Basal release and relaxation responses to 6-nitrodopamine in swine carotid, coronary, femoral, and renal arteries.

Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-NG-Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D2-receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 µM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 µM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D2-like receptors.

Nitric oxide and Ca2+-activated high-conductance K+ channels mediate nothofagin-induced endothelium-dependent vasodilation in the perfused rat kidney.

Nothofagin is a natural 3'-C-ß-D-glucoside of the polyphenol phloretin that is mainly found in Aspalathus linearis, Nothofagus fusca, and Leandra dasytricha. In recent years, nothofagin has been described as a potential therapeutic agent for renal disorders, but the mechanisms that are involved in its renoprotective effects remain unclear. In the present study, perfused rat kidneys were used to test the hypothesis that nothofagin causes the direct relaxation of renal arteries. The molecular mechanisms that underlie these vascular effects were also investigated. The left kidney from Wistar rats was coupled in a perfusion system and continuously perfused with physiological saline solution (PSS). Initially, preparations with and without the endothelium were contracted with phenylephrine and received injections of 1-300 nmol nothofagin. The preparations were then perfused with PSS that contained phenylephrine plus KCl, indomethacin, l-NAME, tetraethylammonium, glibenclamide, 4-aminopyridine, iberiotoxin, charybdotoxin, and apamin. After 15 min under perfusion, nothofagin was injected again. In preparations with an intact endothelium, nothofagin dose-dependently reduced perfusion pressure. Endothelium removal or the inhibition of nitric oxide synthase by l-NAME prevented the vasodilatory effect of nothofagin at all doses tested. Perfusion with PSS that contained KCl or tetraethylammonium chloride also abolished the vasodilatory effect of nothofagin. Treatment with glibenclamide, 4-aminopyridine, and apamin did not affect the vasodilatory effect of nothofagin. Iberiotoxin (selective Ca2+-activated high-conductance K+ channel [KCa1.1] blocker) and charybdotoxin (selective KCa1.1 and Ca2+-activated intermediate-conductance K+ channel [KCa3.1] blocker) application blocked the vasodilatory effect of nothofagin at all doses tested, pointing to a predominant role for KCa1.1 in the action of nothofagin. However, these data cannot exclude a potential contribution of endothelial KCa3.1 channel in the nothofagin-induced vasodilation. Overall, our findings indicate that nothofagin induces vasodilation in renal arteries, an effect that is mediated by Ca2+ -activated high-conductance K+ channels opening and endothelial nitric oxide production.

TNF-α inhibition decreases MMP-2 activity, reactive oxygen species formation and improves hypertensive vascular hypertrophy independent of its effects on blood pressure.

Systemic arterial hypertension is a public health problem associated with an increased risk of cardiovascular disease. Matrix metalloproteinases (MMP) are endopeptidases that participate in hypertension-induced cardiovascular remodeling, which may be activated by oxidative stress. Angiotensin II (Ang II), a potent hypertrophic and vasoconstrictor peptide, increases oxidative stress, MMP-2 activity and tumor necrosis factor (TNF-α) expression. In vitro studies have shown that TNF-α is essential for Ang II-induced MMP-2 expression. Thus, this study evaluated whetherTNF-α inhibition decreases the development of hypertension-induced vascular remodeling via reduction of MMP-2 activity and reactive oxygen species (ROS) formation. Two distinct pharmacological approaches were used in the present study: Pentoxifylline (PTX), a non-selective inhibitor of phosphodiesterases that exerts anti- inflammatory effects via inhibition of TNF-α, and Etanercept (ETN), a selective TNF-α inhibitor. 2-kidney and 1-Clip (2K1C). 2-kidney and 1-Clip (2K1C) and Sham rats were treated with Vehicle, PTX (50 mg/Kg and 100 mg/kg daily) or ETN (0.3 mg/Kg and 1 mg/kg; three times per week). Systolic blood pressure (SBP) was measured weekly by tail cuff plethysmography. Plasma TNF-α and IL-1ß levels were evaluated by enzyme-linked immunosorbent assay (ELISA) technique. The vascular hypertrophy was examined in the aorta sections stained with hematoxylin/eosin. ROS in aortas was evaluated by dihydroethidium and chemiluminescence lucigenin assay. Aortic MMP-2 levels and activity were evaluated by gel zymography and in situ zymography, respectively. The 2K1C animals showed a progressive increase in SBP levels and was accompanied by significant vascular hypertrophy (p < 0.05 vs Sham). Treatment with PTX at higher doses decreased SBP and vascular remodeling in 2K1C animals (p < 0.05 vs 2K1C vehicle). Although the highest dose of ETN treatment did not reduce blood pressure, the vascular hypertrophy was significantly attenuated in 2K1C animals treated with ETN1 (p < 0.05). The increased cytokine levels and ROS formation were reversed by the highest doses of both PTX and ETN. The increase in MMP-2 levels and activity in 2K1C animals were reduced by PTX100 and ETN1 treatments (p < 0.05 vs vehicle 2K1C). Lower doses of PTX and ETN did not affect any of the evaluated parameters in this study, except for a small reduction in TNF-α levels. The findings of the present study suggest that PTX and ETN treatment exerts immunomodulatory effects, blunted excessive ROS formation, and decreased renovascular hypertension-induced MMP-2 up-regulation, leading to improvement ofvascular remodeling typically found in 2K1C hypertension. Therefore, strategies using anti-hypertensive drugs in combination with TNF alpha inhibitors could be an attractive therapeutic approach to tackle hypertension and its associated vascular remodeling.

Antioxidants as Renoprotective Agents for Ischemia during Partial Nephrectomy.

Small renal masses have been diagnosed increasingly in recent decades, allowing surgical treatment by partial nephrectomy. This treatment option is associated with better renal function preservation, in comparison with radical nephrectomy. However, for obtaining a bloodless field during surgery, occlusion of renal artery and veins is often required, which results in transitory ischemia. The renal ischemia-reperfusion injury is associated with increased reactive oxygen species production leading to renal tissue damage. Thus, the use of antioxidants has been advocated in the partial nephrectomy perioperative period. Several antioxidants were investigated in regard to renal ischemia-reperfusion injury. The present manuscript aims to present the literature on the most commonly studied antioxidants used during partial nephrectomy. The results of experimental and clinical studies using antioxidants during partial nephrectomy are reported. Further, alimentary sources of some antioxidants are presented, stimulating future studies focusing on perioperative antioxidant-rich diets.

Biomonitoring the cardiorenal effects of Luehea divaricata Mart.: An ethnoguided approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Luehea divaricata Mart. (Malvaceae) is an important medicinal species that is widely used as a diuretic in the Brazilian Pantanal region. An ethanolic supernatant that was obtained from an infusion of leaves of this species (ESLD) was recently shown to exert hypotensive and diuretic activity. Nevertheless, the secondary metabolites that are responsible for this activity and the molecular mechanisms of pharmacological action remain unknown. AIM: We performed a detailed study to identify possible active metabolites that are present in different ESLD fractions and investigated their effects on renal and peripheral arteriolar tone. We further evaluated their interrelations with sustained diuretic and hypotensive actions. MATERIALS AND METHODS: The ESLD was first obtained from L. divaricata leaves, and liquid-liquid fractionation was performed. The fractions were analyzed by liquid chromatography-mass spectrometry. An ethyl acetate fraction (AceFr), n-butanolic fraction (ButFr), and aqueous fraction (AqueFr) were then orally administered in male Wistar rats in a single dose or daily for 7 days. The doses were previously defined based on the yield that was obtained from each fraction. Hydrochlorothiazide was used as a positive control. Blood pressure, heart rate, urinary volume, pH, density, and urinary sodium, potassium, chloride, and calcium levels were measured. Serum levels of nitrite, thiobarbituric acid reactive species, nitrotyrosine, aldosterone, vasopressin, and plasma angiotensin converting enzyme activity were also measured. Finally, the direct effects of the ButFr on renal and mesenteric arteriolar tone and the role of nitric oxide and prostaglandins in the renal and hemodynamic effects were investigated. RESULTS: Of the fractions that were tested, only the ButFr exerted significant diuretic and saluretic effects. The AceFr and ButFr also had acute hypotensive effects, but only the ButFr maintained its response after 7 days of treatment. Prolonged treatment with the ButFr increased serum nitrite levels and significantly reduced oxidative and nitrosative markers of stress. Additionally, the ButFr caused a vasodilatory response in the renal and mesenteric arteriolar beds through the release of nitric oxide and prostaglandins. Finally, the diuretic and hypotensive effects of the ButFr were completely blocked by pretreatment with Nω-nitro-L-arginine methyl ester and indomethacin, thus demonstrating the direct involvement of nitric oxide and prostaglandins in these effects. CONCLUSION: The ButFr that was obtained from Luehea divaricata exerted sustained diuretic and hypotensive effects. These effects were apparently attributable to the release of nitric oxide and prostaglandins, which reduce renal and peripheral arteriolar tone and lead to an increase in the glomerular filtration rate and a reduction of global peripheral resistance. These findings suggest that the ButFr may be a potential complementary therapy for several conditions in which diuretic and hypotensive effects are required.

Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature.

Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models.

Alkaline Phosphatase Inhibitors Attenuate Renovascular Responses to Norepinephrine.

Tissue nonspecific alkaline phosphatase (TNAP) contributes to the production of adenosine by the kidney, and A1-receptor activation enhances renovascular responses to norepinephrine. Therefore, we hypothesized that TNAP regulates renovascular responsiveness to norepinephrine. In isolated, perfused rat kidneys, the TNAP inhibitor l-p-bromotetramisole (0.1 mmol/L) decreased renal venous levels of 5'-AMP (adenosine precursor) and adenosine by 61% (P<0.0384) and 62% (P=0.0013), respectively, at 1 hour into treatment and caused a 10-fold rightward shift of the concentration-response relationship to exogenous norepinephrine (P<0.0001). Similarly, 2 other TNAP inhibitors, levamisole (1 mmol/L) and 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (0.02 mmol/L), also right shifted the concentration-response relationship to norepinephrine. The ability of TNAP inhibition to blunt renovascular responses to norepinephrine was mostly prevented or reversed by restoring A1-adenosinergic tone with the A1-receptor agonist 2-chloro-N6-cyclopentyladenosine (100 nmol/L). All 3 TNAP inhibitors also attenuated renovascular responses to renal sympathetic nerve stimulation, suggesting that TNAP inhibition attenuates renovascular responses to endogenous norepinephrine. In control propranolol-pretreated rats, acute infusions of norepinephrine (10 µg/kg/min) increased mean arterial blood pressure from 95±5 mm Hg to a peak of 169±4 mm Hg and renovascular resistance from 12±2 mm Hg/mL/min to a peak of 55±12 mm Hg/mL/min; however, in rats also treated with intravenous l-p-bromotetramisole (30 mg/kg), the pressor and renovascular effects of norepinephrine were significantly attenuated (blood pressure: basal and peak, 93±7 and 146±6 mm Hg, respectively; renovascular resistance: basal and peak, 13±2 and 29±5 mm Hg/mL/min, respectively). TNAP inhibitors attenuate renovascular and blood pressure responses to norepinephrine, suggesting that TNAP participates in the regulation of renal function and blood pressure.

Efferent pathways in sodium overload-induced renal vasodilation in rats.

Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. The present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280-350 g) were anesthetized with sodium thiopental (40 mg. kg(-1), i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 µg • kg(-1), i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml • kg(-1) b.wt., i.v.) was infused over 60 s. In sham rats (n = 6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; atosiban, 40 µg • kg(-1) • h(-1), i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. The combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia.

Inhibitory effects of sertraline in rat isolated perfused kidneys and in isolated ring preparations of rat arteries.

OBJECTIVES: Sertraline is often prescribed to patients suffering with end stage renal disease, but its action on kidney has not been investigated. We aimed to investigate the pharmacological action of sertraline on rat kidney with emphasis on the underlying mechanisms involved in the vascular actions of the drug. METHODS: The effects of sertraline were evaluated in rat isolated perfused kidneys and on ring preparations of mesenteric or segmental rat renal artery. KEY FINDINGS: In kidneys, sertraline prevented the effects of phenylephrine on perfusion pressure, glomerular filtration rate, urinary flow and renal vascular resistance. In mesenteric rings sertraline inhibited phenylephrine-induced contractions with potency 30-times lower than verapamil. Sertraline reversed sustained contractions induced by phenylephrine or 60mm K(+) within a similar concentration range. In segmental isolated rings, sertraline also reversed contractions induced by phenylephrine or 60mm K(+) with the same concentration range, but with higher potency compared with mesenteric preparations. Under Ca(2+) -free conditions, sertraline did not change the intracellularly-mediated phasic contractions induced by phenylephrine or caffeine. Sertraline was ineffective against contractions induced by extracellular Ca(2+) restoration after thapsigargin treatment and Ca(2+) store depletion with phenylephrine. Conversely, sertraline decreased the contractions induced by Ca(2+) addition in tissues under high K(+) solution or phenylephrine plus verapamil. CONCLUSIONS: In rat isolated kidneys and in rat ring preparations of mesenteric or renal vessels, sertraline had antispasmodic effects that appeared to be caused by a direct action on vascular smooth muscle cells. Its actions were ineffective against Ca(2+) -releasing intracellular pathways, but appeared to interfere with sarcolemmal Ca(2+) influx with reduced permeability of both receptor- and voltage-gated Ca(2+) channels.

Astaxanthin-enriched-diet reduces blood pressure and improves cardiovascular parameters in spontaneously hypertensive rats.

The aim of this study was to investigate the effects of astaxanthin-enriched diet on blood pressure, cardiac hypertrophy, both vascular structure and function and superoxide ((*)O(2-)) production in spontaneously hypertensive rats (SHR). Twelve-week-old SHR were treated for 8 weeks with an astaxanthin-enriched diet (75 or 200mg/kg body weight per day). Systolic blood pressure was monitorized periodically during the study by the tail cuff method. At the end of the study animals were sacrificed and heart, kidneys and aorta were removed. Left ventricular weight/body weight ratio was used as left ventricular hypertrophy index (LVH). Vascular function and structure were studied in conductance (aortic rings) and resistance (renal vascular bed) arteries. Also (*)O(2-) production was evaluated by lucigenin-enhanced chemiluminescence. Systolic blood pressure was lower in astaxanthin-treated groups than the control group from the first week of treatment, and LVH was significantly reduced. Astaxanthin improved endothelial function on resistance arteries, but had no effect on aorta. These effects were accompanied by a decrease in oxidative stress and improvements in NO bioavailability. Taken together, these results show that diet supplemented with astaxanthin has beneficial effects on hypertension, by decreasing blood pressure values, improving cardiovascular remodeling and oxidative stress.

Vascular structure and oxidative stress in salt-loaded spontaneously hypertensive rats: effects of losartan and atenolol.

BACKGROUND: Renin-angiotensin system (RAS) modulation by high dietary sodium may contribute to salt-induced hypertension, oxidative stress, and target organ damage. We investigated whether angiotensin II (Ang-II) type 1 (AT1)-receptor blockade (losartan) could protect the aorta and renal arteries from combined hypertension- and high dietary salt-related oxidative stress. METHODS: Spontaneously hypertensive rats (3-month-old, n = 10/group) received tap water (SHR), water containing 1.5% NaCl (SHR+S), 1.5% NaCl and 30 mg losartan/kg/day (SHR+S+L), or 50 mg atenolol/kg/day (SHR+S+A). Atenolol was used for comparison. Ten Wistar-Kyoto rats (WKY) were controls. Systolic blood pressure (SBP) was determined by tail plethysmography. After 5 months of treatment, vascular remodeling and oxidative stress (superoxide production and NAD(P)H-oxidase activity (chemiluminescence), malondialdehyde (MDA) content (high-performance liquid chromatography), endothelial nitric oxide synthase (eNOS) activity [(14)C-arginine to (14)C citrulline], CuZn-SOD activity (spectrophotometry)) were studied. RESULTS: In SHR, salt-loading significantly aggravated hypertension, urinary protein excretion, intraparenchymal renal artery (IPRArt) perivascular fibrosis, aortic and renal artery oxidative stress, and induced endothelial cell loss in IPRArts. In salt-loaded SHR, 5-month losartan and atenolol treatments similarly reduced SBP, but only losartan significantly prevented (i) urinary protein excretion increase, (ii) or attenuated hypertension-related vascular remodeling, (iii) aortic MDA accumulation, (iv) renal artery eNOS activity lowering, and (v) aortic and renal artery superoxide dismutase (SOD) activity reduction. In SHR+S, the contributions to aortic superoxide production were as follows: uncoupled eNOS > xanthine oxidase (XO) > NAD(P)H oxidase. CONCLUSIONS: In this salt-sensitive genetic hypertension model, losartan protects from hypertension- and high dietary salt-related vascular oxidative stress, exceeding the benefits of BP reduction. Also, during salt overload, BP-independent factors contribute to vascular remodeling, at least part of which derive from AT1-receptor activation.

Aqueous garlic extracts prevent oxidative stress and vascular remodeling in an experimental model of metabolic syndrome.

The organosulfur profile and the effect on oxidative stress and vascular remodeling in fructose-fed rats (FFR) were evaluated in Fuego INTA and Morado INTA garlic cultivars. Wistar rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. During the last 6 weeks of a 12 week period of the corresponding diet, a subgroup of control and FFR received an aqueous extract of Fuego INTA and Morado INTA. Fuego INTA showed higher levels of total thiosulfinates, allicin, and pungency than Morado INTA. FFR showed an increase of systolic blood pressure, aortic NAD(P)H oxidase activity, plasma thiobarbituric acid reactive substances, and vascular remodeling that was significantly reduced after both garlic administrations. The beneficial effect was slightly higher when Fuego INTA was administered. Both aqueous garlic extracts prevent oxidative stress and vascular remodeling in rats with metabolic syndrome, suggesting the existence of slight differences among cultivars.

Effects of immunosuppressive drugs on rat renal ischemia reperfusion injury.

INTRODUCTION: Recent evidence has demonstrated that the immune response and, more specifically, lymphocytes (T and B) and dendritic cells participate as mediators of renal ischemia reperfusion injury (IRI). The aim of this study was, therefore, to evaluate the effect of various immunosuppressive drugs with known activity to prevent IRI among rats undergoing a scheme that is potentially applicable in the clinic. METHODS: Male Sprague-Dawley rats (200-300 g) underwent 60 minutes of ischemia by renal artery clamping and contralateral nephrectomy. The experimental groups (n = 6-7) were as follows: I, Sham; II, Control; III, Rapamycin (R; 1 mg/kg); IV, Methylprednisolone (M; 15 mg/kg); V, Vitamin D3 (VD3; 2 microg/kg); VI, VD3 (1 microg/kg); and VII, M (15 mg/kg) + R (1 mg/kg). Each drug was administered in 2 doses at 6 hours and 1 hour before surgery. Creatinine (Cr) was determined on days 0.1, 2, 3, 5, and 7, and Cr clearance was determined on days 3 and 7. At 7 days nephrectomy was performed to obtain samples for histology to evaluate the degree of acute tubular necrosis. RESULTS: Mortality from renal insufficiency was between 0 and 33%, except in group V (66%; 4/6; P = .01). Kidney function was similar to controls in all groups except for creatinine at 7 days between group VI (VD3) and control (1.05 vs 0.65; P < .05) but no difference in Cr clearance. Histologically moderate to severe renal damage was greater in groups V and VI (VD3) than controls (P = .04). CONCLUSION: We observed that none of the drugs conferred protection against IRI in a time setting relevant to kidney transplantation. Controversy exists regarding R, because some prior studies have shown a deleterious effect on IRI injury, although we did not observe any deleterious effect.

Effect of renal embolization with trisacryl and PAVc.

OBJECTIVES: Evaluate the degree of vascular occlusion, vascular recanalization, and necrosis of the vascular wall caused by polyvinyl alcohol-covered polyvinyl acetate (PVAc) particles compared to trisacryl particles after renal embolization. METHODS: Seventy-nine female albino New Zealand rabbits underwent arterial catheterization of the right kidney. Thirty-three animals were embolized with trisacryl particles, thirty-one with PVAc particles, and fifteen were kept as controls. Four animals were excluded (three trisacryl and one PVAc) due to early death. Five subgroups of six animals were created. The animals in the different groups were sacrificed either 48 hours, 5 days, 10 days, 30 days, or 90 days after embolization. The control group was divided into subgroups of three animals each and kept for the same periods of time. The kidneys were dyed with hematoxylin-eosin and Masson's trichrome and then examined using optical microscopy. RESULTS: There were significant differences in the degree of vascular occlusion caused by the trisacryl and the PVAc particles between the five-day and the ten-day groups. Additional differences were noted between the five-day and 48-hour groups in regard to the amount of necrosis. For both findings, the PVAc group members showed adequate tissue reaction (ischemia and volumetric reduction) and less recanalization than those treated with trisacryl. CONCLUSION: The use of PVAc as an embolization material exhibited an adequate tissue reaction (ischemia and volumetric reduction), more expressive vascular occlusion and necrosis, and less recanalization than the trisacryl material.

Effect of renal embolization with trisacryl and PAVc

OBJECTIVES: Evaluate the degree of vascular occlusion, vascular recanalization, and necrosis of the vascular wall caused by polyvinyl alcohol-covered polyvinyl acetate (PVAc) particles compared to trisacryl particles after renal embolization. METHODS: Seventy-nine female albino New Zealand rabbits underwent arterial catheterization of the right kidney. Thirty-three animals were embolized with trisacryl particles, thirty-one with PVAc particles, and fifteen were kept as controls. Four animals were excluded (three trisacryl and one PVAc) due to early death. Five subgroups of six animals were created. The animals in the different groups were sacrificed either 48 hours, 5 days, 10 days, 30 days, or 90 days after embolization. The control group was divided into subgroups of three animals each and kept for the same periods of time. The kidneys were dyed with hematoxylin-eosin and Masson's trichrome and then examined using optical microscopy. RESULTS: There were significant differences in the degree of vascular occlusion caused by the trisacryl and the PVAc particles between the five-day and the ten-day groups. Additional differences were noted between the five-day and 48-hour groups in regard to the amount of necrosis. For both findings, the PVAc group members showed adequate tissue reaction (ischemia and volumetric reduction) and less recanalization than those treated with trisacryl. CONCLUSION: The use of PVAc as an embolization material exhibited an adequate tissue reaction (ischemia and volumetric reduction), more expressive vascular occlusion and necrosis, and less recanalization than the trisacryl material.

Effect of chronic aspirin administration on an experimental model of metabolic syndrome.

1. The aim of the present study was to examine the effect of chronic administration of aspirin on metabolic and cardiovascular parameters in fructose-fed rats (FFR), an experimental model of metabolic syndrome. 2. Chronic treatment of FFR with aspirin (10 mg/kg per day for 6 weeks) partially reversed the increment in systolic blood pressure. In addition, chronic aspirin treatment normalized relative heart weight and vascular remodelling of renal and carotid arteries, measured as lumen diameter: medial thickness ratio. 3. Furthermore, chronic aspirin administration completely reversed glucose intolerance and decreased the oxidative status that characterizes the FFR model, as indicated by decreased plasma levels of thiobarbituric acid-reactive substances and aortic NAD(P)H oxidase activity. 4. Prevention of oxidative stress and vascular remodelling in FFR may contribute to the protective actions attributed to aspirin in the treatment of metabolic syndrome.

Nitric oxide and prostacyclin-dependent pathways involvement on in vitro induced hypothermia.

Nitric oxide and prostacyclin are endogenous endothelium-derived vasodilators, but little information is available on their release during hypothermia. This study was carried out to test the hypothesis that endothelium may modulate vascular reactivity to decreased temperature changes. Segments of contracted (prostaglandin F(2alpha), 2x10(-6)M) canine coronary, femoral, and renal arteries, with and without endothelium, were in vitro ("organ chambers") exposed to progressive hypothermia (from 37 to 10 degrees C) in graded steps. The study is limited to physiological measurements of vascular tone, in the presence or absence of PGI(2) and/or NOS inhibitors, which show correlation with the relaxation. Hypothermia induced vasodilatation of vessels with intact endothelium, which became endothelium-independent below 20 degrees C. This vasodilatation began at 35 degrees C and, in the presence of indomethacin (2x10(-6)M), at 30 degrees C. Endothelium-dependent vasodilatation to hypothermia was blocked by L-NMMA or L-NOARG (10(-5)M), two competitive inhibitors of nitric oxide synthase (n=5 each, P<0.05). Oxyhemoglobin (2x10(-6)M) also inhibited vasodilatation induced by hypothermia (n=6, P<0.05). Pretreatment with either atropine or pirenzepine (10(-6)M) inhibited hypothermia-mediated vasodilatation (n=5 each, P<0.05). The present in vitro study concluded that the endothelium is sensitive to temperature variations and indicated that PGI(2) and NO-dependent pathways may be involved endothelium-dependent relaxation to hypothermia. The endothelium-dependent vasodilatation to hypothermia, in systemic and coronary arteries, is mediated by the M1 muscarinic receptor.

Vascular and renal effects of dopamine during extracellular volume expansion: Role of nitric oxide pathway.

OBJECTIVE: The aim of the study was to determine the possible role of NO-system activation in vascular and renal effects of the dopaminergic system and the probable interaction between both systems during acute volume expansion in rats. DESIGN AND METHODS: Expanded (10% bw) and non-expanded anaesthetized male Wistar rats were treated with haloperidol, a DA receptor antagonist (3 mg/kg bw, ip). Mean arterial pressure, diuresis, natriuresis, renal plasma flow, glomerular filtration rate, nitrites and nitrates excretion (NOx) were determined. NADPH diaphorase activity was measured using a histochemistry technique in kidney, aorta and renal arteries. NOS activity in kidney and aorta from expanded and non-expanded animals was determined with L-[U14C]-arginine substrate, in basal conditions and after DA (1 microM) administration. RESULTS: The hypotensive effect of L-arg and hypertension induced by L-NAME were not modified by haloperidol. This blocker reverted the increase in diuresis, natriuresis and RPF induced by L-arg in both groups. Dopaminergic blockade induced a decrease in NOx excretion and in NADPH-diaphorase activity in glomeruli, proximal tubule and medullar collecting duct and in endothelium and vascular smooth muscle of renal arteries. DA induced an increase in NOS activity in renal medulla and cortex in both groups, but no changes in the aorta were observed. CONCLUSIONS: Our results suggest that renal DA would be associated with the renal response induced by NO during extracellular volume expansion. NO-system activation would be one of the mechanisms involved in renal DA activity during saline load, but NO appears not to be involved in DA vascular effects.

Cyclosporine A and NAC on the inducible nitric oxide synthase expression and nitric oxide synthesis in rat renal artery cultured cells.

BACKGROUND: The immunosuppressor cyclosporine A (CsA) presents the nephrotoxicity as its major side effect that is mostly attributed to a renal vasoconstriction. This may be due to an excessive generation of vasoconstrictors like reactive oxygen species (ROS), or due to a reduction of vasodilators such as the nitric oxide, which in turn, can be caused by increased amounts of ROS. We evaluated the effect of CsA and the antioxidant N-acetylcysteine (NAC) on inducible nitric oxide synthase (iNOS) mRNA expression and nitric oxide synthesis, in rat renal artery vascular smooth muscle cells (rVSMCs) primary culture. METHODS: In cells treated during 72 hours with CsA (10 microg/mL), its vehicle (control) (10 microL/mL), Escherichia coli lipopolysaccharide (LPS) (100 microg/mL), CsA + LPS, NAC (6.13 mmol/L), or CsA + NAC, we determined the nitric oxide synthesis (Griess and chemiluminescence methods), iNOS expression [reverse transcription-polymerase chain reaction (RT-PCR)] and cell viability (acridine orange method). RESULTS: In rVSMCs, LPS increased nitric oxide and iNOS expression; CsA decreased basal and LPS-induced nitric oxide and iNOS expression; NAC increased nitric oxide and blunted the nitric oxide reduction caused by CsA, with no effect on iNOS. CsA reduced cell viability. CONCLUSION: In this study, CsA reduced nitric oxide synthesis in rVSMCs, both through iNOS down-regulation and reduction of cell viability, which could be responsible for the vasoconstrictive effect of the CsA. In the effect of CsA on nitric oxide, probably a role is also played by free radical production, as this effect was blunted by NAC.

Effect of nebivolol on cardiovascular changes associated with a rat model of insulin-resistance.

Nebivolol is a vasodilator that combines beta-adrenergic blocking activity with a relaxant effect on vascular smooth muscle cells (VSMC) mediated by the endothelial nitric oxide (NO) pathway. FFR provide a model of dietary-induced insulin-resistance syndrome, which has been used to study the pathophysiological mechanisms associated with this syndrome. Our main objective was to examine the effect of long-term administration of nebivolol on metabolic and cardiovascular variables in fructose-fed rats (FFR), a model in which an altered bioavailability of NO has been already described. Male Wistar rats were randomly assigned to 4 groups (n = 8 each): I. Control (C); II. Control + nebivolol (C+N): 1 mg/kg(-1) x day(-1) in drinking water during the last 4 weeks. III. FFR: rats receiving fructose in drinking water as a 10% (w/v) solution during 8 weeks, and IV. FFR+N: idem II plus III. During the 8 weeks experimental period, variations in systolic blood pressure (SBP), glucose tolerance test (GTT) and plasma thiobarbituric acid-reactive substances (TBARS) were assessed. At the end of this experimental period, rats were killed and heart and kidneys were excised for calculation of relative heart weight (RHW) and histological evaluation of lumen to media ratio (L/M) in renal arteries. Rats from FFR group increased their SBP and RHW, showed glucose intolerance and an increment in lipid peroxidation. Moreover, FFR showed vascular remodeling in renal arteries evidenced by changes in L/M. Although the metabolic changes were not reverted by the administration of nebivolol, this drug successfully decreased SBP, TBARS levels and reverted structural changes such as cardiac hypertrophy and renal arterial remodeling. Data demonstrate that nebivolol administration could participate in the reversion of cardiovascular structural changes associated with the insulin-resistance syndrome.