Dalton Valentim Vassallo

Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries

Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 microg/kg, subsequent dose 0.07 microg.kg(-1).day(-1) im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 +/- 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 100 microM). Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with l-NAME, the l-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2(-) production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

Monitorização ambulatorial da pressão arterial em indivíduos normotensos submetidos a duas sessões únicas de exercícios: resistido e aeróbio

OBJECTIVE: To assess the influence of 2 single exercise sessions on blood pressure in sedentary normotensive individuals: one of resistive exercise training (circuit weight training) and the other of aerobic exercise training. METHODS: Using ambulatory blood pressure monitoring, this study assessed 25 individuals as follows: in a controlled situation at rest (ABPM 1); after resistive exercise training (ABPM 2); and after aerobic exercise training (ABPM 3). Resistive exercise training was performed as circuit weight training with an intensity of 40% of each individuals maximum strength. The aerobic exercise training was performed on a cycloergometer with intensity between 60% and 70% of the maximum heart rate (HR) reached during previous exercise testing. RESULTS: Systolic blood pressure (SBP) values during 24 hours and during subperiods of wakefulness and sleep showed no statistically significant variations when the results obtained at rest were compared with those of ABPM2 and ABPM3, and when the results of ABPM2 were compared with those of ABPM3. The mean heart rate during 24 hours and in the wakefulness period showed significant increases (P<0.05), when ABPM2 was compared with ABPM3. CONCLUSION: A single session of resistive exercise training in normotensive individuals was sufficient to cause significant reductions in blood pressure levels after exercise in the period of sleep. The session of aerobic exercise training in these same individuals was more effective in significantly reducing blood pressure levels.

Toxic Effects of Mercury on the Cardiovascular and Central Nervous Systems

Environmental contamination has exposed humans to various metal agents, including mercury. This exposure is more common than expected, and the health consequences of such exposure remain unclear. For many years, mercury was used in a wide variety of human activities, and now, exposure to this metal from both natural and artificial sources is significantly increasing. Many studies show that high exposure to mercury induces changes in the central nervous system, potentially resulting in irritability, fatigue, behavioral changes, tremors, headaches, hearing and cognitive loss, dysarthria, incoordination, hallucinations, and death. In the cardiovascular system, mercury induces hypertension in humans and animals that has wide-ranging consequences, including alterations in endothelial function. The results described in this paper indicate that mercury exposure, even at low doses, affects endothelial and cardiovascular function. As a result, the reference values defining the limits for the absence of danger should be reduced.

Vasorelaxant effects of eugenol on rat thoracic aorta.

Eugenol is a natural pungent substance and the main component of clove oil, with vasorelaxant action. To elucidate some of the possible mechanisms involved in this action isometric tension was measured in aortic rings from male Wistar rats precontracted with phenylephrine (PHE, 10(-7) M) or KCl (75 mM). Responses to increasing concentrations of eugenol (10(-6)-10(-2) M) were obtained in the presence and absence of endothelium. In the presence of eugenol, dose-response curves to PHE (10(-9) to 10(-4) M) and KCl (5-125 mM) were displaced downwards. Concentration-dependent relaxation was observed in rings precontracted with PHE (10(-7) M) and KCl (75 mM). The tension increment produced by increasing external calcium concentration (0.25-3 mM) was also reduced by eugenol (300 microM) treatment. The inhibitory effects of eugenol (300 microM) were compared to those induced by nifedipine (0.01 microM), a selective Ca(2+) channel blocker, producing similar relaxant effects. Two other protocols were performed. After precontraction with PHE (10(-7) M), increasing concentrations of eugenol (10(-6)-10(-2) M) were used before and after N(w)-nitro-L-arginine (L-NAME, 10(-4) M) and methylene blue (10(-5) M) treatment. Eugenol-induced relaxation was reduced by endothelial damage (rubbing), L-NAME and methylene blue treatments. Results suggested that eugenol produces smooth muscle relaxation resulting from the blockade of both voltage-sensitive and receptor-operated channels that are modulated by endothelial-generated nitric oxide.

Alterations in phenylephrine-induced contractions and the vascular expression of Na+,K+-ATPase in ouabain-induced hypertension

Hypertension development, phenylephrine‐induced contraction and Na+,K+‐ATPase functional activity and protein expression in aorta (AO), tail (TA) and superior mesenteric (SMA) arteries from ouabain‐ (25 μg day−1, s.c., 5 weeks) and vehicle‐treated rats were evaluated. Ouabain treatment increased systolic blood pressure (127±1 vs 160±2 mmHg, n=24, 35; P<0.001) while the maximum response to phenylephrine was reduced (P<0.01) in AO (102.8±3.9 vs 67.1±10.1% of KCl response, n=12, 9) and SMA (82.5±7.5 vs 52.2±5.8%, n=12, 9). Endothelium removal potentiated the phenylephrine response to a greater extent in segments from ouabain‐treated rats. Thus, differences of area under the concentration‐response curves (dAUC) in endothelium‐denuded and intact segments for control and ouabain‐treated rats were, respectively: AO, 56.6±9.6 vs 198.3±18.3 (n=9, 7); SMA, 85.5±15.4 vs 165.4±24.8 (n=6, 6); TA, 13.0±6.1 vs 39.5±10.4% of the corresponding control AUC (n=6, 6); P<0.05. The relaxation to KCl (1 – 10 mM) was similar in segments from both groups. Compared to controls, the inhibition of 0.1 mM ouabain on KCl relaxation was greater in AO (dAUC: 64.8±4.6 vs 84.0±5.1%, n=11, 14; P<0.05), similar in SMA (dAUC: 39.1±3.9 vs 43.3±7.8%, n=6, 7; P>0.05) and smaller in TA (dAUC: 62.1±5.5 vs 41.4±8.2%, n=12, 13; P<0.05) in ouabain‐treated rats. Protein expression of both α1 and α2 isoforms of Na+,K+‐ATPase was augmented in AO, unmodified in SMA and reduced in TA from ouabain‐treated rats. These results suggest that chronic administration of ouabain induces hypertension and regional vascular alterations, the latter possibly as a consequence of the hypertension.

Aerobic exercise reduces oxidative stress and improves vascular changes of small mesenteric and coronary arteries in hypertension

Regular physical activity is an effective non‐pharmacological therapy for prevention and control of hypertension. We investigated the effects of aerobic exercise training in vascular remodelling and in the mechanical and functional alterations of coronary and small mesenteric arteries from spontaneously hypertensive rats (SHR).

Time-dependent hyperreactivity to phenylephrine in aorta from untreated diabetic rats: role of prostanoids and calcium mobilization.

Diabetes alters vascular smooth muscle contractility. Changes in reactivity to phenylephrine (Phe) in aortas from controls and untreated 1- and 4-week streptozotocin (STZ)-induced diabetic rats were investigated. In 1-week diabetic (DB1) aortas, the maximum response (E(max)) and sensitivity (pD(2)) to Phe were similar to controls (CT1), but in 4-week diabetic (DB4) aortas, the E(max) for Phe was increased compared to CT4 aortas (E(max), DB4: 125+/-8.4% vs. CT4: 89.8+/-4.5%, P<.001). Endothelial denudation increased the response to Phe, and E(max) was increased in the DB4 aortas compared to CT4 (E(max), DB4: 156+/-4.2% vs. CT4: 125+/-3.8%, P<.001). Pretreatment of CT4 and DB4 aortas with indomethacin reduced E(max) and pD(2) for Phe. After indomethacin treatment, no differences in E(max) and pD(2) to Phe were observed in either group. SQ 29548 did not alter the Phe actions in CT4 aortas. However, in DB4 aortas, E(max) was reduced to control level. CT4 and DB4 aortas incubated in free-Ca(2+) solution plus Phe, contracted upon addition of CaCl(2), this response was increased in DB4 aortas. No changes were observed for acetylcholine (ACh) or sodium nitroprusside (SNP) responses. Nitric oxide (NO) release in response to Phe determined by acute L-NAME administration showed no differences in the percentage increase of the contraction in CT1 and DB1 aortas, but was enhanced in DB4 aortas. Results suggested that diabetes induces time-dependent changes in the vascular reactivity to Phe. This response is not related to a reduction of endothelium-derived NO but might be due to an increase in prostaglandin H(2) (PGH(2))/thromboxane A(2) (TxA(2)) and/or an enhanced extracellular Ca(2+) influx.

Endothelial dysfunction of rat coronary arteries after exposure to low concentrations of mercury is dependent on reactive oxygen species

BACKGROUND AND PURPOSE Exposure to mercury is known to increase cardiovascular risk but the underlying mechanisms are not well explored. We analysed whether chronic exposure to low mercury doses affects endothelial modulation of the coronary circulation.

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation

1 The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg−1 day−1, s.c.) for 7 days on the vascular reactivity of rat‐isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2 Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO‐treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO‐treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO‐treated rats. The presence of Nω‐nitro‐L‐arginine methyl ester shifted the concentration–response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 μM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3 Neither losartan (10 μM) nor indomethacin (10 μM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml−1) and L‐arginine (5 mM), but neither catalase (300 U ml−1) nor apocynin (100 μM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO‐treated rats. 4 In conclusion, our data suggest that ISO treatment alters the endothelial cell‐mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which inactivates some of the basal NO produced and counteracts NO‐mediated negative modulation even in the presence of high NO production and antioxidant defence.

Ouabain‐induced hypertension alters the participation of endothelial factors in α‐adrenergic responses differently in rat resistance and conductance mesenteric arteries

This study compares the role of endothelial factors in α‐adrenoceptor contractile responses in mesenteric resistance (MRA) and superior (SMA) mesenteric arteries from ouabain‐treated (8.0 μg day−1, 5 weeks) and untreated rats. The role of the renin–angiotensin system was also evaluated. Ouabain treatment increased systolic blood pressure. In addition, ouabain reduced the phenylephrine response in SMA but did not alter noradrenaline responses in MRA. Endothelium removal or the nitric oxide synthase (NOS) inhibitor (L‐NAME, 100 μM) increased the responses to α‐adrenergic agonists in both vessels. After ouabain treatment, both endothelial modulation and the L‐NAME effect were increased in SMA, while only the L‐NAME effect was increased in MRA. Endothelial NOS expression remained unaltered after ouabain treatment. Indomethacin (10 μM) similarly reduced the noradrenaline contraction in MRA from both groups; in contrast, in SMA, indomethacin only reduced phenylephrine‐induced contractions in segments from untreated rats. Co‐incubation of L‐NAME and indomethacin leftward shifted the concentration–response curves for noradrenaline more in MRA from ouabain‐treated rats; tetraethylammonium (2 mM) shifted the noradrenaline curves further leftward only in MRA from untreated rats. Losartan treatment prevents the development of hypertension but not all vascular changes observed after ouabain treatment. In conclusion, a rise in endothelial NO and impaired prostanoid participation might explain the reduction in phenylephrine‐induced contraction in SMA after ouabain treatment. An increase in the modulatory effect of endothelial NO and impairment of endothelium‐dependent hyperpolarizing factor effect might explain why the ouabain treatment had no effect on noradrenaline responses in MRA.