Infective endocarditis caused by Salmonella enteritidis in a dialysis patient: a case report and literature review.

BACKGROUND: Infective endocarditis is significantly more common in haemodialysis patients as compared with the general population, the causative pathogen is generally Staphylococcus aureus; there have been no previously reported cases of infective endocarditis caused by a Salmonella species in haemodialysis patients. CASE PRESENTATION: We report the case of a 68 year-old woman on haemodialysis who developed infective endocarditis as a result of Salmonella enteritidis. Although we treated the patient with ceftriaxone combined with ciprofloxacin, infective endocarditis was not detected early enough and unfortunately developed into cerebral septic emboli, which ultimately resulted in death. CONCLUSION: Although there are several reports that Salmonella endocarditis without cardiac failure can be successfully treated with antibiotics alone, early surgical intervention is essential for some cases to prevent life-threatening complications. Transesophageal echocardiography should be performed in any patient with high clinical suspicion of infective endocarditis. To the best of our knowledge, this is the first case-report of Salmonella endocarditis in a haemodialysis patient.

Association of (pro)renin receptor mRNA expression with angiotensin-converting enzyme mRNA expression in human artery.

BACKGROUND/AIMS: A significant role of (pro)renin receptor in the pathogenesis of end-organ damage has been suggested only in animal studies. This study was conducted to examine the mRNA expression of (pro)renin receptor in human artery. METHODS: In 141 kidney failure patients, the mRNA was harvested from arterial fragments obtained during surgery constructing an arteriovenous access for hemodialysis therapy, and expression levels of (pro)renin receptor and other components of the renin-angiotensin system were determined. RESULTS: Arterial (pro)renin receptor expression was similar in diabetic and non-diabetic patients, although plasma prorenin levels were significantly higher in the diabetic patients than in the non-diabetic patients. The arterial (pro)renin receptor mRNA levels of the hypertensive patients, who had not been treated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers, were significantly lower than those of the patients who had been treated with either drug. Multiple regression analyses showed a significant association with a large coefficient between the arterial mRNA level of the (pro)renin receptor and the arterial mRNA level of ACE; this significant association disappeared in patients who had been treated with either drug. CONCLUSION: (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients.

Renin, prorenin and the kidney: a new chapter in an old saga.

The binding of prorenin to the (pro)renin receptor triggers 2 major pathways: a nonproteolytic conformational change in prorenin to its active form (angiotensin II-dependent pathway) and an intracellular pathway via the (pro)renin receptor itself (angiotensin II-independent pathway). In diabetic animals, an increased plasma prorenin level not only causes the generation of angiotensin II via the angiotensin II-dependent pathway, it also stimulates the transliteration receptors own intracellular signaling pathway in a manner that is independent of the generated angiotensin II. Thus, the administration of a "handle" region peptide (HRP), which acts as a decoy peptide and competitively inhibits the binding of prorenin to the (pro)renin receptor, has a beneficial effect in the kidneys of diabetic animals with low plasma renin levels. However, the benefits of HRP are slightly reduced in animal models of essential hypertension with relatively high plasma renin levels, and these benefits disappear altogether in animal models of hypertension with extremely high plasma renin levels. Thus, in the kidneys of animal models of diabetes and/or hypertension, both renin and prorenin competitively bind to the (pro)renin receptor and contribute to the pathophysiology of nephropathy. Consequently, renin, prorenin and the (pro) renin receptor may be important therapeutic targets for the prevention and regression of nephropathy in patients with diabetes and/or hypertension.

Add-on benefits of amlodipine and thiazide in nondiabetic chronic kidney disease stage 1/2 patients treated with valsartan.

Hypertension frequently requires combination therapy to attain efficient control to prevent cardiovascular diseases effectively. This study was conducted to determine which add-on treatment is better, namely calcium channel blockers or diuretics, in improving vascular damage. In 70 nondiabetic chronic kidney disease stage 1/2 patients who had been already treated with angiotensin II type 1 receptor blocker valsartan for at least 12 months, amlodipine or hydrochlorothiazide was added to their existing medication. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE), and 24-hour ambulatory blood pressure (BP) were determined before and 12 months after the start of add-on treatments. Add-on amlodipine and add-on hydrochlorothiazide significantly and similarly decreased 24-hour ambulatory BP by 18 and 19 mm Hg, respectively, PWV by 206 and 184 cm/s, respectively, and UAE, but did not change the IMT. The decreases in BP significantly contributed to the decreases in PWV and UAE and suggested that the decrease in serum cholesterol level brought about by add-on amlodipine also contributed to the decrease in UAE. These results suggest that 12 months of add-on treatment with either amlodipine or hydrochlorothiazide could have beneficial effects in nondiabetic chronic kidney disease stage 1/2 patients already being treated with valsartan.

Cardio-ankle vascular index and ankle pulse wave velocity as a marker of arterial fibrosis in kidney failure treated by hemodialysis.

BACKGROUND: Patients with kidney failure treated with hemodialysis have a high incidence of cardiovascular diseases caused by accelerated arteriosclerosis. However, accurate evaluation of the extent of arteriosclerosis is difficult. This study sought to compare the strength of predictions of arterial fibrosis by using a new parameter, the cardio-ankle vascular index (CAVI), versus pulse wave velocity (PWV) in patients with kidney failure treated with hemodialysis. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 103 patients with kidney failure undergoing surgical construction of an arteriovenous access for hemodialysis therapy. INDEX TEST: CAVI and PWV. REFERENCE TEST: Arterial fibrosis, evaluated by using Masson trichrome stain on part of the brachial artery obtained during surgery, expressed as percentage of fibrosis of the layer of vascular smooth muscle cells. RESULTS: Median percentage of arterial stiffness was 52.85%. Mean PWV and CAVI were 18.3 +/- 5.6 (SD) m/s and 9.9 +/- 2.6, respectively. Multivariate regression analysis showed that arterial fibrosis was significantly associated with older age (0.247%/y; 95% confidence interval, 0.013 to 0.482) and CAVI (6.117%/unit; 95% confidence interval, 4.764 to 4.740), but not with systolic blood pressure (0.039%/mm Hg; 95% confidence interval, -0.076 to 0.153) or PWV (-0.044%/m/s; 95% confidence interval, -0.646 to 0.558). The area under the receiver operating characteristic curve to predict greater than median percentage of arterial stiffness was 0.892 for CAVI and 0.779 for PWV (P = 0.006). LIMITATION: It is unclear whether arterial fibrosis of the brachial artery evaluated by using CAVI is applicable for arteriosclerosis of other arterial districts, and clinical outcomes were not evaluated in this study. CONCLUSION: CAVI reflects the histological arterial fibrosis of hemodialysis patients and is a useful clinical marker for evaluating arterial stiffness in these patients.

Involvement of (pro)renin receptor in the glomerular filtration barrier.

(Pro)renin receptor-bound prorenin not only causes the generation of angiotensin II via the nonproteolytic activation of prorenin, it also activates the receptor's own intracellular signaling pathways independent of the generated angiotensin II. Within the kidneys, the (pro)renin receptor is not only present in the glomerular mesangium, it is also abundant in podocytes, which play an important role in the maintenance of the glomerular filtration barrier. Recent in vivo studies have demonstrated that the overexpression of the (pro)renin receptor to a degree similar to that observed in hypertensive rat kidneys leads to slowly progressive nephropathy with proteinuria. In addition, the handle region peptide, which acts as a decoy peptide and competitively inhibits the binding of prorenin to the receptor, is more beneficial than an angiotensin-converting enzyme inhibitor with regard to alleviating proteinuria and glomerulosclerosis in experimental animal models of diabetes and essential hypertension. Thus, the (pro)renin receptor may be upregulated in podocytes under hypertensive conditions and may contribute to the breakdown of the glomerular filtration barrier.

The (pro)renin receptor and the kidney.

Prorenin binding to the (pro)renin receptor not only causes a nonproteolytic activation of prorenin leading to the activation of the renin-angiotensin system (RAS), but also stimulates the receptor's own intracellular signaling pathways independent of the RAS. Within the kidneys, the (pro)renin receptor is present in the glomerular mesangium and podocytes, which play an important role in the maintenance of the glomerular filtration barrier. Therefore, prorenin-receptor blockers, which competitively bind to the receptor as a decoy peptide, have superior benefits with regard to proteinuria and glomerulosclerosis in experimental animal models with elevated plasma prorenin levels such as diabetes and hypertension compared with conventional RAS inhibitors, possibly by inhibiting both the nonproteolytic activation of prorenin and RAS-independent intracellular signals.

Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade.

Activation of prorenin by (pro)renin receptor stimulates the tissue renin-angiotensin system and plays a significant role in the development of nephropathy in diabetic animals. This study examined whether (pro)renin receptor blockade inhibits the progression of nephropathy that has already developed in diabetic rats. Seventeen-week-old heminephrectomized streptozotocin-induced diabetic rats with an increased urinary protein excretion and a significant glomerulosclerosis had been treated for 12 wk with the (pro)renin receptor blocker (PRRB), angiotensin-converting enzyme inhibitor (ACEi), or vehicle peptide by using subcutaneously implanted osmotic minipumps. At the end of observation, in diabetic rats that were treated with vehicle, urinary protein excretion was progressively increased and a significant progression of glomerulosclerosis was observed. In diabetic rats that were treated with PRRB, however, no further increase in urinary protein excretion or glomerulosclerosis was observed, but 12-wk treatment with ACEi only attenuated further increases in urinary protein excretion and glomerulosclerosis. The enhanced expression of activated prorenin was observed in the kidneys of diabetic rats that were treated with vehicle, whereas it was markedly suppressed in the kidneys of diabetic rats that were treated with PRRB but not ACEi. These results suggest that (pro)renin receptor blockade does not only inhibit the progression of nephropathy but also reverses the glomerulosclerosis that has already developed in diabetic rats.

Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats.

For defining the pathogenic effects of the (pro)renin receptor-transgenic rat, strains that overexpressed the human receptor were generated. Although transgenic rats were normotensive and euglycemic and had a renal angiotensin II (AngII) level that was comparable to that of wild-type rats, transgenic rats developed proteinuria with aging and significant glomerulosclerosis at 28 wk of age. In kidneys of 28-wk-old transgenic rats, mitogen-activated protein kinases (MAPK) were activated without recognizable tyrosine phosphorylation of the EGF receptor, and expression of TGF-beta1 was enhanced. In vivo infusion of the (pro)renin receptor blocker peptide (formerly handle region decoy peptide) significantly inhibited the development of glomerulosclerosis, proteinuria, MAPK activation, and TGF-beta1 expression in the kidneys, but the angiotensin-converting enzyme inhibitor did not attenuate these changes despite a significant decrease in the renal AngII level. In addition, recombinant rat prorenin stimulated MAPK activation in the human receptor-expressed cultured cells, but human receptor was unable to evoke the enzyme activity of rat prorenin. Thus, human (pro)renin receptor elicits slowly progressive nephropathy by AngII-independent MAPK activation in rats. This study clearly provided in vivo evidence for the AngII-independent MAPK activation by human (pro)renin receptor and induction of glomerulosclerosis with increased TGF-beta1 expression.

Add-on amlodipine improves arterial function and structure in hypertensive patients treated with an angiotensin receptor blocker.

The present study was designed to determine whether adding amlodipine further improved functional and structural cardiovascular damage in hypertensive patients whose blood pressure was already well controlled with an angiotensin II type 1 receptor blocker (ARB). The cardiothoracic ratio on chest radiographs, level of urinary albumin excretion, pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, and 24 hour ambulatory blood pressure (BP) were evaluated before and 12 months after the start of add-on of amlodipine or placebo in 50 hypertensive patients being treated with an ARB. The add-on amlodipine therapy significantly improved the PWV from 1689 +/- 61 to 1447 +/- 47 cm/s and the IMT from 0.88 +/- 0.08 to 0.75 +/- 0.06 mm in the hypertensive patients treated with an ARB without altering their mean 24 hour ambulatory BP values, but did not alter the cardiothoracic ratio or urinary albumin excretion. Amlodipine also significantly decreased the variability of ambulatory BP, but the decrease did not significantly contribute to the changes in PWV or IMT. Thus, the add-on low-dose amlodipine therapy had benefits in terms of the vascular function and vascular structure of hypertensive patients treated with an ARB that were independent of its depressor effects. The antiatherogenic pleiotropic properties of amlodipine have a preventive effect on the progression of arterial stiffness in hypertensive patients treated with an ARB.

(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells.

Blockade of (pro)renin receptor has benefits in diabetic angiotensin II type-1a-receptor-deficient mice, suggesting the importance of (pro)renin receptor-mediated intracellular signals. To determine the mechanism whereby the human (pro)renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK) in a dose- and time-dependent manner but did not influence activation of p38 or c-Jun NH(2)-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro)renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro)renin receptor-mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.

Benefits of candesartan on arterial and renal damage of non-diabetic hypertensive patients treated with calcium channel blockers.

BACKGROUND/AIM: Although long-term, intensive blood pressure (BP) control with calcium channel blockers (CCBs) reduced arterial stiffness and renal damage of hypertensive patients, combination therapy with antihypertensive drugs is frequently needed to maintain the intensive BP control. The present study was conducted to examine add-on benefits of candesartan therapy on hypertensive patients treated with CCBs for at least 12 months. METHODS: Pulse wave velocity (PWV), urinary albumin excretion (UAE), intima-media thickness (IMT) of the carotid arteries, and 24-hour ambulatory BP were determined in 50 non-diabetic hypertensive patients treated with CCBs before and 12 months after the start of therapy with candesartan or placebo. RESULTS: Candesartan significantly decreased clinic BP and tended to decrease ambulatory BP, but the decreases were similar to those in the placebo group except nocturnal BP decrease, which was significantly enhanced by candesartan. Add-on candesartan significantly decreased PWV and UAE compared to placebo, but IMT was unchanged with candesartan or placebo. The decrease in clinic BP or nocturnal BP decrease did not contribute to the improvement of PWV or UAE. CONCLUSION: Add-on candesartan functionally improved the stiffened arteries of hypertensive patients treated with CCBs by the end of 12 months of treatment independently of its effects on BPs.

Prorenin receptor blockers: effects on cardiovascular complications of diabetes and hypertension.

When the 'handle region' of the prorenin prosegment interacts with the (pro)renin receptor, the prorenin molecule partially changes the conformation to an enzymatically active state. On the other hand, the receptor triggers its own intracellular signalling pathways independent of the renin-angiotensin system (RAS). The 'handle region' peptide competitively binds to the receptor as a decoy peptide and inhibits both the non-proteolytic activation of prorenin and the RAS-independent intracellular signals. Therefore, prorenin receptor blockers including the decoy peptide may have superior benefits on end-organ damage in diabetes and hypertension compared with conventional RAS inhibitors.

Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage.

Prorenin is activated without proteolysis by binding of prorenin receptor to the pentameric "handle region" (HR) of prorenin prosegment. It was hypothesized that such activation occurs in the kidneys of hypertensive rats and causes tissue renin-angiotensin system (RAS) activation and end-organ damage. Because the HR's binding to its binding protein made the adjacent tetrameric "gate region" (GR) accessible to its specific antibody, immunohistochemistry of the GR was performed to test the hypothesis. Methods also were devised specifically to inhibit the nonproteolytic activation by the decapeptide corresponding to the HR as a decoy. Immunohistochemistry of the GR demonstrated that the majority of nonproteolytically activated prorenin is present in podocytes of the kidneys from stroke-prone spontaneously hypertensive rats, in which activation of renal tissue RAS, proteinuria, and glomerulosclerosis occurred. Continuous subcutaneous administration of the HR decoy peptide completely inhibited both nonproteolytic activation of tissue prorenin and activation of tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of proteinuria and glomerulosclerosis. These studies clearly demonstrated that nonproteolytic activation of prorenin in glomeruli is critically involved in renal tissue RAS activation, leading to renal damage in hypertensive animals.

Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice.

Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy.

Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension.

In contrast to proteolytic activation of inactive prorenin by cleavage of the N-terminal 43 residue peptide, we found that prorenin is activated without proteolysis by binding of the prorenin receptor to the pentameric "handle region" I(11P)LLKK(15P). We hypothesized that such activation occurs in hypertensive rats and causes cardiac renin-angiotensin system (RAS) activation and end-organ damage. To test this hypothesis, we devised methods of specifically inhibiting nonproteolytic activation by decapeptide spanning the pentameric handle region peptide as a decoy. In stroke-prone spontaneously hypertensive rats (SHRsp) fed a high-salt diet, arterial pressure started to rise significantly with a marked increase in the cardiac prorenin receptor mRNA level at 8 weeks of age, and cardiac fibrosis had developed by 12 weeks of age. By immunohistochemistry using antibodies to the active site of the renin molecule, we demonstrated increased proteolytic or nonproteolytic activation of prorenin in the heart but not in plasma of SHRsp. Continuous subcutaneous administration of the handle region peptide completely inhibited the increased staining by antibodies to the active site of the renin molecule, indicating the increased nonproteolytic but not proteolytic activation of prorenin in the heart of SHRsp. Administration of the handle region peptide also inactivated tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of cardiac fibrosis. These results clearly demonstrate the significant role of nonproteolytically activated tissue prorenin in tissue RAS activation leading to cardiac fibrosis and significant inhibition of the cardiac damage produced by chronic infusion of the handle region peptide.

Low doses of losartan and trandolapril improve arterial stiffness in hemodialysis patients.

BACKGROUND: Hemodialysis patients have uremic dyslipidemia, represented by elevated serum intermediate-density lipoprotein cholesterol (IDL-C) levels, and an increased cardiovascular mortality rate. This study was performed to determine the low-dose effects of the angiotensin II receptor blocker losartan and the angiotensin-converting enzyme inhibitor trandolapril on pulse wave velocity (PWV), which predicts cardiovascular morbidity and mortality in hemodialysis patients. METHODS: Serum lipid levels and PWV were monitored for 12 months in 64 hemodialysis patients who were administered low doses of losartan or trandolapril or a placebo. RESULTS: At the start of the study, there were no differences in patient characteristics among the 3 groups. PWV tended to increase in the placebo group during the 12-month study period, but decreased significantly in the losartan and trandolapril groups, and decreases in PWV were similar in the losartan and trandolapril groups. There were no changes in blood pressure, hematocrit, erythropoietin dose, ankle-brachial index, serum lipid levels, serum 8-isoprostane levels, or serum C-reactive protein levels during the 12-month study period, but there was an increase in serum triglyceride levels in the losartan group and a decrease in serum IDL-C levels in the losartan and trandolapril groups. CONCLUSION: In hemodialysis patients, trandolapril is as effective as losartan in decreasing PWV independent of its depressor effect and in suppressing elevated IDL-C levels. Long-term blockade of the renin-angiotensin system may have a beneficial effect on the acceleration of atherosclerosis and uremic dyslipidemia.

Ovariectomy enhances renal cortical expression and function of cyclooxygenase-2.

BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors are used as analgesics in postmenopausal women, who develop edema and require a salt-restricted diet. This study was performed to determine the renal expression of COX-2 and on COX-2-dependent regulation of renal blood flow (RBF) in ovariectomized rats. METHODS: Sprague-Dawley rats were divided into 4 groups: sham-operated rats fed a normal-salt diet (Sh+NS) or a low-salt diet (Sh+LS), and bilaterally ovariectomized rats fed a normal-salt diet (Ox+NS) or a low-salt diet (Ox+LS) (N= 6 in each group). Estrogen replacement therapy was performed on other ovariectomized rats. A renal clearance study was performed in anesthetized animals. RESULTS: Ovariectomy increased renal cortical COX-2 expression independently of dietary salt intake (Sh+NS

Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin.

We found that when a site-specific binding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage.

Anandamide decreases glomerular filtration rate through predominant vasodilation of efferent arterioles in rat kidneys.

For determining the effects of anandamide (ANA) on renal hemodynamics and microcirculation, a clearance study was performed in Sprague-Dawley rats that received injections of ANA in doses of 15, 150, and 1500 pmol/kg. At doses up to 150 pmol/g, ANA significantly decreased GFR and increased renal blood flow (RBF) without affecting mean arterial pressure (MAP). In the presence of the cannabinoid type 1 (CB1) receptor antagonist AM251, only the 15-pmol/kg dose significantly increased GFR and RBF without altering MAP, with higher doses having no effect on GFR, RBF, or MAP. By contrast, AM281, which antagonizes cannabinoid receptors nonselectively, inhibited the GFR, RBF, and MAP responses to ANA. The arteriolar responses to ANA were also assessed in vitro by the blood-perfused juxtamedullary nephron technique. Higher doses of ANA significantly increased the diameter of both afferent and efferent arterioles, whereas lower doses elicited predominant efferent arteriolar dilation. AM251 attenuated the afferent arteriolar response to ANA and inhibited the efferent arteriolar response to ANA, whereas AM281 inhibited the responses in both arterioles. The CB1 receptor mRNA was expressed in afferent arterioles, and immunohistochemical staining demonstrated the presence of CB1 receptors in both afferent and efferent arterioles. These results suggest that ANA causes afferent arteriolar dilation via both CB1 and non-CB1 receptors and greater efferent arteriolar dilation via CB1 receptors, resulting in a decreased GFR and an increased RBF without affecting MAP.