperinsulinemic state in the SHR without effectively lowering blood pressure suggests that factors other than serum insulin concentration are important in the modulation of blood pressure.     

Caloric restriction lowers blood pressure in the spontaneously hypertensive rat

In the spontaneously hypertensive rat (SHR), caloric restriction without sodium restriction is associated with reduced blood pressure. Four days of fasting lowered blood pressure 19% while 4 days of eating 50% of ad lib intake reduced blood pressure 10%. Similar dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto—WKY). These data are consistent with the hypothesis that caloric restriction lowers sympathetic activity.     

Aminopeptidase-induced elevations and reductions in blood pressure in the spontaneously hypertensive rat

In vitro results indicated that human placenta-derived aminopeptidase A (APA) was very effective at hydrolyzing aspartate from the angiotensin molecule, thus converting angiotensin II to angiotensin III, but was not active against angiotensin III. In vivo experiments revealed significant elevations in blood pressure when APA was intracerebroventricularly infused into anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats (WKY), with maximum mean (+/- s.e.m.) increases of 30.0 +/- 2.5 and 32.5 +/- 3.7 mmHg, respectively. By contrast, in vitro incubation results utilizing leucine aminopeptidase M (LAP-M) indicated very active degradation of angiotensin III, with less rapid degradation of angiotensin II. The intracerebroventricular infusion of LAP-M significantly reduced blood pressure, particularly in the SHR, but also in WKY, -65.8 +/- 5.1 and -42.5 +/- 6.1 mmHg, respectively. Pretreatment with the specific angiotensin receptor antagonist, Sar1, Thr8 angiotensin II (sarthran) significantly diminished the subsequent APA-induced increase in blood pressure in members of both strains. Pretreatment with sarthran has previously been shown to significantly diminish LAP-M-induced decreases in blood pressure in SHR. Thus, the effects of these aminopeptidases appear to be primarily dependent upon the brain angiotensinergic system, and are consistent with the hypothesis that angiotensin III is the primary active form of central angiotensin.     

Biometric genetic analysis of blood pressure in the spontaneously hypertensive rat

The spontaneously hypertensive rat is the most widely studied animal model of essential hypertension, yet the genetics of transmission of high blood pressure in this strain have not been clearly defined. It has been proposed that in the spontaneously hypertensive rat, blood pressure follows a simple additive mode of inheritance and that the hypertension is primarily determined by a single major locus. To investigate the genetics of transmission of increased blood pressure in the spontaneously hypertensive rat, we performed a biometric genetic analysis of multiple, direct measurements of arterial pressure in unanesthetized, unrestrained rats derived by crossing spontaneously hypertensive rats with two different inbred normotensive strains, the Charles River Wistar-Kyoto rat and the Lewis rat. In both crosses, approximately 60% of the variation in blood pressure could be assigned to genotypic variation. The data fit an additive-dominance model of inheritance in which alleles decreasing blood pressure were partially dominant. Thus, in offspring derived from crosses between spontaneously hypertensive rats and Wistar-Kyoto rats or spontaneously hypertensive rats and Lewis rats that are raised under ordinary laboratory conditions, increased blood pressure is not determined by simple additive effects of alleles at a single major locus. The current findings are consistent with the possibility that in the spontaneously hypertensive rat, hypertension may arise from mutations in alleles that ordinarily act in a dominant fashion to suppress blood pressure.     

吡格列酮配合生活方式干预对自发性高血压大鼠血压的影响

目的 评价胰岛素增敏剂吡格列酮(PIO)配合生活方式干预对自发性高血压大鼠(SHR)的降压作用.方法 35只SHR随机分为3组(SHR对照组,PIO用药组及PIO配合生活方式干预组),药物添加到大鼠饮水中,生活方式干预为每日减少投食量并游泳6～15 min,周期为12 w,采用间接方法测量血压.结果 PIO及配合生活方式干预组大鼠饮食控制良好,游泳能力逐渐增强,无意外死亡.PIO有良好的降压效果,药物配合生活方式干预降压效果更佳,体重控制良好.结论 PIO及配合生活方式干预具有良好的降低SHR血压效果,生活方式干预可作为纠正胰岛素抵抗(IR)的方法之一应用到高血压的治疗当中.     

Increased dietary calcium lowers blood pressure in the spontaneously hypertensive rat

The effect of increased dietary calcium on the development of hypertension in spontaneously hypertensive (SH) rats was investigated by feeding lab chow fortified with calcium carbonate (2.5% calcium, hCa) beginning at 4 wk of age. A control SH group was fed regular lab chow (1.2% calcium, rCa). Two groups of age-matched Wistar-Kyoto (WKY) rats were treated in parallel. Systolic blood pressure (BP) was measured weekly until the age of 18 wk using a tail cuff method. The hCa diet significantly attenuated the time course of hypertension in SH rats even though both SH groups eventually developed hypertension. The hCa also lowered BP in WKYs, but to a lesser extent. Urine output (24-hr volumes) was not affected by hCa, but in both SH and WKY groups fed the hCa diet, the excretion of Na+, K+ and Ca++ was markedly elevated at 11, 15, and 19 wk of age. Urine osmolality was also elevated. Plasma Na+, Ca++ and osmolality were not significantly altered by the diet in either SH or WKY rats; plasma potassium was significantly lower in the SH group fed the hCa diet than in the group given rCa. The hCa diet did not significantly affect the body or heart, kidney, adrenal, or thymus weights. The results suggest that hCa diet may attenuate genetic hypertension by inducing an osmotic diuresis.     

Effect of oral sucrose on blood pressure in the spontaneously hypertensive rat

In the spontaneously hypertensive rat (SHR) increased carbohydrate intake without alteration in sodium intake is associated with elevated blood pressure. One week of feeding sucrose-supplemented chow increased blood pressure an average of 14mm Hg (9%) in three separate groups of SHR, but did not affect blood pressure in normotensive rats of the same strain (Wistar-Kyoto-WKY). Fat supplementation (isocaloric to sucrose) was without effect on blood pressure in SHR. These data are consistent with the hypothesis that diet-induced increases in sympathetic activity may elevate blood pressure in susceptible animals.     

吡格列酮配合生活干预对SHR大鼠降压及主动脉壁的保护作用

目的 观察胰岛素增敏剂吡格列酮(PIO)配合生活干预对自发性高血压大鼠(SHR)的降压、降糖、调脂作用,以及对主动脉壁的保护作用.方法 SHR大鼠45只,随机分为4组:对照组,PIO组,生活干预组,PIO+生活干预组.药物添加到大鼠饮水中,生活干预为每日减少投食量并游泳6～15 min,实验周期为12 w.采用尾动脉血压间接测量法定期测血压,并采用生化分析仪测定血糖,血脂.采用光镜方法观察各组大鼠主动脉壁形态学变化情况.结果 PIO有良好的降压、降糖、调脂作用,PIO配合生活干预的降压、降糖、降脂效果更佳,血管保护作用最强.结论 PIO及配合生活干预具有良好的降低SHR大鼠血压及血管保护作用,生活干预可作为纠正IR的方法之一应用到高血压的治疗当中.     

Caloric restriction alters arterial blood pressure and baroreflex responsiveness of the spontaneously hypertensive rat

Aging is associated with an increase in blood pressure and the occurrence of hypertension. Caloric restriction retards the aging process, in general, and is a commonly used therapeutic approach to the control of high blood pressure. The aim of this study was to examine the effects of long term caloric restriction on mean arterial blood pressure, heart rate and the baroreflex responsiveness of spontaneously hypertensive (SH) rats. Male, 3-month-old SH rats were allowed to eat ad libitum or were fed only 60% of the ad libitum amount. After 4 months, cannulas were inserted in the left femoral artery and vein under anesthesia. On the following day the blood pressure and heart rate were measured in the conscious rat. The basal mean arterial pressure of the calorie restricted rats (166±4 mm Hg, N=5) was significantly less than that of the ad libitum fed rats (182±4 mm Hg, N=4). The basal heart rates of the calorie restricted and ad libitum fed rats were 296±12 beats/min and 323±8 beats/min, respectively. The difference between the means was not significant (p>0.1). Nitroprusside and phenylephrine infusions were used to induce hypotensive and hypertensive episodes, respectively. For nitroprusside, the relationship between the change in mean arterial pressure and the reflex heart rate response was significantly steeper in the calorie restricted group (1.90±0.37 beats/min/mm Hg) than in the ad libitum fed group (0.86±0.1 beats/min/mm Hg). For phenylephrine the relationships were 0.98±0.09 and 0.52±0.18 beats/min/mm Hg, respectively. These results demonstrate that chronic caloric restriction reduces mean arterial pressure and enhances baroreflex responsiveness in the SH rat.     

Thromboxane synthesis and blood pressure in spontaneously hypertensive rats

The present study examines effects of administration of OKY 046, an inhibitor of thromboxane synthesis, for 100 days on systemic blood pressure and renal function in spontaneously hypertensive rats and in normotensive control rats. Untreated spontaneously hypertensive rats had higher values for thromboxane excretion in the urine and higher values for blood pressure than did normotensive control rats. Administration of OKY 046 decreased systolic and mean arterial blood pressure and urinary excretion of thromboxane and protein in spontaneously hypertensive rats. Administration of OKY 046 decreased thromboxane excretion in the urine of normotensive control rats but had no effect on blood pressure or protein excretion. Renal function, as assessed by the clearances of inulin and p-aminohippuric acid, was greater in spontaneously hypertensive rats treated with OKY 046 than in those receiving vehicle alone. In normotensive control rats, OKY 046 administration did not affect renal function. These results suggest that increased renal synthesis of thromboxane may play a role in the pathogenesis of the elevated blood pressure of spontaneously hypertensive rats.     

Metformin attenuates the postprandial fall in blood pressure in type 2 diabetes

Metformin has been shown to modulate the cardiovascular response to intraduodenal glucose in patients with type 2 diabetes (T2DM), and may have the capacity to regulate postprandial blood pressure (BP), which is often inadequately compensated in T2DM, resulting in postprandial hypotension. In the present study, we evaluated the acute effects of metformin on the BP and heart rate (HR) responses to oral glucose in patients with T2DM. Ten diet-controlled T2DM patients were evaluated on two occasions in a double-blind, randomized, crossover design. Participants received either metformin 1 g or saline (control) intraduodenally 60 minutes before ingesting a 50 g glucose drink labelled with 150 mg ¹³C-acetate. BP, HR, plasma glucagon-like peptide-1 (GLP-1) and gastric emptying (breath test) were evaluated over 180 minutes. Systolic and diastolic BP decreased and HR increased after oral glucose (P < 0.001 for all) on both days. Metformin attenuated the fall in systolic BP (P < 0.001), increased plasma GLP-1 concentrations (P < 0.05) and slowed gastric emptying (P < 0.05) without significantly affecting diastolic BP or HR. In conclusion, metformin acutely attenuates the hypotensive response to oral glucose, associated with augmented GLP-1 secretion and delayed gastric emptying, effects potentially relevant to its favourable cardiovascular profile.     

Ligand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats

AIMS: The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERalpha and ERbeta, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERalpha agonist 16alpha-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERbeta-deficient mice exhibit elevated blood pressure and since the ERbeta agonist 8beta-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERbeta agonist 8beta-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR. METHODS AND RESULTS: Treatment of ovariectomized SHR with 8beta-VE2 for 12 weeks conferred no uterotrophic effects but lowered elevated systolic blood pressure (-38 +/- 5 mmHg, n = 31, P < 0.001 vs. placebo) as well as peripheral vascular resistance (-31.3 +/- 4.6%, P < 0.001 vs. placebo). 8beta-VE2 enhanced aortic ERbeta expression (+75.7 +/- 7.1%, P < 0.01 vs. placebo), improved NO-dependent vasorelaxation, augmented phosphorylation of the vasodilator-stimulated phosphoprotein in isolated aortic rings (P < 0.05 vs. placebo), increased cardiac output (+20.4 +/- 2.5%, P < 0.01 vs. placebo), and attenuated cardiac hypertrophy (-22.2 +/- 3.2%, p < 0.01 vs. placebo). 8beta-VE2, in contrast to oestradiol, did not enhance cardiac alpha-myosin heavy chain expression. CONCLUSION: Ligand-dependent activation of ERbeta confers blood pressure lowering effects in SHR that are superior to those of 17beta-estradiol or the ERalpha agonist 16alpha-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.     

高血压病和糖尿病患者餐后状态血压及心率变化的研究

目的　研究高血压病 (EH)和 2型糖尿病 (DM)患者餐后状态血压和心率的变化特点。　方法　 187例患者 ,分 3组 :高血压病组 (EH,71例 ) ,2型糖尿病组 (DM,49例 )和 2型糖尿病伴高血压组 (DM EH,6 7例 )。观察各组 2 4h动态血压和心率 ,进标准定量饮食 ,分析进餐前后收缩压(SBP)、舒张压 (DBP)和心率的变化。　结果　 EH组和 DM EH组 2 4h平均收缩压 (2 4h ABPS)和2 4h平均舒张压 (2 4h ABPD)较 DM组明显增高 (P<0 .0 1) ,而 DM组和 DM EH组 2 4h平均心率较 EH组快 (P<0 .0 1) ;EH组在餐后 30 m in至 6 0 min的 SBP、DBP和心率较餐前对应时间点升高(P<0 .0 1) ,餐后 90 m in SBP、DBP和心率恢复至餐前水平。 DM组和 DM EH组在餐后 30 m in至90 min SBP、DBP和心率下降 (P<0 .0 1) ,餐后 12 0 min SBP、DBP和心率恢复至餐前水平。　结论　高血压病和 2型糖尿病患者餐后状态血压和心率的变化有不同的特点 ,表现为高血压病患者餐后血压升高和心率增快 ,而 2型糖尿病或伴高血压病的 2型糖尿病患者餐后血压和心率下降 ,且其血压和心率恢复至餐前水平较单纯高血压病患者慢。     

Sympathetic nerve activity and blood pressure in normotensive backcross rats genetically related to the spontaneously hypertensive rat

The genetic basis of hyperactivity of the sympathetic nervous system (SNA) in spontaneously hypertensive rats (SHR) was assessed by measuring SNA in animals derived from a backcross (BC) breeding program designed to isolate single gene differences causing changes in blood pressure. Selective breeding of the male hypertensive rats with inbred normotensive female Wistar/Lewis rats yielded progeny with a range of blood pressures, but whose group mean pressures were lower than the group mean pressures of the original SHR. Progressive generations had progressively lower group mean pressures. There was a positive correlation between SNA and mean arterial pressure in BC rats. These results indicate that the genetic defect in SHR may be abnormality in SNA, and the hypertension in these animals is a secondary result of this primary defect. Baroreceptor function was also assessed in SHR and in BC rats. In young (8 to 24 weeks old) SHR, baroreceptor function was similar to that in BC rats, whereas SNA was markedly increased. Only in older (24 to 40 weeks old) SHR was there an abnormality in the gain of baroreceptors. The development of hypertension in SHR therefore appears to be due to increased SNA resulting from a defect in the central nervous system. Changes in baroreceptor function are secondary to the hypertension and occur after the hypertension is established.     

Protein kinase inhibitors and blood pressure control in spontaneously hypertensive rats

Considerable evidence suggests that protein kinase C activation participates in the regulation of vascular smooth muscle tone. The objective of the current study was to examine the relations between inhibition of protein kinase C (PKC) and myosin light-chain kinase (MLCK) and vasorelaxation and blood pressure regulation in spontaneously hypertensive rats (SHR). Putative PKC inhibitors from two chemical classes, staurosporinelike (staurosporine and K252A) and isoquinolinesulfonamides (H7 and HA1004), were tested for their ability to 1) inhibit PKC and MLCK from SHR aorta, 2) relax isolated SHR aorta, and 3) lower blood pressure in conscious SHR. A rank order of potency for the inhibition of PKC and MLCK was established, with the staurosporinelike compounds (staurosporine PKC IC50 = 54 nM) clearly more potent than the isoquinolinesulfonamides (H7 PKC IC50 = 128 microM). The rank order of potency for inhibition of PKC was retained for inhibition of MLCK for all compounds. Staurosporine (EC50 = 75 nM) and H7 (EC50 = 2 microM) caused concentration-dependent relaxation of SHR aorta, but only staurosporine produced vasorelaxation at concentrations consistent with the inhibition of PKC or MLCK. Dose-dependent reductions in arterial pressure of SHR were demonstrated after intravenous injection of staurosporine and HA1004. A single intravenous injection of staurosporine (0.3 mg/kg) lowered blood pressure for more than 10 hours. Staurosporine also lowered blood pressure after oral administration. The depressor response to staurosporine was unaffected by sympathetic beta-adrenergic blockade. In conclusion, the vasorelaxant and antihypertensive actions of staurosporine in SHR are consistent with the inhibition of PKC but could also be equally related to inhibition of MLCK. Not all PKC inhibitors produce vasorelaxation and lower blood pressure. Moreover, the lack of correlation between in vitro vasodilation and PKC or MLCK inhibition for the isoquinolinesulfonamide protein kinase inhibitors H7 and HA1004 suggests that these agents do not cause vasorelaxation in SHR by inhibition of these enzymes.     

Increased insulin sensitivity and basal insulin effectiveness in postprandial reactive hypoglycaemia

Glucose clamp experiments have shown that patients with reactive postprandial hypoglycaemia (PRH) frequently have an increased glucose disposal, but the relative involvement of insulin sensitivity (SI) and glucose effectiveness (Sg) in this process remains unknown. The minimal model approach was used to compare 13 patients in whom moderate reactive hypoglycaemia (<3.3 mmol) had been previously diagnosed and 13 matched controls. The intravenous glucose tolerance test (IVGTT, 0.5 g/kg glucose IV) with 0.02 U/kg insulin given at the 19th min and frequent sampling over 180 min shows that PRH patients exhibit a higher glucose tolerance coefficient Kg (2.99±0.26 vs 2.19±0.12;P<0.02), higher SI [22.9±6.4 vs 7.18±0.14 min^–1/(U/ml) · 10^–4;P<0.01] and higher Sg (3.84±0.35 vs 2.92±0.79 min^–1 · 10^–2;P<0.05). The increase in Sg is explained by an increase in its component basal insulin effectiveness (BIE: 1.2±0.27 min^–1 · 10^–2 in PRH subjects vs 0.58±0.07;P<0.05) rather than an increase in Sg at zero insulin. The increase in BIE results from the high values of SI. In 4 PRH subjects SI and Sg were within the normal range, and the increase in Kg evidenced in the 9 others was explained by an increase in SI alone in 3 cases, in Sg alone in 1 case, and both SI and Sg in 5 cases. Thus, in sedentary subjects, the previously reported rise in tissue glucose assimilation is mainly explained by an increased insulin-mediated glucose disposal rather than non-insulin-mediated glucose disposal.