Control Of Vasomotor Tone Research Articles

Exploration biologique de la fonction endothéliale

The endothelium plays a central role in the maintenance of cardiovascular homeostasis through the expression of numerous receptors or adhesion molecules on the cell membrane, as well as through the synthesis and release of various vasoactive substances. The evaluation of endothelial integrity is based in particular on the quantification of circulating factors synthesized by endothelial cells or regulating their activity, notably those involved in the control of vasomotor tone, coagulation and fibrinolysis processes and inflammation phenomena. The methods of analysis are generally enzyme immunoassays or by mass spectrometry and are carried out on blood or urine samples allowing a non-invasive systemic evaluation of endothelial function. The use of these biomarkers is therefore particularly suitable for clinical studies carried out on large numbers of subjects, particularly during multi-centre intervention trials.

Sensory innervation of perivascular adipose tissue: a crucial role in artery vasodilatation and leptin release.

Electrical field stimulation (EFS) elicits robust sensory neurogenic relaxation responses in the rat isolated mesenteric arterial bed but these responses are absent or difficult to demonstrate in isolated arteries. We believe that this mismatch is due to the absence of perivascular adipose tissue (PVAT) as it is conventionally removed in studies on isolated vessels. We aimed to determine whether sensory nerves are expressed in PVAT, their physiological roles and their possible interactions with PVAT-derived adipokines. Using confocal imaging, enzyme immunoassay (EIA), myography, vascular perfusion, and multiplex analysis of rat mesenteric arteries, we show that PVAT is crucial for the roles of sensory nerves in control of vasomotor tone and adipokine release. Immunofluorescence double staining showed co-expression of calcitonin gene-related peptide (CGRP; sensory neurotransmitter) and PGP9.5 (neuronal marker) in PVAT of mesenteric arteries. CGRP release from dissected PVAT, measured using EIA, was increased by capsaicin which activates sensory nerves. EFS in both mesenteric arteries and perfused mesenteric arterial beds, with and without PVAT, demonstrated neurogenic relaxation in the presence of PVAT, which was greatly attenuated in preparations without PVAT. Neurogenic relaxation due to EFS was associated with release of leptin in PVAT-intact mesenteric arterial beds, which was abolished in preparations without PVAT. Exposure to low oxygen was associated with an attenuated leptin and adiponectin release, but an increase in IL-6 release, from mesenteric arterial beds. Exogenous leptin augmented relaxation to CGRP in mesenteric arteries. These data show, for the first time, expression of sensory nerves within PVAT and that PVAT is crucial for sensory neurogenic vasorelaxation and crosstalk with adipocytes leading to leptin release, which may augment CGRP-mediated relaxation; leptin release is abolished after exposure to conditions of reduced oxygenation.

Chronic fluoxetine treatment increases NO bioavailability and calcium-sensitive potassium channels activation in rat mesenteric resistance arteries

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has effects beyond its antidepressant properties, altering, e.g., mechanisms involved in blood pressure and vasomotor tone control. Although many studies have addressed the acute impact of fluoxetine on the cardiovascular system, there is a paucity of information on the chronic vascular effects of this SSRI. We tested the hypothesis that chronic fluoxetine treatment enhances the vascular reactivity to vasodilator stimuli by increasing nitric oxide (NO) signaling and activation of potassium (K+) channels. Wistar rats were divided into two groups: (I) vehicle (water for 21 days) or (II) chronic fluoxetine (10mg/kg/day in the drinking water for 21 days). Fluoxetine treatment increased endothelium-dependent and independent vasorelaxation (analyzed by mesenteric resistance arteries reactivity) as well as constitutive NO synthase (NOS) activity, phosphorylation of eNOS at Serine1177 and NO production, determined by western blot and fluorescence. On the other hand, fluoxetine treatment did not alter vascular expression of neuronal and inducible NOS or guanylyl cyclase (GC). Arteries from fluoxetine-treated rats exhibited increased relaxation to pinacidil. Increased acetylcholine vasorelaxation was abolished by a calcium-activated K+ channel (KCa) blocker, but not by an inhibitor of KATP channels. On the other hand, vascular responses to Bay 41-2272 and 8-bromo-cGMP were similar between the groups. In conclusion, chronic fluoxetine treatment increases endothelium-dependent and independent relaxation of mesenteric resistance arteries by mechanisms that involve increased eNOS activity, NO generation, and KCa channels activation. These effects may contribute to the cardiovascular effects associated with chronic fluoxetine treatment.

The heart cannot pump blood that it does not receive.

The heart cannot pump blood that it does not receive.

Gap junction regulation of vascular tone: implications of modulatory intercellular communication during gestation.

In the vasculature, gap junctions (GJ) play a multifaceted role by serving as direct conduits for cell-cell intercellular communication via the facilitated diffusion of signaling molecules. GJs are essential for the control of gene expression and coordinated vascular development in addition to vascular function. The coupling of endothelial cells to each other, as well as with vascular smooth muscle cells via GJs, plays a relevant role in the control of vasomotor tone, tissue perfusion and arterial blood pressure. The regulation of cell-signaling is paramount to cardiovascular adaptations of pregnancy. Pregnancy requires highly developed cell-to-cell coupling, which is affected partly through the formation of intercellular GJs by Cx43, a gap junction protein, within adjacent cell membranes to help facilitate the increase of uterine blood flow (UBF) in order to ensure adequate perfusion for nutrient and oxygen delivery to the placenta and thus the fetus. One mode of communication that plays a critical role in regulating Cx43 is the release of endothelial-derived vasodilators such as prostacyclin (PGI2) and nitric oxide (NO) and their respective signaling mechanisms involving second messengers (cAMP and cGMP, respectively) that are likely to be important in maintaining UBF. Therefore, the assertion we present in this review is that GJs play an integral if not a central role in maintaining UBF by controlling rises in vasodilators (PGI2 and NO) via cyclic nucleotides. In this review, we discuss: (1) GJ structure and regulation; (2) second messenger regulation of GJ phosphorylation and formation; (3) pregnancy-induced changes in cell-signaling; and (4) the role of uterine arterial endothelial GJs during gestation. These topics integrate the current knowledge of this scientific field with interpretations and hypotheses regarding the vascular effects that are mediated by GJs and their relationship with vasodilatory vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion and blood flow observed during normal pregnancy.

Ca2+‐activated K+ channels of small and intermediate conductance control the activation of endothelial cell connexin‐ and pannexin‐formed hemichannels

Nitric Oxide (NO), Ca2+‐activated K+ channels (KCa) of small (SKCa) and intermediate (IKCa) conductance and hemichannels formed by connexins (Cx‐HC) or pannexins (Panx‐HC) are involved in the control of vasomotor tone. However, the mechanisms of Cx‐ and Panx‐based hemichannel activation in endothelial cells are unknown. In mesenteric vessels, we evaluated the expression and activity of Cx‐HC and Panx‐HC by immunofluorescence, biotinylation of membrane proteins of endothelial cell luminal surface and ethidium uptake. Cx37, Cx40, Cx43 and Panx‐1 were detected in endothelial cells. Stimulation with acetylcholine (ACh) or the NO‐donor S‐nitroso‐N‐acetyl‐D‐penicillamine (SNAP) increased ethidium uptake in endothelial cells, which was abolished by the NO synthase inhibitor NG‐nitro‐L‐arginine (L‐NA) or by the Panx‐HC blockers probenecid and Panx10 and attenuated by the Cx‐HC blocker La3+. In addition, ACh‐activated ethidium uptake was also abolished by blockade of KCa with tetraethylammonium (TEA) or IKCa with charybdotoxin (ChTX) or triarylmethane‐34(TRAM‐34), but only attenuated by the SKCa blocker apamin. TEA did not affect the SNAP‐activated ethidium uptake. Treatment with TEA, ChTX or apamin also inhibits the ACh‐induced NO production. These results indicate that SKCa and IKCa regulate the activity of Cx‐HC and Panx‐HC through the modulation of NO production.FONDECYT 1100850, ANILLOS ACT‐71

Differential roles of NADPH oxidases in vascular physiology and pathophysiology

Reactive oxygen species (ROS) are produced by all vascular cells and regulate the major physiological functions of the vasculature. Production and removal of ROS are tightly controlled and occur in discrete subcellular locations, allowing for specific, compartmentalized signaling. Among the many sources of ROS in the vessel wall, NADPH oxidases are implicated in physiological functions such as control of vasomotor tone, regulation of extracellular matrix and phenotypic modulation of vascular smooth muscle cells. They are involved in the response to injury, whether as an oxygen sensor during hypoxia, as a regulator of protein processing, as an angiogenic stimulus, or as a mechanism of wound healing. These enzymes have also been linked to processes leading to disease development, including migration, proliferation, hypertrophy, apoptosis and autophagy. As a result, NADPH oxidases participate in atherogenesis, systemic and pulmonary hypertension and diabetic vascular disease. The role of ROS in each of these processes and diseases is complex, and a more full understanding of the sources, targets, cell-specific responses and counterbalancing mechanisms is critical for the rational development of future therapeutics.

Blood Pressure Patterns After Brain Death

The control of vasomotor tone by the rostral ventrolateral medulla oblongata is lost in brain death. Hypotension is not an obligate clinical sign in brain death criteria, because an adequate intravascular volume may temporarily overcome this decrease in blood pressure. However, such an unstable situation is bound to collapse.1,2 Anticipatory knowledge of changes in blood pressure is important to physicians who perform brain death examinations. Delay in declaration of brain death in a hemodynamically unstable patient may jeopardize procurement and prompt pharmaceutical support to maintain adequate blood pressures is required.3,–,5 We aimed to characterize hemodynamic patterns after brain death. We identified patients from a database maintained by our organ procurement organization (LifeSource). Brain death was declared according to a hospital protocol in compliance with the American Academy of Neurology guidelines.6 The use of methylprednisolone and T4 infusions was standardized in 2005. We excluded patients who did not undergo organ procurement and died quickly after admission, and young children (<10 years old). The records of patients who were declared brain dead from 1997 to 2010 were retrospectively reviewed. Blood …

Hypoxia. 4. Hypoxia and ion channel function.

The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes.

Key role of Ca2+‐activated K+ channels of small and intermediate conductance in the NO signaling of resistance vessels

Ca2+‐activated K+ channels (KCa) and nitric oxide (NO) play a central role in the control of vasomotor tone in resistance arteries. To evaluate the contribution of KCa channels to NO‐mediated dilation, we analyzed the vasomotor responses and NO production (chemiluminiscence) induced by the endothelium‐dependent vasodilator, acetylcholine (ACh), or the Ca2+ ionophore, ionomycin, in isolated arterial mesenteric bed of rat. ACh (0.01–10μM) elicited a concentration‐dependent vasodilatation. In phenylephrine‐contracted mesenteries, NO synthase (NOS) inhibition with Nω‐nitro‐L‐arginine (L‐NA) reduced the response to ACh. Blockade of KCa channels with tetraethylammonium (TEA) or inward rectifier K+ channels with Ba2+ blunted the response to ACh. L‐NA inhibited the ACh‐induced relaxation in presence of Ba2+, but not TEA. In addition, TEA blocked the NO production induced by ACh. In KCl‐contracted vessels, the relaxation‐elicited by ACh or 1μM ionomycin was abolished by L‐NA and inhibited by TEA or simultaneous blockade of KCa channels of small (SKCa) and intermediate (IKCa) conductance with apamin and TRAM‐34, respectively. Apamin and TRAM‐34 also abolished the NO production activated by 100nM ACh. These results indicate that functional SKCa and IKCa channels are required for Ca2+‐mediated eNOS activation. Membrane hyperpolarization is not involved in the regulation of NO production by these channels.VRAID 15/2009

NO production and eNOS phosphorylation induced by epinephrine through the activation of β-adrenoceptors

Epinephrine plays a key role in the control of vasomotor tone; however, the participation of the NO/cGMP pathway in response to beta-adrenoceptor activation remains controversial. To evaluate the involvement of the endothelium in the vascular response to epinephrine, we assessed NO production, endothelial NO synthase phosphorylation, and tissue accumulation of cGMP in the perfused arterial mesenteric bed of rat. Epinephrine elicited a concentration-dependent increase in NO (EC(50) of 45.7 pM), which was coupled to cGMP tissue accumulation. Both NO and cGMP production were blocked by either endothelium removal (saponin) or NO synthase inhibition (N(omega)-nitro-L-arginine). Blockade of beta(1)- and beta(2)-adrenoceptors with 1 microM propranolol or beta(3)-adrenoceptor with 10 nM SR 59230A displaced rightward the concentration-NO production curve evoked by epinephrine. Selective stimulation of beta(1)-, beta(2)-, or beta(3)-adrenoceptors also resulted in NO and cGMP production. Propranolol (1 microM) inhibited the rise in NO induced by isoproterenol or the beta(2)-adrenoceptor agonists salbutamol, terbutaline, or fenoterol. Likewise, 10 nM SR 59230A reduced the effects of the beta(3)-adrenoceptor agonists BRL 37344, CGP 12177, SR 595611A, or pindolol. The NO production induced by epinephrine and BRL 37344 was associated with the activation of the phosphatidylinositol 3-kinase/Akt pathway and phosphorylation of eNOS in serine 1177. In addition, in anaesthetized rats, bolus administration of isoproterenol, salbutamol, or BRL 37344 produced NO-dependent reductions in systolic blood pressure. These findings indicate that beta(1)-, beta(2)-, and beta(3)-adrenoceptors are coupled to the NO/cGMP pathway, highlighting the role of the endothelium in the vasomotor action elicited by epinephrine and related beta-adrenoceptor agonists.

The consensus statement on the definition of orthostatic hypotension: a revisit after 13 years

The consensus statement on the definition of orthostatic hypotension: a revisit after 13 years

J008 Vascular smooth muscle modulates endothelial control of vasoreactivity via ros production through myoendothelial communications

Endothelial control of vascular smooth muscle plays a major role in the resulting vasoreactivity implicated in physiological or pathological circulatory processes. However, a comprehensive understanding of endothelial (EC) / smooth muscle cells (SMC) crosstalk is far from complete. Here, we have examined the role of gap junctions in this crosstalk and we demonstrate an active contribution of SMC to endothelial control of vasomotor tone. In small intrapulmonary arteries, quantitative RT-PCR, Western Blot analyses revealed the presence of 3 connexins (Cx): 37, 40 and 43. Immunofluorescence labelling showed the presence of Cx 37, 40 and 43 in EC and the presence of Cx 37 and 40 in SMC. Functional experiments showed that the peptides homologous to the gap 26 and 27 domains of the extracellular loops of Cx 43 (43Gap 26) or Cx 37 and 43 (37-43Gap 27) respectively, (1) interrupt intercellular communications in a specific manner, (2) attenuate the calcium and contractile responses to serotonin (5-HT) simultaneously recorded in pulmonary arteries and (3) abolish the diffusion in SMC of carboxyfluorescein-AM loaded in EC. Similarly, contractile and calcium responses to 5-HT were decreased by superoxide dismutase and catalase which, catabolize superoxide anion (O2•-) and H2O2, respectively. Both Cx- and reactive oxygen species (ROS)-mediated effects on the responses to 5-HT were reversed by (1) L-NAME, a NO synthase inhibitor, or (2) endothelium removal with CHAPS. Electron paramagnetic resonance directly demonstrated that 5-HTinduced ROS production, and more specifically O2•-, originated from the SMC. Finally, 5-HT decreased basal cyclic GMP content in isolated intact arteries, whereas a cocktail of 5-HT, superoxide dismutase and catalase increased basal cyclic GMP content. Altogether, the findings suggest that 5-HT produces O2•- in the smooth muscle and NO in the endothelium. O2•- passes through the myoendothelial junctions to decrease endothelial NO production and thus strengthen pulmonary vasoreactivity. This is the first time that we demonstrate a control of the endothelial NO function by the smooth muscle is demonstrated. Since ROS is often overproduced in many cardiovascular diseases, such process could also be of great importance in pathological conditions.

Gap Junctions in the Control of Vascular Function

Direct intercellular communication via gap junctions is critical in the control and coordination of vascular function. In the cardiovascular system, gap junctions are made up of one or more of four connexin proteins: Cx37, Cx40, Cx43, and Cx45. The expression of more than one gap-junction protein in the vasculature is not redundant. Rather, vascular connexins work in concert, first during the development of the cardiovascular system, and then in integrating smooth muscle and endothelial cell function, and in coordinating cell function along the length of the vessel wall. In addition, connexin-based channels have emerged as an important signaling pathway in the astrocyte-mediated neurovascular coupling. Direct electrical communication between endothelial cells and vascular smooth muscle cells via gap junctions is thought to play a relevant role in the control of vasomotor tone, providing the signaling pathway known as endothelium-derived hyperpolarizing factor (EDHF). Consistent with the importance of gap junctions in the regulation of vasomotor tone and arterial blood pressure, the expression of connexins is altered in diseases associated with vascular complications. In this review, we discuss the participation of connexin-based channels in the control of vascular function in physiologic and pathologic conditions, with a special emphasis on hypertension and diabetes.

Contribution of endothelium‐derived hyperpolarizing factors to the regulation of vascular tone in humans

Endothelium plays a crucial role in the regulation of cardiovascular homeostasis through the release of vasoactive factors. Besides nitric oxide (NO) and prostacyclin, increasing evidences show that endothelium-derived hyperpolarizing factors (EDHF) participate in the control of vasomotor tone through the activation of calcium-activated potassium channels. In humans, the role of EDHF has been demonstrated in various vascular beds including coronary, peripheral, skin and venous vessels. The mechanisms of EDHF-type relaxations identified in humans involved the release by the endothelium of hydrogen peroxide, epoxyeicosatrienoic acids (EETs), potassium ions and electronical communication through the gap junctions. The role of EETs could be particularly important because, in addition contributing to the maintenance of the basal tone and endothelium-dependent dilation of conduit arteries, these factors share many vascular protective properties of NO. The alteration of which might be involved in the physiopathology of cardiovascular diseases. The evolution of EDHF availability in human pathology is currently under investigation with some results demonstrating an increase in EDHF release to compensate the loss of NO synthesis and to maintain the endothelial vasomotor function whereas others reported a parallel decrease in NO and EDHF-mediated relaxations. Thus, the modulation of EDHF activity emerges as a new pharmacological target and some existing therapies in particular those affecting the renin-angiotensin system have already been shown to improve endothelial function through hyperpolarizing mechanisms. In this context, the development of new specific pharmacological agents especially those increasing EETs availability may help to prevent endothelial dysfunction and therefore enhance cardiovascular protection in patients.

Vascular Gap Junctions in Hypertension

The proteins that form the gap junctions (connexins) are widely expressed in organs that are central to the development of hypertension: endocrine organs, kidney, brain, heart, and vasculature (Figure 1). Surprisingly, there is little information on the modification of connexins in hypertension in any of these organs except the vasculature, the subject of our review, but it would be hoped that this lack of information might spur research on these organs. Figure 1. Possible roles for the connexins in the control of blood pressure. A, Electron micrograph of a longitudinal view of an arteriole. Vascular connexins can play multiple roles in regulating function and vasomotor tone. Cell–cell communication, both radial and longitudinal, links the cells of the arteriolar wall. B, Most every organ involved in the control of blood pressure abundantly expresses ≥1 of the connexins. Essentially no experimental evidence exists regarding a possible link between connexins and hypertension in nonvascular tissues. Augmented vasomotor tone typically plays a key role in the development of hypertension, and tone depends on cell–cell communication established by paracrine molecules and, in addition, gap junctions. Paracrine-based linkages between cells of the vasculature are well known, and the possible roles of such linkages in the genesis of hypertension have been extensively explored. Much less is known of the roles of gap junctional communication in establishing vasomotor tone and of the effects of modification of gap junctions on hypertension. The gap junctions are formed by joining 2 hexameric assemblies of connexin protein monomers, that is, hemichannels (1 in Figure 2A). In the vasculature, assays of message and protein show that the hemichannels can be assembled from combinations of 4 connexins, named according to their apparent molecular weight: Cx37, Cx40, Cx43, and Cx45. Two hemichannels are linked to form a gap junction, which can provide both homocellular …

Circadian Blood Pressure and Heart Rate Changes in Patients in a Persistent Vegetative State After Traumatic Brain Injury

Alteration of autonomic nervous system regulation is known to be present in the persistent vegetative state after traumatic brain injury, termed the dysautonomic syndrome. This study assessed the circadian blood pressure and heart rate pattern and variability in the persistent vegetative state through noninvasive 24-hour ambulatory blood pressure monitoring. The study was performed in 20 subjects: 10 patients (six men and four women; mean age, 29.5+/-9.9 years; range, 19-39 years) in a vegetative state (mean, 27.3+/-5.6 days after trauma) and 10 healthy subjects as controls (six men and four women; mean age, 28+/-5.7 years; range, 29-37 years). The patients showed a blood pressure nondipper pattern; 24-hour, daytime, and nighttime values of blood pressure and heart rate were significantly higher in patients than in controls. The day-night difference in heart rate and blood pressure was also significantly lower in patients. Finally, SD and variation coefficients were significantly lower in patients. The results show changes in the variability and circadian blood pressure and heart rate patterns in persistent vegetative state patients with dysautonomic syndrome, as an expression of the sympathetic-parasympathetic activity imbalance in the control of vasomotor tone.

A role for caveolae in cell migration

Caveolae are specialized plasma membrane subdomains capable of transport and sophisticated compartmentalization of cell signaling. Numerous cell functions, including cell type-specific functions, involve caveolae and require caveolin-1, the major protein component of these organelles. Caveolae are particularly abundant in endothelial cells and participate in endothelial transcytosis, vascular permeability, vasomotor tone control, and vascular reactivity. Caveolin-1 drives the formation of plasma membrane caveolae and anchors them to the actin cytoskeleton, modulates cell interaction with the extracellular matrix, pulls together and regulates signaling molecules, and transports cholesterol. Via these functions, caveolin-1 might play an important role in cell movement through control of cell membrane composition and membrane surface expansion, polarization of signaling molecules and matrix proteolysis, and/or cytoskeleton remodeling. Caveolae and caveolin-1 are polarized in migrating endothelial cells, indicating they may play a role in cell motility. Several studies have shown that manipulation of caveolin-1 expression affects cell migration in a complex way. We are reviewing the current data and hypotheses in favor of an essential role for caveolae in cell migration.

Transneuronal tracing from sympathectomized lumbar epaxial muscle in female rats.

Pseudorabies virus (PRV) has been used as a transneuronal tracer to study central neural networks, including the central control of the lordosis-producing, lumbar epaxial muscles. Within muscles, however, the sympathetic innervation of blood vessels poses a confounding source of tracer labeling in the CNS. The present study destroyed sympathetic nerves before injection of PRV, thereby allowing for a more selective uptake by somatic motoneurons. Specifically, a focal sympathectomy was created by the injection of dopamine-beta-hydroxylase immunotoxin (DHIT). When PRV was injected into control rats, both somatic motoneurons within the ventral horn of the spinal cord and sympathetic preganglionic neurons within the intermediolateral column (IML) of the spinal cord became labeled. Additionally, labeled neurons were observed in many brain regions, including those previously implicated in the control of the lordosis reflex (e.g., the medullary reticular formation; MRF) and those previously implicated in the control of vasomotor tone (e.g., the rostral ventrolateral medulla; RVLM). When injected into DHIT-pretreated animals, PRV labeling in ventral horn neurons persisted in many animals; however, labeling in IML was eliminated in almost every case. In these animals, PRV labeling was absent in brain areas traditionally associated with vasomotor tone, such as RVLM, whereas labeling persisted in brain areas previously implicated in the control of the lordosis response, such as MRF. The results support the connectivity of spinal and medullary structures with the somatic control of the lordosis-producing muscles and provide a more detailed description of these portions of the putative lordosis-relevant neurocircuitry.

Renal and Mesenteric Arterial Tone in Rats with Human Renin and Angiotensinogen Genes

P6 The vascular endothelium plays a key role in the control of vasomotor tone, local hemostasis, and vascular wall proliferation processes. We characterized vascular functions in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen. In dTGR, the endothelium-mediated relaxations of noradrenaline (NA)-precontracted renal (large conduit vessel) and mesenteric arterial (smaller conduit vessel) rings to acetylcholine (ACh) were markedly impaired, compared to normotensive Sprague Dawley rats (p&lt;0.05). In contrast, the endothelium-independent relaxation to sodium nitroprusside (SNP) were similar in both strains. Preincubation of the arterial rings with the NOS inhibitor L-NAME and the COX inhibitor diclofenac inhibited relaxations to ACh almost completely in dTGR, suggesting that endothelial dysfunction could be attributed, at least in part, to reduced relaxation via arterial K+ channels. Contractions to Ang II, ET-1, and NA were decreased in dTGR suggesting agonist-dependent down-regulation of the receptors. The vascular media-to-lumen ratio was similar in both strains, indicating that vascular functions were characterized during an early stage of hypertension. 24-hour urinary NOx excretion, a marker of total body NO generation, was markedly decreased in dTGR (p&lt;0.05). AT1 receptor blockade by valsartan (30 mg/kg p.o. for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. We also quantified AT1, AT2, neutral endopeptidase (NEP), and ACE expressions in the kidney by autoradiography. In dTGR, AT1, AT2 and NEP expressions were decreased, whereas ACE expression was unchanged. The activity of renal xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, was increased by 50 % in dTGR, and normalized by valsartan. Our findings indicate that hypertension in dTGR is associated with endothelial dysfunction, down-regulation of Ang II, ET-1, and NA receptors, as well as increased renal XOR activity. AT1 receptor blockade effectively normalized blood pressure, alterations in arterial function, and renal XOR activity.