R. Bello

Mechanisms of gastroprotection by transdermal nitroglycerin in the rat

Nitric oxide (NO) donors prevent experimentally‐induced gastric mucosal damage, but their clinical utility is limited by short duration of action or unsuitability of the pharmaceutical form employed. This study analyses the gastroprotection elicited by a clinically used mode of continuous administration of an NO donor, namely the nitroglycerin patch. Application to rats of a transdermal patch that releases doses of nitroglycerin comparable to those used in man (40, 80, 160 and 400 ng min−1 rat−1) reduced gastric damage induced by indomethacin (25 mg kg−1, p.o. or s.c.). The nitroglycerin patch (160 ng  min−1 rat−1) also diminished damage by oral administration (1 ml) of acidified bile salts (100 mg kg−1 taurocholic acid in 150 mM HCl) or 50% ethanol. Transdermal nitroglycerin (160 ng min−1 rat−1) did not influence basal gastric blood flow, as measured by lasser‐doppler flowmetry, but prevented its reduction by indomethacin. Transdermal nitroglycerin (160 ng min−1 rat−1) prevented in vivo leukocyte rolling and adherence in the rat mesentery microvessels superfused with indomethacin, as evaluated by intravital microscopy. The transdermal nitroglycerin patch protects the gastric mucosa from damage by mechanisms that involve maintenance of mucosal blood flow and reduction of leukocyte‐endothelial cell interaction.

Analgesic and central depressor effects of the dichloromethanol extract from Schinus molle L.

The analgesic and central depressor effects of the dichloromethanol extract of Schinus molle L. were analysed in in vivo models. This extract showed low acute toxicity, CNS depressor activity and analgesic effect. Following further fractionation, the hexane/dichloromethane (75/25) fraction showed the most interesting results. Thus, this fraction caused a total inhibition of motor activity and significantly reduced the threshold of pain to chemical stimulus.

Angiotensin II is involved in nitric oxide synthase and cyclo-oxygenase inhibition-induced leukocyte-endothelial cell interactions in vivo

Chronic inhibition of nitric oxide synthase (NOS) provokes a hypertensive state which has been shown to be angiotensin II (Ang‐II) dependent. In addition to raising blood pressure, NOS inhibition also causes leukocyte adhesion. The present study was designed to define the role of Ang‐II in hypertension and in the leukocyte‐endothelial cell interactions induced by acute NOS or cyclo‐oxygenase (COX) inhibition using intravital microscopy within the rat mesenteric microcirculation. While pretreatment with an Ang‐II AT1 receptor antagonist (losartan) reversed the prompt increase in mean arterial blood pressure (MABP) caused by indomethacin, it had no effect on the increase evoked by systemic L‐NAME administration. Pretreatment with losartan inhibited the leukocyte rolling flux, adhesion and emigration which occurs after 60 min NOS inhibition by 83, 80 and 70% respectively, and returned leukocyte rolling velocity to basal levels. Losartan significantly reduced the leukocyte‐endothelial cell interaction elicited by COX inhibition. In contrast, leukocyte recruitment induced by acute mast cell activation was not inhibited by losartan. AT1 receptor blockade also prevented the drop in haemodynamic parameters such as mean red blood cell velocity (Vmean) and shear rate caused by NOS and COX inhibition. In this study, we have demonstrated a clear role for Ang‐II in the leukocyte‐endothelial cell interactions and haemodynamic changes which arise in the absence of NO or prostacyclin (PGI2). This is of interest since leukocyte recruitment, which culminates in the vascular lesions that occur in hypertension, atherosclerosis and myocardial ischemia‐reperfusion injury, might be prevented using AT1 Ang‐II receptor antagonists.

Transdermal nitroglycerin prevents nonsteroidal anti-inflammatory drug gastropathy

Abstract The application of a transdermal nitroglycerin patch (2–30 μg/3 h/rat) protected, in a dose-dependent manner, the rat gastric mucosa against damage induced by the nonsteroidal anti-inflammatory agent indomethacin (20 mg/kg s.c.).

In vitro pharmacological evaluation of the dichloromethanol extract from Schinus molle l.

The pharmacological activity of the dichloromethanol extract of Schinus molle L. (SM‐DCM) was analysed in in vitro models. Preincubation of the isolated guinea‐pig ileum or rat uterus preparations with the extract (100 μg/mL) abolished the contractile effects of histamine and serotonin respectively. At the same dose, the extract partially reduced the contractile effects of acetylcholine on the isolated rat duodenum. A 10 μg/mL dose showed an inhibitory effect on histamine and serotonin, but not on acetylcholine‐induced contractions (NS). No significant effect was found with a 1 μg/mL dose.

In vitro studies of methanol and dichloromethanol extracts of Juniperus oxycedrus L.

The present study evaluated the effect of methanol and dichloromethanol extracts obtained from the leaves and stems of Juniperus oxycedrus against neurotransmitter‐induced contraction in different isolated tissues of rats and guinea‐pigs. Diverse concentrations of these extracts inhibit the concentration curve response to histamine, serotonin and acetylcholine. These results contribute to explaining the use of this plant in folk medicine.

Effects on arterial blood pressure of methanol and dichloromethanol extracts from Juniperus oxycedrus L.

The present study analysed the effect of the methanol and dichloromethanol extracts from Juniperus oxycedrus on arterial blood pressure in anaesthetized rats. The arterial blood pressure of normotensive rats was significantly reduced by the i.v. administration of both extracts. The hypotensive effect of these extracts was independent of the adrenergic system. These results may explain the vasorelaxing actions observed in other Juniperus species.

Effects on Arterial Blood Pressure of the Methanol and Dichloromethanol Extracts from Schinus molle L. in Rats

The effects on arterial blood pressure of the methanol and dichloromethanol extracts from Schinus molle L. were analysed in urethane anaesthetized rats. In normotensive rats, the mean arterial blood pressure was significantly reduced by the i.v. administration of both extracts. The dichloromethanol extract inhibited the effects of noradrenaline on arterial blood pressure in the anaesthetized rat and it reduced the maximal contractile effect (Emax) induced by noradrenaline on rat vas deferens in the organ bath. However, the methanol extract did not modify the effects of noradrenaline in the evaluated tests.

Cardiovascular effects of the methanol and dichloromethanol extracts from Teucrium flavum L.

The effects on arterial blood pressure and heart rate of the methanol and dichloromethanol extracts from Teucrium flavumL. were analysed in urethane anaesthetized rats. Mean arterial blood pressure was significantly reduced by the i.v. administration of both extracts to normotensive rats. The methanol extract also induced a decrease in the heart rate, while the dichloromethanol extract lacked any effect on this parameter.

Low endotoxemia prevents the reduction of gastric blood flow induced by NSAIDs: role of nitric oxide

The role of nitric oxide (NO) in the effects of low endotoxemia on gastric damage and blood flow has been evaluated in indomethacin‐treated rats. Pretreatment (−1 h) with endotoxin (40 μg kg−1) reduced gastric damage induced by indomethacin (20 mg kg−1) in conscious rats. Endotoxin prevented the reduction in gastric blood flow (laser Doppler flowmetry) induced by indomethacin in pentobarbital‐anaesthetised rats. Pretreatment with an NO‐synthase (NOS) inhibitor (L‐NAME, 1 mg kg−1) reversed the protective effect of endotoxin on gastric blood perfusion. Endotoxin did not modify the expression of mRNA for endothelial NOS or inducible NOS in the gastric corpus when evaluated 1 h postinjection. However, a 3.8‐fold increase in inducible NOS mRNA and a 61% reduction in endothelial NOS mRNA were observed in the gastric corpus 4 h after endotoxin administration. Evaluation of both total and Ca2+‐dependent NOS activity by analysing the rate of conversion of L‐arginine to L‐citrulline in gastric corpus homogenates showed no differences between animals treated with endotoxin and those treated with saline 1 or 4 h beforehand. Ca2+‐independent NOS activity was almost non‐apparent in control as well as in endotoxin‐treated rats at all the time points analysed. Low endotoxemia preserves blood perfusion and protects the gastric mucosa against the deleterious effects of indomethacin through the endogenous NO release. NO synthesis in response to endotoxin does not involve the inducible NOS, but probably depends on the post‐translational/biochemical regulation in vivo of a Ca2+‐dependent NOS, most probably endothelial NOS.