T. Tano

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.

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.

Relaxant Effects of Sildenafil on the Human Isolated Bladder Neck

OBJECTIVE To evaluate potential in vitro relaxant actions of sildenafil on human isolated bladder neck smooth muscle. METHODS Bladder neck strips were sampled from patients (aged 55-77 years) submitted to prostatic surgery (6 adenomectomies and 1 radical prostatectomy). These were carefully dissected into 1-2 x 0.5-cm pieces and suspended in an organ bath containing 30 mL of a modified Krebs Henseleit solution, bubbled with 95% O(2)/5% CO(2). After tissue stabilization and viability test with KCl, the tissue was precontracted with phenylephrine, and a concentration-response relaxant curve to sildenafil was constructed. The effect of sildenafil was also assessed in tissues treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (inhibitors of nitric oxide synthase and guanylyl cyclase, respectively). RESULT Sildenafil induced significant bladder neck relaxation at all concentrations tested. The maximum relaxation was 86.97% +/- 6.69%, obtained with a high concentration of sildenafil (5.1 x 10(-4) M). Both L-NAME and ODQ significantly reduced sildenafil-induced relaxation. CONCLUSIONS Sildenafil was effective in inducing bladder neck smooth muscle relaxation in vitro. This effect was almost abolished by L-NAME and ODQ, clearly demonstrating a dependence of the nitric oxide-cyclic guanosine monophosphate pathway. Our in-vitro results suggest that sildenafil might be useful in improving lower urinary tract symptoms due to benign prostatic hyperplasia.

Role of the NO-cGMP pathway in the systemic antinociceptive effect of clonidine in rats and mice

The mechanism underlying the analgesic effect of clonidine, an alpha(2)-adrenoceptor agonist, remains uncertain. Activation of alpha(2)-adrenoceptor induces the release of nitric oxide (NO) from endothelial cells, which has led us to test the hypothesis that the observed antinociceptive effect induced by the systemic administration of clonidine depends on the NO-cGMP pathway. The possible involvement of an opioid link in the antinociceptive effect of clonidine was also evaluated. The antinociceptive effect induced by systemic administration (intravenous or intraperitoneal) of clonidine was evaluated using the rat paw formalin, mice tail-flick and writhing tests. Clonidine (3-120 microg/kg) induces a dose-dependent antinociceptive effect in the formalin, tail-flick and writhing tests. The antinociceptive effect of clonidine in a dose that had no sedative effect assessed by rota rod test, was significantly reduced by NO-synthase and guanylyl cyclase inhibition. The antinociceptive effect of morphine, but not clonidine, was inhibited by naloxone. Our current results suggest that the antinociceptive effect of systemic clonidine does not involve the opioid receptor and is modulated by the NO-cGMP pathway.

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.

Inhibitory effect of sildenafil on the human isolated seminal vesicle

To investigate the effects of sildenafil on noradrenaline‐ and potassium‐induced contractions of isolated human seminal vesicles (SVs), as premature ejaculation is a relatively common male sexual dysfunction that currently lacks an adequate therapy, and recent in vitro tests showed that sildenafil induces relaxation of rodent isolated SVs, but it is not known whether it also inhibits isolated human SV.