R. Soares de Moura

Antihypertensive, vasodilator and antioxidant effects of a vinifera grape skin extract.

Cumulative evidence suggests that moderate wine consumption exerts a cardioprotective effect. We investigated the occurrence of an antihypertensive effect of an alcohol‐free hydroalcoholic grape skin extract (GSE) obtained from skins of a vinifera grape (Vitis labrusca) in experimental rodent hypertension models. The vasodilator effect of GSE (polyphenols concentration 55.5 mg g−1) was also assessed in the isolated mesenteric vascular bed of Wistar rats and the antioxidant effect was studied on lipid peroxidation of hepatic microsomes. Oral administration of GSE significantly reduced systolic, mean and diastolic arterial pressure in Wistar rats with desoxycorticosterone acetate‐salt and NG‐ nitro‐L‐arginine methyl ester (L‐NAME) induced experimental hypertension. In the rat isolated mesenteric vascular bed pre‐contracted with norepinephrine, bolus injections of GSE induced endothelium‐dependent vasodilatation that was substantially inhibited by L‐NAME, but not by indometacin, tetraethylammonium or glibenclamide. Lipid peroxidation of hepatic microsomes estimated as malondialdehyde production was concentration‐dependently inhibited by GSE. In conclusion, the antihypertensive effect of GSE might be owing to a combination of vasodilator and antioxidant actions of GSE. These findings also suggest that the beneficial effect of moderate red wine consumption could be owing to an antihypertensive action induced by compounds occurring in the skin of vinifera grapes.

Effect of niflumic acid on noradrenaline‐induced contractions of the rat aorta

1 The effects of niflumic acid, an inhibitor of calcium‐activated chloride channels, were compared with the actions of the calcium channel antagonist nifedipine on noradrenaline‐evoked contractions in isolated preparations of the rat aorta. 2 The cumulative concentration‐effect curve to noradrenaline (NA) was depressed by both nifedipine and niflumic acid in a reversible and concentration‐dependent manner. The degree of inhibition of the maximal contractile response to NA (1 μm) produced by 10 μm niflumic acid (38%) was similar to the effect of 1 μm nifedipine (39%). 3 Contractions to brief applications (30 s) of 1 μm NA were inhibited by 55% and 62% respectively by 10 μm niflumic acid and 1 μm nifedipine. 4 In the presence of 0.1 μm nifedipine, niflumic acid (10 μm) produced no further inhibition of the NA‐evoked contractions. Thus, the actions of niflumic acid and nifedipine were not additive. 5 In Ca‐free conditions the transient contraction induced by 1 μm NA was not inhibited by niflumic acid (10 μm) and therefore this agent does not reduce the amount of calcium released from the intracellular store or reduce the sensitivity of the contractile apparatus to calcium. 6 Niflumic acid 10 μm did not inhibit the contractions produced by KCl (up to 120 mM) which were totally blocked by nifedipine. Contractions induced by 25 mM KCl were completely inhibited by 1 μm levcromakalim but were unaffected by niflumic acid. 7 It was concluded that niflumic acid produces selective inhibition of a component of NA‐evoked contraction which is probably mediated by voltage‐gated calcium channels. These data are consistent with a model in which NA stimulates a calcium‐activated chloride conductance which leads to the opening of voltage‐gated calcium channels to produce contraction.

Bronchodilator activity of Mikania glomerata Sprengel on human bronchi and guinea‐pig trachea

The effects of aqueous extracts and hydro‐alcoholic extract (HAE), and of a dichloromethane fraction (MG1) obtained from the HAE of Mikania glomerata leaves on isolated respiratory and vascularsmooth muscle have been investigated. Aqueousextracts and HAE induced a significant inhibition on the histamine contractions on the isolated guinea‐pig trachea. HAE extract induced a concentration‐dependent relaxation on guinea‐pig trachea pre‐contracted with histamine (IC50 0.34 (0.29‐0.39) mg mL−1), acetylcholine (IC50 0.72 (0.67‐0.77) mg ml−1) or K+ (IC50 1.41 (1.18‐1.64) mg mL−1) and on isolated human bronchi precontracted with K+ (IC50 0.34 (0.26‐0.42) mg mL−1). The dichloromethane fraction induced a concentration dependent relaxation in guinea‐pig trachea precontracted with K+ (IC50 0.017 (0.012‐0.022) mg mL−1). The dichloromethane fraction had also a small vasodilator effect on the isolated mesenteric vascular bed and on the isolated rat aorta, and a significant reduction of the oedema induced by subplantar injections of Bothrops jararaca venom in mice. When tested on plasmid DNA, MG1 did not damage the DNA. Chromatographic analysis showed the presence of 11.4% w/w coumarin in MG1. The results supported the indication of M. glomerata products for the treatment of respiratory diseases where bronchoconstriction is present.

Inhibitory action of niflumic acid on noradrenaline- and 5-hydroxytryptamine-induced pressor responses in the isolated mesenteric vascular bed of the rat

The effects of niflumic acid, an inhibitor of calcium‐activated chloride currents, were compared with the actions of the calcium channel blocker nifedipine on noradrenaline‐ and 5‐hydroxytryptamine (5‐HT)‐induced pressor responses of the rat perfused isolated mesenteric vascular bed. Bolus injections of noradrenaline (1 and 10 nmol) increased the perfusion pressure in a dose‐dependent manner. Nifedipine (1 μm) inhibited the increase in pressure produced by 1 nmol noradrenaline by 31±5%. Niflumic acid (10 and 30 μm) also inhibited the noradrenaline‐induced increase in perfusion pressure and 30 μm niflumic acid reduced the pressor response to 1 nmol noradrenaline by 34±6%. The increases in perfusion elicited by 5‐HT (0.3 and 3 nmol) were reduced by niflumic acid (10 and 30 μm) in a concentration‐dependent manner and 30 μm niflumic acid inhibited responses to 0.3 and 3 nmol 5‐HT by, respectively, 49±8% and 50±7%. Nifedipine (1 μm) decreased the pressor response to 3 nmol 5‐HT by 44±9%. In the presence of a combination of 30 μm niflumic acid and 1 μm nifedipine the inhibition of the pressor effects of noradrenaline (10 nmol) and 5‐HT (3 nmol) was not significantly greater than with niflumic acid (30 μm) alone. Thus the effects of niflumic acid and nifedipine were not additive. In Ca‐free conditions the transient contractions induced by 5‐HT (3 nmol) were not reduced by 30 μm niflumic acid, suggesting that this agent does not inhibit calcium release from the intracellular store or the binding of 5‐HT to its receptor. Niflumic acid 30 μm did not inhibit the pressor responses induced by KCl (20 and 60 μmol) which were markedly reduced by 1 μm nifedipine. In addition, 1 μm levcromakalim decreased pressor responses produced by 20 μmol KCl. These data suggest that niflumic acid does not block directly calcium channels or activate potassium channels. It is concluded that niflumic acid selectively reduces a component of noradrenaline‐ and 5‐HT‐induced pressor responses by inhibiting a mechanism which leads to the opening of voltage‐gated calcium channels. Our data suggest that the Ca2+‐activated chloride conductance may play a pivotal role in the activation of voltage‐gated calcium channels in agonist‐induced constriction of resistance blood vessels.

The role of bradykinin, AT2 and angiotensin 1-7 receptors in the EDRF-dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat

The mechanisms involved in the vasodilator actions of angiotensin II (Ang II) have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the Ang II vasodilator effect using rat isolated mesenteric vascular bed (MVB). Under basal conditions, Ang II does not affect the perfusion pressure of MVB. However, in vessels precontracted with norepinephrine, Ang II induces vasodilation followed by vasoconstriction. Vasoconstrictor, but not the vasodilation of Ang II, is inhibited by AT1 antagonist (losartan). The vasodilator effect of Ang II was not inhibited by AT2, angiotensin IV and angiotensin 1–7 receptor antagonists alone (PD 123319, divalinal, A 779, respectively). The vasodilator effect of Ang II is significantly reduced by endothelial removal (deoxycholic acid), but not by indomethacin. Inhibition of NO‐synthase by NG‐nitro‐L‐arginine methyl ester (L‐NAME) and guanylyl cyclase by 1H‐[1,2,3] oxadiazolo [4,4‐a] quinoxalin‐1‐one (ODQ) reduces the vasodilator effect of Ang II. This effect is also reduced by tetraethylammonium (TEA) or L‐NAME, and a combination of L‐NAME plus TEA increases the inhibitory effect of the antagonists alone. However, indomethacin does not change the residual vasodilator effect observed in vessels pretreated with L‐NAME plus TEA. In vessels precontracted with norepinephrine and depolarized with KCl 25 mM or treated with Ca2+‐dependent K+ channel blockers (charybdotoxin plus apamin), the effect of Ang II was significantly reduced. However, this effect is not affected by ATP and voltage‐dependent K+ channel blockers (glybenclamide and 4‐aminopyridine). Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin (BK) and Ang II in the rat MVB. The inhibitory effect of the B2 receptor antagonist HOE 140 on the vasodilator effect of Ang II is further enhanced by PD 123319 and/or A 779. The present findings suggest that BK plays an important role in the endothelium‐dependent vasodilator effect of Ang II. Probably, the link between Ang II and BK release is modulated by receptors that bind PD 123319 and A 779.

Antihypertensive and endothelium-dependent vasodilator effects of Alpinia zerumbet, a medicinal plant.

Alpinia zerumbet (K. Schum), a medicinal plant originated from West Asia, is used in the northeast and southeast of Brazil as infusions or decoctions as a diuretic, antihypertensive, and antiulcerogenic. Experiments were undertaken to determine whether a hydroalcoholic extract obtained from leaves of Alpinia zerumbet (AZE) induces vasodilation in the mesenteric vascular bed (MVB), and an antihypertensive effect was also assessed in rats with DOCA-salt hypertension. In MVB precontracted with norepinephrine, AZE induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3]oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of AZE. In vessels precontracted with norepinephrine, the vasodilator effect of AZE was not changed by 4-aminopyridine, glibenclamide, or by charybdotoxin plus apamin. Concentrations of atropine, pyrilamine, and yohimbine that significantly reduced the vasodilator effect of acetylcholine, histamine, and clonidine, respectively, did not change the vasodilator effect of AZE. HOE 140, which significantly reduced the vasodilator effect of bradykinin, induced a slight but significant reduction on the vasodilator effect of AZE. Chronic oral administration of AZE induced a significant reduction in systolic, mean, and diastolic arterial pressure in rats with DOCA-salt hypertension. Probably the vasodilator effect of AZE is dependent on the activation of the NO-cGMP pathway and independent of activation of ATP-dependent, voltage-dependent, and calcium-dependent K+ channels. Bradykinin receptors may also participate in the vasodilator effect of AZE. Finally, the vasodilator and antihypertensive effects of AZE demonstrated in the present study provide experimental support for the indication of Alpinia zerumbet as an antihypertensive medicinal plant.

Inhibition of L-arginine transport in platelets by asymmetric dimethylarginine and NG-monomethyl-L-arginine: Effects of arterial hypertension

1. Nitric oxide (NO) produced by human platelets plays an important role in all stages of platelet activation. l‐Arginine, the precursor for NO synthesis, modulates NO production by platelets. The l‐arginine analogues asymmetric dimethylarginine (ADMA) and NG‐monomethyl‐l‐arginine (l‐NMMA) are endogenous inhibitors of nitric oxide synthase (NOS), involved in the physiopathology of arterial hypertension. The aim of the present study was to investigate the inhibitory effects of endogenous and exogenous l‐arginine analogues on l‐arginine influx in platelets from healthy controls and hypertensive patients.

Schistosoma mansoni: Preparation, characterization of (Na+ + K+)ATPase from tegument and carcass

The preparation and some biochemical properties of a (Na+ + K+)ATPase from male adult Schistosoma mansoni are described. After incubation in a membrane disruption medium, the tegument and carcass of the worms were separated and treated to obtain fractions enriched in (Na+ + K+)ATPase. The activity of the tegumental ouabain sensitive (Na+ + K+)ATPase at 37 C was 20.3 mumole Pi X mg-1 protein X hr-1 and represented 32% of the total ATPase activity. The (Na+ + K+)ATPase prepared from the carcass had a lower specific activity (3.7 mumole Pi X mg-1 protein X hr-1) but a higher relative activity (55%). Similar concentrations of Na+ and K+ activated the enzymes from both sources, and both enzymes were inhibited by similar concentrations of calcium. However, the enzyme from carcass was ten times more sensitive to ouabain than the enzyme from tegument. Comparison with results obtained on the (Na+ + K+)ATPase of human heart showed that the enzymes from the worms were more resistant to ouabain. The half maximal inhibitory concentration of dihydroouabain compared to that of ouabain was also different in the enzymes from human and worm. We conclude that (1) there exists at least one structural difference between the (Na+ + K+)ATPase of S. mansoni and that of the human host, and (2) it is useful to separately study the enzymes from tegument and carcass because they differ in sensitivity to cardiac glycosides.

ANGIOTENSIN II-MEDIATED VASODILATION IS REDUCED IN ADULT SPONTANEOUSLY HYPERTENSIVE RATS DESPITE ENHANCED EXPRESSION OF AT2 RECEPTORS

1 The vasodilator action of angiotensin (Ang) II has not yet been demonstrated in spontaneously hypertensive rats (SHR), nor have any possible changes in this response during the development of hypertension. 2 In the present study, the vasodilator effect of AngII was evaluated in the rat isolated, preconstricted mesenteric arterial bed (MAB) from 6‐ (young) and 24‐week‐old (adult) SHR and compared with effects on MAB from age‐matched normotensive rats (control). 3 Angiotensin II (10–300 nmol) induced vasodilation in noradrenaline (NA)‐preconstricted MAB that was greater in vessels from young compared with adult rats in both the control and SHR groups. Angiotensin II‐induced vasodilation was reduced by the angiotensin AT2 receptor antagonist PD 123319 (10 µmol/L), the angiotensin‐(1–7) receptor antagonist A779 (1 µmol/L) and the bradykinin B2 receptor antagonist HOE‐140 (0.01 µmol/L), but not by the AT1 receptor antagonist losartan (30 µmol/L). Expression of AT2 receptors was weak in vessels from adult control rats compared with that in young control rats, whereas in young SHR AT2 receptor expression was increased compared with that in young control rats. This increased expression of AT2 receptors was maintained in adult SHR and there was no significant difference in AT2 receptor expression between young and old SHR. 4 The findings of the present suggest that AngII induces an AT2 receptor‐mediated vasodilator effect in the MAB via activation of angiotensin‐(1–7) and bradykinin receptors, an action that is reduced in adult control rats and adult SHR. In adult control rats, the attenuated response of AngII is probably due to endothelial dysfunction and reduced expression of AT2 receptors, whereas in adult SHR it is associated with endothelial dysfunction alone. Increased expression of AT2 receptors in SHR may represent a counteracting response for modulating blood pressure.

Effect of propofol on human fetal placental circulation

BACKGROUND Propofol is an alternative to thiopental for induction of general anaesthesia for cesarean section. It crosses the placenta and induces vasodilatation of isolated vessels and may therefore alter fetal placental vascular resistance. The direct effect of propofol on the fetal placental circulation was studied in vitro. The actions of propofol on vasoconstrictive effects induced by angiotensin II (Ang II), bradykinin (BK), prostaglandin F(2alpha) (PGF(2alpha)) and potassium chloride (KCl) were evaluated. METHODS Full-term healthy human placentas (n=48) were perfused with modified Tyrodes solution using a pulsatile pump. Placental perfusion pressure was measured in response to injection of Ang II, BK, KCl and PGF(2alpha) before and after perfusion with propofol (1.7 x 10(-5) and 5.6 x 10(-5) M). RESULTS BK, Ang II, KCl and PGF(2alpha) induced a dose-dependent increase in placental perfusion pressure. Propofol induced a concentration-dependent decrease in placental perfusion pressure, but this was not observed with the propofol solvent (Intralipid). Propofol, but not Intralipid, reduced the vasoconstrictor effects of BK, KCl and PGF(2alpha), while the effect of Ang II was not changed. The effect of KCl was abolished in placentas perfused with Ca(2+)-free solution, while the effect of Ang II was not altered. CONCLUSIONS Propofol induced vasodilatation and inhibited the vasoconstrictive effects of BK and PGF(2alpha), in the human placenta. These findings suggest that propofol may not reduce fetal placental blood flow. Since propofol reduced the vasoconstricting effect of KCl but not that of AngII, we propose that the vasodilatory effect of propofol in the human placenta involves inhibition of Ca(2+) channels.