AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats

The aims of this study were to determine the contribution of the AT2 receptor to the antihypertensive and regional vasodilatory effects of AT1 receptor blockade in adult spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive (2K1C) rats, and sham-operated normotensive rats. Several studies have provided evidence to support the notion that the AT2 receptor may have opposing effects to those mediated by the AT1 receptor. We therefore tested the hypothesis that the depressor and vasodilator effects of acute AT1 receptor blockade are dependent on AT2 receptor activation. Heart rate, mean arterial pressure, and regional hemodynamics were measured over a 4-day protocol in rats that received the following treatments in randomized order: saline vehicle, the AT1 receptor antagonist candesartan (0.1 mg/kg iv bolus), the AT2 receptor antagonist PD-123319 (50 microg.kg(-1).min(-1)), or both antagonists. Intravenous candesartan reduced mean arterial pressure in all groups of rats, and this was accompanied by renal and mesenteric vasodilation. Neither saline nor PD-123319 significantly affected these variables. Concomitant PD-123319 administration partially reversed the depressor and mesenteric vasodilator effects of candesartan in sham-operated normotensive rats but not in SHR or 2K1C rats. These data indicate that the AT2 receptor contributes to the blood pressure-lowering and mesenteric vasodilator effects of AT1 receptor blockade in the acute setting in conscious normotensive but not hypertensive rats.     

Morphological changes in the kidney after 5/6 nephrectomy and low-dose radiation

In the present study, we investigated the effect of low-dose irradiation of experimental nephrectomized rats. We hypothized that the low-dose irradiation may slow down the development of focal-segmented glomerulosclerosis (FSGS) after 5/6 nephrectomy. Experiments were performed with 32 male Wistar rats, divided into four groups. The first group contained only operated animals. Animals in the second and third groups were irradiated on the next day after operation with 1 and 3 Gy, respectively. The healthy animals made the forth, control group. Attention was focused on physiological and morphological changes after low-dose (1 and 3 Gy) irradiation. We measured blood pressure, proteinuria, serum creatinin and cysC. Morphological changes of glomerulus and tubules were studied. Animals of the first group had significantly thicker glomerular basement membrane, compared to animals of other groups. The morphological study demonstrated degeneration of the tubular epithelium, tubular atrophy and FSGS. Besides, it was shown that changes in the third group (3 Gy) were less than in nephrectomized (first group) and 1 Gy (second group). The animals of the third group (3 Gy) had significantly lower proteinuria and FSGS. We conclude that our hypothesis, suggesting that low-dose irradiation slows down the development of FSGS, was confirmed.     

Reductions in blood pressure after acute exercise by hypertensive rats

Postexercise reductions in blood pressure at rest have been reported for hypertensive subjects. To determine whether post-exercise hypotension would occur in spontaneously hypertensive rats and to test the hypothesis that any reductions would result because of decreases in regional vascular resistances, hypertensive rats (n = 19) were instrumented with indwelling arterial catheters and Doppler probes to measure regional blood flows from the iliac, superior mesenteric, and renal arteries. Data were collected from animals who performed a 20- and a 40-min treadmill test at between 60 and 70% of their maximum O2 uptake. When the animals ran for 20 min, there was a pre- to postexercise drop in mean arterial pressure (MAP) from 158 +/- 3.6 to 150 +/- 3.6 mmHg (P less than 0.05), which was recorded 30 min after the exercise had ceased. The pre- to postexercise reduction in MAP after 40 min of treadmill running was from 154 +/- 3.1 to 138 +/- 3.0 mmHg (P less than 0.05) as recorded 30 min postexercise. Postexercise heart rate was significantly lower after the 40-min exercise bout, from a preexercise mean of 351 +/- 3 beats/min to 324 +/- 5 beats/min 30 min after the treadmill had stopped. Surprisingly, marked pre- to postexercise reductions in regional vascular resistance were not observed in either the iliac, superior mesenteric, or renal vascular beds. These data demonstrated the existence of postexercise hypotension in genetic hypertensive rats and suggested that reductions in cardiac output were the primary hemodynamic mechanism for this finding.     

Alpha-lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats

Cardiovascular effects of subcutaneous administration of synthetic alpha-lactorphin, a tetrapeptide (Tyr-Gly-Leu-Phe) originally derived from milk alpha-lactalbumin, were studied in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY) with continuous radiotelemetric monitoring. Alpha-lactorphin dose-dependently lowered blood pressure (BP) without affecting heart rate in SHR and WKY. The lowest dose which reduced BP was 10 microg/kg, and the maximal reductions in systolic and diastolic BP (by 23+/-4 and 17+/-4 mm Hg, respectively) were observed at 100 microg/kg dose in SHR. No further reductions were obtained at a higher dose of 1 mg/kg. There were no significant differences in the BP responses to alpha-lactorphin between SHR and WKY. Naloxone (1 and 3 mg/kg s.c.), a specific opioid receptor antagonist, abolished the alpha-lactorphin-induced reduction in BP and reversed it into a pressor response, which provides evidence for an involvement of opioid receptors in the depressor action of the tetrapeptide.     

Lowering of blood pressure in hypertensive rats by SKF 64139 and SKF 72223

The effects of a centrally acting phenylethanolamine N-methyl-transferase (PNMT) inhibitor, SKF 64139, and of its analog, SKF 72223, which is devoid of PNMT inhibitory activity on blood pressure and heart rate, were investigated in spontaneously hypertensive rats (SHR) and in DOCA-salt hypertensive rats. SKF 64139 lowers blood pressure and decreases pulse rate, while SKF 72223 lowers blood pressure and transiently increases pulse rate in SH-rats and in DOCA-salt hypertensive rats. SKF 72223 has no effect on blood pressure or heart rate in normotensive Wister-Kyoto rats. These results suggest that the antihypertensive action elicited by these two tetrahydroisoquinoline (TIQ) derivatives is not due to lowering of central epinephrine (E) levels. To determine whether the cardiovascular response elicited by SKF 72223 is due to stimulation of presynaptic alpha 2-adrenoreceptors, or to blockade of alpha 1-adrenoreceptors, we have examined its effect in combination with the partial alpha 2-agonist clonidine, or with the alpha 1-antagonist prazosin. The administration of clonidine slightly decreases the antihypertensive action of SKF 72223. The clonidine induced reduction in pulse rate is reversed by SKF 72223. In animals pretreated with prazosin, SKF 72223 elicits an additional decrease in blood pressure. Since SKF 64139 and SKF 72223 interact with alpha 2-adrenoreceptors, it is suggested that blockade of peripheral vascular alpha 2-adrenoreceptors might be in part responsible for their antihypertensive action. However, the antihypertensive action of these two drugs might also be due to some central mechanisms.     

Chronopharmacology of oxacalcitriol in 5/6 nephrectomized rats

We previously reported on the merits of the chronopharmacological effects of 1,25(OH) 2 vitaminD3 in 5/6 nephrectomized rats (Tsuruoka et al, Life Scineces 2002; 71: 1809-1820). In this study, the chronopharmacological effect of 22-oxacalcitriol (OCT), a newly developed active vitaminD3 analogue with less calcemic activity, was evaluated by a single and repeated dosing of the drug. The 5/6 nephrectomized animals were kept in rooms with a 12-h light/dark cycle. Single (12.5 microg/kg, i.v.) and repeated (5 microg/kg, i.v. three times a week for 12 weeks) dosing of OCT or vehicle was given at either 2 hours after lights on (2HALO) or 14 hours after lights on (14HALO). The severity of hypercalcemia and hyperphosphatemia was significantly milder when the drug was given at 14HALO. Serum concentrations of total OCT and albumin of the 2HALO and 14HALO trials did not differ significantly. The decrease of parathyroid hormone concentration was greater in the 14HALO trial while the increase in urinary ratio of Ca to creatinine was greater in the 2HALO trial. The suppression of urinary deoxypyridinoline excretion, an index of bone resorption capacity of osteoclast, and the increase in bone density of both femurs were greater in the 14HALO trial. These results suggest that the adverse reactions of OCT were ameliorated and its efficacy was enhanced after dosing of the drug at 14HALO. Chronopharmacological differences of OCT were more prominent than those seen with other vitamin D analogues. Dosing-time-dependent variation in the sensitivity of the drug to osteoclast were involved in the mechanisms of these events.     

Chronic decrease of blood pressure by rat relaxin in spontaneously hypertensive rats

Relaxin is an ovarian polypeptide hormone which is present in large amounts in the rat during the second half of gestation. During this period, blood pressure declines markedly, especially in spontaneously-hypertensive rats (SHR). To test the hypothesis that relaxin might be implicated in this decrease in blood pressure, we infused the hormone in female non-pregnant rats by means of an osmotic mini pump. Our results show that intravenous infusion of purified rat relaxin (1.8 micrograms/day) markedly reduced systolic blood pressure for at least 5 or 6 days in SHR. This decrease was highly significant from 24 hours after the beginning of the infusion and remained significant after 5 days. Rat relaxin was ineffective in control Wistar-Kyoto rats (WKY). Infusion of purified porcine relaxin (3.0 micrograms/day) also diminished blood pressure in SHR, but the effect was less pronounced and developed more slowly, reaching statistical significance on the fourth day of infusion. SHR not receiving relaxin maintained their original systolic blood pressure throughout the experiment. These results indicate that relaxin is involved in the regulation of blood pressure during gestation.     

Val-Glu-Pro对原发性高血压大鼠的体内降压作用

Val-Glu-Pro(VEP)是从钝顶螺旋藻(Spirulina platensis)中发现的一种血管紧张素转化酶(ACE)抑制肽.以原发性高血压大鼠(SHR)为模型,检测单次口服和一周间口服VEP的降压效果,并通过Real-timePCR和酶联免疫吸附法(ELISA)探索其对肾素-血管紧张素系统(RAS)主要成分在SHR大鼠肾脏和血清中的表达调控作用.结果表明:口服VEP的最低有效降压剂量为5mg/kg,加大剂量后表现出剂量效应,最低加权收缩压(WSBP)出现在口服后6h,最低加权舒张压(WDBP)出现在口服后4 h.在一周间口服试验中,10 mg/kg VEP处理组的WSBP在第5日显著低于负对照组.此外,口服VEP显著下调了SHR大鼠肾脏中肾素(renin)、ACE、血管紧张素Ⅱ(AngⅡ)类型1受体(AT1)的mRNA表达,并上调AngⅡ类型2受体(AT2)的mRNA表达,说明VEP的降压效果可能与对RAS系统的抑制作用相关,在高血压的预防和治疗中具有潜在的应用前景.     

Pro-oxidant effect of dehydroepiandrosterone in rats is mediated by PPAR activation

DHEA-treatment exerts a dual effect, prooxidant or antioxidant, depending on the dosage and, therefore, on the tissue concentration reached. In agreement with previous studies showing a prooxidant effect of DHEA, here we show that pharmacological doses of DHEA produce increased H(2)O(2) levels and a marked reduction of GSH content in rat liver. DHEA, also increases both catalase (by 30%) and cytochrome-C-reductase (by 30%) activities in the liver cytosol. The effectiveness of the state of increased oxidative stress is also documented by changes in fatty acid pattern of the microsomal membranes. Moreover, DHEA, at high doses, enhances beta-oxidation, as demonstrated by an increase of acyl-CoA-oxidase activity and of cytochrome P450 4A content, confirming that it acts as a PPARs inducer. Both PPARs induction and proxidant effects completely disappear when DHEA is administered at lower doses. Seven days treatment (4 or 10 mg) is unable to affect either levels of proxidant species and of antioxidant molecules, or cytochrome P450 4A content and beta-oxidation. Prolonged DHEA treatment (4 mg/day) for three weeks not only is unable to affect PPARs activation and beta-oxidation, but it also exerts a protective effect against ADP/Fe(2+) induced lipid peroxidation. This latter result confirms the antioxidant effects of DHEA at low doses, as already previously documented.     

Antithrombotic effect of L-arginine in hypertensive rats.

The aim of the study was to evaluate the effect of L-arginine (L-Arg) on haemostasis in stasis model of venous thrombosis in renal hypertensive rats. The effect of the single dose (i.v. 300 mg/kg bolus+300 mg/kg/h) and of the 10-day application (p.o. 1 g/kg, once daily) of L-Arg was determined. L-Arg reduced the blood pressure both in the acute and long-term application. The single dose of L-Arg decreased the occurrence rate of the thrombus whereas long-term administration reduced significantly the thrombus weight. There were no differences in prothrombin time and activated partial thromboplastin time while the fibrinogen concentration decreased both in the acute and the long-term experiment. L-Arg shortened euglobulin clot lysis time and bleeding time in the long-term application. The chronic L-Arg treatment also inhibited significantly collagen-induced platelet aggregation. The overall haemostasis and coagulation potentials were inhibited and the fibrinolysis potential was higher in the group receiving this amino-acid. The results show that L-Arg, in a complex way, evokes the antithrombotic effect in the model of venous thrombosis in hypertensive rats.     

Chronic kidney disease after 5/6 nephrectomy disturbs the intestinal microbiota and alters intestinal motility

Organ–organ crosstalk is involved in homeostasis. Gastrointestinal symptoms are common in patients with renal failure. The aim of this study was to elucidate the relationship between gastrointestinal motility and gastrointestinal symptoms in chronic kidney disease. We performed studies in C57BL/6 mice with chronic kidney disease after 5/6 nephrectomy. Gastrointestinal motility was evaluated by assessing the ex vivo responses of ileum and distal colon strips to electrical field stimulation. Feces were collected from mice, and the composition of the gut microbiota was analyzed using 16S ribosomal RNA sequencing. Mice with chronic kidney disease after 5/6 nephrectomy showed a decreased amount of stool, and this constipation was correlated with a suppressed contraction response in ileum motility and decreased relaxation response in distal colon motility. Spermine, one of the uremic toxins, inhibited the contraction response in ileum motility, but four types of uremic toxins showed no effect on the relaxation response in distal colon motility. The 5/6 nephrectomy procedure disturbed the balance of the gut microbiota in the mice. The motility dysregulation and constipation were resolved by antibiotic treatments. The expression levels of interleukin 6, tumor necrosis factor-α, and iNOS in 5/6 nephrectomy mice were increased in the distal colon but not in the ileum. In addition, macrophage infiltration in 5/6 nephrectomy mice was increased in the distal colon but not in the ileum. We found that 5/6 nephrectomy altered gastrointestinal motility and caused constipation by changing the gut microbiota and causing colonic inflammation. These findings indicate that renal failure was remarkably associated with gastrointestinal dysregulation.     

Effect of nephrectomy and captopril on autoregulation of cerebral blood flow in rats

The present study investigated the effect of circulating versus locally present renin on cerebral blood flow (CBF) and its autoregulation in rats. CBF was measured repetitively with the intracarotid 133Xe injection method, whereas blood pressure was lowered to determine the lower limit of autoregulation. To remove renin from the blood, rats were bilaterally nephrectomized and kept alive with peritoneal dialysis for 48 h. Five groups of animals were studied: 1) nephrectomized dialyzed rats, 2) nephrectomized dialyzed rats given a single intravenous dose of the angiotensin-converting enzyme inhibitor captopril (10 mg/kg), 3) sham nephrectomized and dialyzed rats, 4) rats receiving drugs as dialyzed rats but no surgery, and 5) rats given the same diet as the other groups but no drugs and no surgery. Baseline blood pressure was significantly lower in nephrectomized rats compared with controls. Nephrectomy, captopril, sham operation, or dialysis did not influence baseline CBF. The lower limit of CBF autoregulation was significantly lower in nephrectomized (53 +/- 4 mmHg) and sham-operated (58 +/- 4 mmHg) rats compared with diet control rats (78 +/- 3 mmHg). Captopril significantly decreased the lower limit in nephrectomized rats (35 +/- 2 mmHg). Thus removal of circulating renin caused no change in the lower limit of autoregulation. By contrast, captopril lowered the lower limit even in the absence of circulating renin and hence appeared to exert its effect on components of the renin-angiotensin system in the cerebral resistance vessel walls.     

Synthesis and Antiretroviral Evaluation of Various 5-Alkyl-6-AZA-5,6-Dihydrouridine

Abstract

Various 5-alkyl-6-aza-5,6-dihydrouridine were synthesized from the corresponding triazinic heterocycles and acetylated ribose. These nucleosides were tested for inhibitory activity on lentivirus Visna-Maedi.     

应用植入式遥测技术观察自发性高血压大鼠血压的昼夜波动

目的应用植入式遥测技术观察自发性高血压大鼠在清醒无束缚状态下血压昼夜波动变化。方法取8只SPF级3月龄雄性SHR大鼠,进行C50-PXT植入子植入手术,恢复7 d后,用遥测系统进行24 h连续清醒无束缚的血压监测,并用EMKA分析软件对动态血压心率均值、24 h血压心率趋势等指标进行分析。结果 3月龄的SHR大鼠血压和心律呈昼夜节律性变化,白昼阶段血压明显低于夜间阶段(P<0.01),血压在1∶30～2∶30和20∶30～21∶30时出现两个高峰期,14∶00～14∶30时出现一低谷期。其中夜间阶段平均收缩压为166.02 mmHg,两个收缩压峰值分别为172.13 mmHg和171.38 mmHg;白昼平均收缩压是162.73 mmHg,收缩压谷底值为155.73mmHg。而心率两个高峰期出现在1∶30～2∶00和20∶00～21∶00,高峰值分别为375.00次/分和373.26次/分;心率低谷出现在11∶00左右,谷底值为310.91次/分,白昼和夜间的平均心率分别为328.85次/分和346.05次/分。结论 3月龄的SHR大鼠血压和心律呈昼夜节律性变化,血压和心率在夜间出现两个高峰,白昼出现一个低谷,且夜间的平均血压和心率要高于白昼,SHR大鼠的血压和心率的节律变化与其活动有关。植入式遥测技术可准确反映SHR大鼠血压昼夜的节律性变化,有助于正确评价抗高血压药物的作用和高血压的生理机制研究。     

Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats

Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (V(max)) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg(-1)·day(-1) for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg (P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml (P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15-trans-EET was more potent (ED(50) 10(-10) M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED(50) 10(-9) M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and trans-isomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.     

Dihydroergotoxine decreases blood pressure in spontaneously hypertensive rats by interacting with peripheral dopamine receptors

Dihydroergotoxine (10 micrograms/kg s.c.) decreased mean carotid blood pressure in urethane-anaesthetized spontaneously hypertensive rats but failed to modify the same parameter in normotensive rats. The effect was statistically significant 20 min after the injection and relatively long lasting (up to 90 min). Pharmacological characterization of the phenomenon indicated that it is mediated by stimulation of dopamine receptors, since pretreatment with haloperidol, cis-flupentixol but not with trans-flupentixol, completely prevent the reduction in blood pressure induced by dihydroergotoxine. Moreover, a challenge dose of dihydroergotoxine did not reduce mean blood pressure values in spontaneously hypertensive rats pretreated with domperidone or (-)sulpiride, but not with (+)sulpiride. These results suggest that the ergot derivative modifies the cardiovascular system by interaction with peripheral dopamine receptors of the DA2 type.     

Regional blood flows and cardiac hemodynamics in renovascular and mineralocorticoid hypertensive rats

Regional blood flows and cardiac hemodynamics were studied in 3 models of hypertensive rats: one-kidney DOC-saline, one-kidney, one-clip and two-kidney, one-clip hypertension and in normotensive control rats. All hypertensive models were characterized by increased peripheral vascular resistance and normal cardiac output. Coronary and cerebral blood flows varied among the hypertensive models but did not significantly differ from the normotensive rats. However, coronary blood flow of one-kidney, one-clip rats (8.4 +/- 1.3 ml X min-1 X g-1) was significantly higher than that of the two-kidney one-clip rats (6.5 +/- 1.2 ml X min.-1 X g-1, P less than 0.05). Cerebral blood flow of DOC-saline rats was lower than that of two-kidney one-clip or one-kidney one-clip renovascular rats. Renal blood flows of the unclipped kidney of two-kidney renovascular rats (3.77 +/- 0.85 ml X min-1 X g-1) and DOC-saline rats (2.95 +/- 0.83 ml X min-1 X g-1) were significantly lower than those of normotensive rats (5.92 +/- 1.16 ml X min-1 X g-1, P less than 0.05). In conclusion, although vascular resistance becomes elevated in all models of experimental hypertension, regional vascular resistance and blood flow distribution may differ depending on the vasoconstrictor mechanisms that participate in each model.     

Gαq／11介导的细胞信号转导在两肾一夹肾性高血压大鼠主动脉中的变化

实验以两肾一夹肾性高血压大鼠为模型,研究主动脉Gαq/11倡导 的细胞信号转导的变化及其意义。制备两肾一夹肾性高血压大鼠模型,分别于术后第1、2、4和8周测定动脉血压,用免疫印迹法检测主动脉组织中Gαq/11亚单位和细胞个信号调节激酶1／2（ERK1／2）含量,测定磷脂酶C（phospholipase C,PLC)活性。结果显示高血压组大鼠于术后第2周血压开始升高;主动脉Gαq/11和ERK1／2含量于术后第1周增加（分别为57.53%和40.16%）,并维持在高水平（P＜0.01）;术后主动脉PLC活性亦增加（P＜0.05）。实验表明,肾素依赖性高血压能引起大鼠主动脉Gαq/11介导的细胞信号转导系统激活,并参与高血压的发生和发展。     

Differential inhibition of noradrenaline release mediated by inhibitory A1-adenosine receptors in the mesenteric vein and artery from normotensive and hypertensive rats

Mesenteric arteries and veins are densely innervated by sympathetic nerves and are crucial in the regulation of peripheral resistance and capacitance, respectively, thus, in the control of blood pressure. Presynaptic adenosine receptors are involved in vascular tonus regulation, by modulating noradrenaline release from vascular postganglionic sympathetic nerve endings. Some studies also suggest that adenosine receptors (AR) may have a role in hypertension. We aim at investigating the role of presynaptic adenosine receptors in mesenteric vessels and establish a relationship between their effects (in mesenteric vessels) and hypertension, using the spontaneously hypertensive rats (SHR) as a model of hypertension. Adenosine receptor-mediated modulation of noradrenaline release was investigated through the effects of selective agonists and antagonists on electrically-evoked [³H]-noradrenaline overflow. CPA (A₁AR selective agonist: 1–100 nM) inhibited tritium overflow, but the inhibition was lower in SHR mesenteric vessels. IB-MECA (A₃AR selective agonist: 1–100 nM) also inhibited tritium overflow but only in WKY mesenteric veins. CGS 21680 (A_2AAR selective agonist: up to 100 nM) failed to facilitate noradrenaline release in mesenteric veins, from both strains, but induced a similar facilitation in the mesenteric arteries. NECA (non-selective AR agonist: 1, 3 and 10 μM), in the presence of A₁ (DPCPX, 20 nM) and A₃ (MRS 1523, 1 μM) AR selective antagonists, failed to change tritium overflow. In summary, the modulatory effects mediated by presynaptic adenosine receptors were characterized, for the first time, in mesenteric vessels: a major inhibition exerted by the A₁ subtype in both vessels; a slight inhibition mediated by A₃ receptors in mesenteric vein; a facilitation mediated by A_2A receptors only in mesenteric artery (from both strains). The less efficient prejunctional adenosine receptor mediated inhibitory effects can contribute to an increase of noradrenaline in the synaptic cleft (both in arteries and veins), which might conduce to increased vascular reactivity.