Lucrecia Moreno

Anatomical differences in responsiveness to vasoconstrictors in the mesenteric veins from normal and portal hypertensive rats

The present study evaluates the effects of pre-hepatic portal hypertension, induced in rats by partial portal vein ligation, on the responsiveness of rostral (proximal) and caudal (distal) rings from the mesenteric vein. The anatomical origin of the sample influenced the response to vasoconstrictors in sham-operated animals, and this pattern of reactivity was specifically modified in portal-ligated rats. In veins from sham-operated rats, contraction induced by a submaximal concentration of KCl (60 mM) was greater in proximal than in distal rings. Vasopressin and 5-hydroxytryptamine contracted mainly distal rings, methoxamine showed a greater effect on proximal rings, and endothelin-1 and angiotensin-II contracted vein rings independently of their anatomical origin. In veins from portal hypertensive rats, responses to KCl (60 mM) were increased in distal rings, and all rings exhibited enhanced reactivity to vasopressin and 5-hydroxyptyptamine as well as attenuation of the response to methoxamine. Responses to endothelin-1 were decreased in proximal vein rings from portal hypertensive rats whereas responses to angiotensin-II were not influenced by the anatomical origin. Incubation with atropine, propranolol or indomethacin, did not modify the responses to vasopressin and 5-hydroxytryptamine in tissues from either sham-operated or portal hypertensive animals. Likewise, the hyporeactivity to methoxamine and endothelin-1 in rings from portal hypertensive rats persisted in the presence of the nitric oxide inhibitor NG-nitro-l-arginine methyl ester. These results suggest the physiological existence of anatomical differences in the responsiveness to vasoconstrictors throughout the mesenteric vein and that changes in the responsiveness of the mesenteric vein induced by portal hypertension are specific for each agonist and possibly result from individual variations at a receptor or post-receptor level.

Nitric oxide and sensory afferent neurones modulate the protective effects of low-dose endotoxin on rat gastric mucosal damage.

Pretreatment (1 h) with low doses (5-40 micrograms/kg i.p.) of Escherichia coli endotoxin dose dependently reduced the gastric mucosal damage induced by a 10 min challenge with 1 ml ethanol (50% and 100%) in conscious rats. Treatment with the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 5 and 10 mg/kg i.p.), significantly inhibited the protective effects of endotoxin (40 micrograms/kg i.p.). The actions of L-NAME were reversed by the prior administration of L-arginine (100 mg/kg i.p.). The protective effects of endotoxin were not influenced by pretreatment with dexamethasone (5 mg/kg s.c. twice) or indomethacin (5 mg/kg s.c.). However, ablation of sensory afferent neurons by capsaicin pretreatment (20, 30 and 50 mg/kg s.c.) abolished the mucosa protective effects of endotoxin (40 micrograms/kg). These findings suggest that the protection elicited by low doses of endotoxin against ethanol-induced mucosal damage involves synthesis of nitric oxide and activation of sensory neurones.

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.

Role of central glutamate receptors, nitric oxide and soluble guanylyl cyclase in the inhibition by endotoxin of rat gastric acid secretion

This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cyclic GMP in the acute inhibitory effects of low doses of peripheral endotoxin on pentagastrin‐stimulated acid production. Vagotomy or intracisternal (i.c.) microinjections of the NO‐inhibitor, NG‐nitro‐L‐arginine methyl esther (L‐NAME; 200 μg rat−1) restored acid secretory responses in endotoxin (10 μg kg−1, i.v.)‐treated rats. The acid‐inhibitory effect of i.v. endotoxin (10 μg kg−1, i.v.) was prevented by prior i.c. administration of the NMDA receptor antagonists, dizocilpine maleate (MK‐801; 10 nmol rat−1) and D‐2‐amino‐5‐phosphono‐valeric acid (AP‐5; 20 nmol rat−1), or the AMPA/kainate antagonist 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX; 10 nmol rat−1). However, the competitive metabotropic glutamate receptor antagonist (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG; 20–1000 nmol rat−1) did not antagonize the effects of endotoxin. I.c. administration of L‐glutamate (0.1 nmol rat−1) inhibited pentagastrin‐stimulated gastric acid secretion. Coadministration with L‐NAME (200 μg rat−1) prevented the inhibition of gastric acid secretion by the aminoacid. I.c. administration of 1H‐[1,2,4]Oxazodiolo[4,3‐a]quinoxalin‐1‐one (ODQ; 100 nmol rat−1), a soluble guanylyl cyclase (sGC) blocker, reversed the hyposecretory effect of endotoxin. I.c. administration of the cyclic GMP analogue 8‐Bromoguanosine‐3,5‐cyclic monophosphate (8‐Br‐cGMP; 100–300 nmol rat−1) reduced gastric acid production in a dose‐dependent manner. We conclude that central NMDA and AMPA/kainate receptors are involved in the acid inhibitory effect of peripherally administered endotoxin. This central pathway involves synthesis of NO, which acts on the enzyme sGC.

Role of the Endothelium in the Relaxation Induced by Propofol and Thiopental in Isolated Arteries from Man

Induction of anaesthesia with intravenous propofol and thiopental is often accompanied by hypotension. This study evaluates whether propofol and thiopental induce relaxation of isolated arteries from man and whether this effect is modulated by the endothelium.

Gastric mucosal resistance to acute injury in experimental portal hypertension

The gastric mucosa of portal hypertensive rats exhibits important microvascular changes and a nitric oxide (NO)‐dependent hyperemia. This study analyses whether portal hypertensive mucosa exhibits changes in its ability to withstand aggression. Portal hypertension was induced by partial portal vein ligation (PPVL) or common bile duct ligation (CBDL) and gastric damage was induced by oral administration of ethanol or aspirin. Experiments were performed in conscious or anaesthetized rats and some animals were pre‐treated with the NO‐synthesis inhibitor L‐NAME. Conscious PPVL or CBDL rats showed an increased resistance to the damaging effects of ethanol. Oral administration of aspirin produced less gastric damage in PPVL conscious rats than in the control group. The protective effects of portal hypertension were maintained in animals anaesthetized with ketamine and absent when pentobarbital was employed. Pre‐treatment with L‐NAME restored the damaging effects of ethanol and aspirin in PPVL rats without modifying the level of damage in control animals. Gastric bleeding induced by oral aspirin, as measured by the luminal release of 51Cr‐labelled erythrocytes, was significantly greater in PPVL rats than in control animals. Semi‐quantitiative analysis by RT – PCR of the mRNA for endothelial NO‐synthase (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) levels showed that the expression of iNOS was slightly increased in both the gastric mucosa and smooth muscle of PPVL rats. No changes were observed in eNOS and nNOS expression. Conscious portal hypertensive rats exhibit an enhanced resistance to acute gastric damage which is absent under the influence of some types of anaesthesia and seems related to an increased synthesis of nitric oxide. However, mucosal lesions in these animals show an augmented bleeding per area of injury.

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.