Acute effects of aspartame on systolic blood pressure in spontaneously hypertensive rats

Summary Exogenous tyrosine lowers blood pressure in spontaneously hypertensive rats (SHR). The artificial sweetener aspartame also elevates blood and brain tyrosine levels in rats by being hydrolyzed to phenylalanine, which is then rapidly hydroxylated to tyrosine in the liver. Hence we tested the ability of aspartame; its hydrolytic products phenylalanine, aspartic acid and methanol; and of tyrosine itself to lower blood pressure in SHR. For one week prior to experimentation rats were acclimated to the indirect blood pressure measurement technique; on the day of an experiment they received I.P. injections (mg/kg) of aspartame (12.5–200), tyrosine (25–200) or phenylalanine (100–200), or of aspartic acid or methanol in the doses theoretically contained within 200 mg/kg aspartame. Animals receiving 50, 100 or 200 mg/kg of aspartame exhibited maximum falls in blood pressure of 17.3, 24.2 and 19.3 mmHg, respectively. All changes were significant, as determined by ANOVA and the Newman-Keuls test (p<0.05). Tyrosine or phenylalanine also lowered blood pressure, but aspartic acid or methanol produced no significant effects. Co-administration of aspartame with valine, a large neutral amino acid that competes with phenylalanine or tyrosine for brain uptake, attenuated aspartame's hypotensive effect. These observations suggest that the neurochemical changes produced by aspartame lead to predicted tyrosine-induced changes in blood pressure.     

Effect of prolonged clonidine treatment and its withdrawal on noradrenaline turnover in the cerebral cortex and medulla oblongata of the spontaneously hypertensive rat

Summary We have investigated the effect of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.5 mg-kg^–1 · 24 h^–1 for 10 days) and of withdrawal of this treatment on ingestive behaviour and on the cerebral turnover of noradrenaline in the adult spontaneously hypertensive rat (SHR). Clonidine amplified the fall in food and water intakes induced by minipump implantation. Ingestive behaviour returned to normal by the 4th to the 5th day in controls and by the 7th to the 8th day in clonidinetreated SHR. Clonidine withdrawal produced an increase in water intake above pre-implantation values. Body weight fell during clonidine treatment, then recovered slightly during withdrawal. After 5 days' treatment total DOPEG levels (an index of noradrenaline turnover) were reduced in cerebral cortex and medulla oblongata. The noradrenaline metabolite levels increased following withdrawal of drug treatment, the increase being more marked and faster in onset in cerebral cortex than in medulla oblongata. Thus prolonged treatment with clonidine decreases noradrenaline turnover and withdrawal of such treatment increases turnover. Send offprint requests to J. Atkinson at the above address     

New Method for Imaging Innervation of the Renal Preglomerular Vasculature. Alterations in Hypertensive Rats

Objective : To develop a new method for viewing adrenergic innervation along renal preglomerular vessels; to assess nerve densities and vascular lesions along arcuate arteries (ArcA), arcuate arterial branches (ArcB), and interlobular arteries (ILA) in spontaneously hypertensive rats (SHR) and in angiotensin II (AngII) and in N^G‐nitro‐l ‐arginine methyl ester (l ‐NAME) hypertensive rats. Methods : Preglomerular vasculatures were isolated after HCl maceration and were immunostained against synaptophysin, a membrane protein of synaptic vesicles. Lesions were stained with Sudan black. Longitudinal nerve densities and relative frequencies of ArcA, ArcB, and ILA endowed with sudanophilic lesions were assessed separately. Results : Synaptophysin immunostaining revealed the vascular neural plexus. Nerves were adrenergic, as the plexus was destroyed by treatment with 6‐hydroxy dopamine. Vascular lesions were not seen in SHR, and increased nerve density was observed along ArcA and ILA. In l ‐NAME‐ and AngII‐hypertensive rats, vascular lesions affected predominantly ArcB and ILA, and nerve density was reduced by 12% and 28% (ArcA), 37% and 31% (ArcB), and by 55% and 34% (ILA), respectively, versus normotensive controls. Endothelin‐1 receptor blockade did not affect AngII‐induced hypertension but prevented both lesion development and reduction of density of the vascular neural plexus. Conclusions : The method we have devised provides a direct en face view of the vascular adrenergic innervation of isolated preglomerular vasculature. Measurements in hypertensive rat models suggest a link between vascular lesions and reduction in nerve density in hypertension. Endothelin‐1 likely plays a key role in mediating both vascular injury and altered vascular nerve density in hypertension.     

Volume loading hypoalgesia in SHR, WKY and F1 offspring of a SHR × WKY cross

The effects of volume loading on a nociceptive reflex, arterial blood pressure and heart rate were studied in spontaneously hypertensive rats (SHRs), Wistar Kyoto normotensive rats (WKYs) and the F₁ offspring of a SHR × WKY cross. Volume loading resulted in significantly greater inhibition of the tail-flick reflex to painful radiant heat in SHRs compared to WKYs. The F₁ offspring of a SHR × WKY cross showed levels of hypoalgesia to volume loading that were intermediate to those of SHRs and WKYs. There were no differences between these strains in their hypotensive and bradycardic responses to volume loading. These findings are discussed in terms of cardiovascular-somatosensory interactions.     

CENTRAL CARDIOVASCULAR EFFECTS OF DIHYDROPYRIDINES IN SPONTANEOUSLY HYPERTENSIVE RATS

Summary— Intracerebroventricular (i.c.v.) injections of dihydropyridine derivatives calcium channel agonist (BAY K8644) and antagonists (nifedipine, nicardipine, PN 200–110) induced opposite long-lasting changes in blood pressure (BP) in pentobarbital anesthetized spontaneously hypertensive rats (SMR). I.c.v. nifedipine (NIF), nicardipine (NIC), and PN 200–110 decreased mean blood pressure dose-dependently and stereoselec-tively, (+) NIC and (+) PN being 8 and 3 times more potent than their (-) isomers, respectively. The decrease in BP was due to a withdrawal of the sympathetic tone, since NIF- and NIC-induced falls in BP were suppressed after either hexamethonium (HXM), 6 OHDA or bilateral adrenalectomy. I.c.v. BAY K8644 increased BP dose-dependently. The i.c.v. BAY K8644-induced hypertensive effect was inhibited: a), by NIF and (+) PN but not by (-) PN, therefore probably occurring at central DHP sites; b), by HXM and reserpine, thus probably mediated by an increase in sympathetic tone; c), by i.c.v. methylatropine (MA) while i.v. MA and i.c.v. HXM had no inhibitory effect, thus probably involving central muscarinic sites. In SHR, NIC did not after the K+-evoked ACh release but suppressed the BAY K8644-induced increase in ACh release. In anesthetized normotensive control rats (WKY), neither i.c.v. NIF, NIC or BAY K8644 changed BP, nor did the latter after ACh release. Moreover, in conscious WKY, i.c.v. nicardipine increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data suggest that central DHP sites may be involved in the cholinergic transmission and may participate in genetic hypertension via sympathetic tone.     

Blood pressure and sympathetic activity in spontaneously hypertensive rats during food restriction

Summary Young (7 weeks) spontaneously hypertensive rats (SHR) were kept on food-restriction (33%) during 4 weeks with (0.3% saline as drinking water) or without sodium supplementation. Body weight and indirect systolic blood pressure (tail plethysmography) were followed each weak. During the last week of the intervention period 24 hour excretions of sodium, dopamine and nor-adrenaline were measured. Vascular pressor responses to noradrenaline were evaluated in pithed rats and the sympathetic nerve activity was assessed from the disappearance of endogenous noradrenline in the heart after synthesis inhibition. Despite a clear retardation of the growth rate in food-restricted rats the development of hypertension was not influenced. Food-restriction was associated with a moderate suppression of sympathetic activity. Furthermore, the vascular pressor responses to noradrenaline were decreased but this was reversed following sodium supplementation. It is concluded that despite evidence of sympathetic suppression weight reduction does not reduce the blood pressure in SHR once the blood pressure has started to rise.     

Environmental enrichment improves cognitive deficits in Spontaneously Hypertensive Rats (SHR): Relevance for Attention Deficit/Hyperactivity Disorder (ADHD)

The interaction between genes and environment seems to be relevant for the development of Attention Deficit/Hyperactivity Disorder (ADHD), one of the most prevalent childhood psychiatric diseases. The occurrence of ADHD is typically associated with poor academic performance, probably reflecting learning difficulties and/or cognitive impulsiveness. The inbred Spontaneously Hypertensive Rats (SHR) strain has often been considered as an animal model of ADHD, since they ‘naturally’ display the main ADHD symptomatology. Although pharmacological agents improve SHR's cognitive deficits, little is known about the involvement of environmental factors in SHR disabilities and to what extent ‘protective’ non-pharmacological factors may be considered as strategy for ADHD prevention. Here we investigated whether the rearing environment during neurodevelopment may counteract later cognitive deficits presented by adult SHR. Wistar (WIS) rats were also used to investigate whether the putative effects of environmental enrichment depend on a specific genetic background. The animals were reared in enriched environment (EE) or standard environment (SE) from the post-natal day 21 until 3 months of age (adulthood) and tested for cognitive and non-cognitive phenotypes. EE improved SHR's performance in open field habituation, water maze spatial reference, social and object recognition tasks, while non-cognitive traits, such as nociception and hypertension, were not affected by EE. Response of WIS rats was generally not affected by the present EE. These results show that the general low cognitive performance presented by SHR rats strongly depends on the rearing environment and they may suggest modifications of the familial environment as a putative preventive strategy to cope with ADHD.     

卡托普利长程干预对自发性高血压大鼠左心室重塑及冠脉微血管结构的影响

目的 :以自发性高血压大鼠 (SHR)为研究对象 ,观察血管紧张素转换酶抑制剂 (ACEI)卡托普利对SHR左室肥厚、左室心肌纤维化及冠脉微血管结构的影响。方法 :2 0周龄雄性SHR 2 0只 ,随机分为卡托普利(Cap)干预组和对照组 ,每组 10只 ,观察卡托普利干预后 13周内血压变化 ,并于观察期末测左心室重 /体重 (LVW /BW ) ;通过图像分析、形态学观察 ,确定左心室胶原分数 (CF)、标准化血管周胶原面积 (PVCA)及肌间动脉中膜厚度(AMT)。结果 :卡托普利 ( 10 0mg·kg-1·d-1)可使SHR的SBP显著降低 ,治疗 4周后达最大降压效应 ,且该效应于第 13周末仍可维持 (P <0 0 1) ;Cap干预组LVW /BW显著低于对照组 [( 3 42± 0 2 1)mg/gvs ( 3 96± 0 18)mg/g(P <0 0 1) ] ,CVF、PVCA和AMT在Cap干预组显著亦低于对照组 ,肌间和血管外胶原纤维明显减少 ,动脉中膜变薄。结论 :卡托普利能显著逆转SHR病理性LVH、心肌纤维化及冠脉微血管结构异常 ,其长期应用具有较好的心肌保护和修复效应     

自发性高血压大鼠NHE-1基因表达与左心室肥厚的相关性

目的：探讨自发性高血压大鼠（SHR）NHE-1基因表达与左心室肥厚的相关性.方法：对SHR和同源血压正常大鼠（WKY）进行平均血压、左室重量（LVW）和体重（BW）的测定，同时采用实时定量荧光检测两组大鼠心肌组织中NHE-1 mRNA的拷贝数.结果：SHR组与WKY组相比，SHR组的LVW、LVW/BW明显高于WKY组（r左室重=0.700，r左室重/体重之比=0.617，P＜0.01），大鼠的平均血压与LVW量、LVW/BW呈正相关（P＜0.01）；SHR组的心肌组织NHE-1 mRNA的表达增高（P＜0.01）.结论：SHR的心肌组织NHE-1 mRNA的表达增高，提示NHE-1可能参与心肌肥厚的发生、发展过程.     

基质金属蛋白酶-9与自发性高血压大鼠心肌纤维化的相关性研究

目的:探讨基质金属蛋白酶-9(MMP-9)与自发性高血压大鼠(SHR)心肌纤维化的相关性。方法:将16只14周龄雄性SHR随机平分为ACEI组和对照组,另以8只同龄雄性SD大鼠作为正常对照组。ACEI组以卡托普利100mg/(kg.d)灌胃,SHR对照组不灌药,于灌药12周后麻醉下取出大鼠心脏。免疫组化分析MMP-9、Collagen和的表达;RT-PCR检测MMP-9mRNA表达;MASSON染色测量胶原容积分数(CVF);碱水解法测定羟脯氨酸(Hypro)含量。结果:(1)SHR对照组LVI、CVF、Hypro、MMP-9、Collagen和的表达明显高于正常对照组(P<0.01);相对于SHR对照组,ACEI组各参数则显著降低(P<0.05);(2)MMP-9与上述指标呈高度正相关(P<0.01)。结论:MMP-9与SHR心肌纤维化密切相关,ACEI能抑制MMP-9的表达。