Protection of the rat gastric mucosa by prostaglandin E2: Possible relation to stimulation of the alkaline secretion

Exogenous prostaglandins have specific protective effects on the gastric mucosa called cytoprotection which is proposed to be connected to the stimulatory effects of prostaglandins on the gastric nonparietal secretions. The protection by oral prostaglandin E₂ (PGE₂) against indomethacin-induced gastric erosions was studied in the rat, as was the effect on the protection of blocking the gastric alkaline secretion by acetazolamide. PGE₂ reduced dose-dependently the indomethacin gastric erosion formation, confirming previous results from others. Acetazolamide caused very little damage when given alone but potentiated the indomethacin erosion formation in a dose-related way. PGE₂ was less protective or without effect against lesions caused by indomethacin when given together with acetazolamide, but protection could be obtained by increasing the doses of PGE₂. Indomethacin and acetazolamide are both blockers of the gastric bicarbonate secretion, which is stimulated by PGE₂. The potentiation of indomethacin induced lesions by acetazolamide and the antagonistic actions between acetazolamide and PGE₂ on mucosal protection are compatible with the hypothesis that stimulation of the alkaline secretion is one mechanism of cytoprotection of the gastric mucosa by PGE₂.     

Studies on the role of prostaglandins in the regulation of retinal blood flow

Prostaglandin E₁ was injected close to retinal arterioles by iontophoresis. Vasodilatation apparently similar to that caused by hypercapnia or hypoxia was observed. Inhibitors of prostaglandin synthetase were injected into the circulation. There was a reversible inhibition of the retinal vasodilation normally induced by hypercapnia. It is concluded that prostaglandin E₁ satisfies two criteria for a candidate for a mediator of hypercapnia-induced arteriolar dilatation. The effect of hypoxia appears more complicated.     

The effect of buffered aspirin on plasma indomethacin

Summary Plasma indomethacin levels have been compared in 10 subjects following 100 mg of indomethacin from two different formulations, with similar disintegration and dissolution profiles. In four of these ten subjects plasma indomethacin levels were estimated after pretreatment with, and concurrent administration of, a buffered aspirin. The percentage of protein binding of indomethacin in the presence of salicylate was also estimated. No significant differences between peak plasma indomethacin levels with or without buffered aspirin were detected, but the rate of indomethacin absorption as shown by plasma levels, was significantly increased by pretreatment with and concurrent administration of, buffered aspirin. This was associated with a marked increase in side effects.     

Histochemical Studies of Testicular δ5 -3β-Hydroxysteroid Dehydrogenase and 17β-Hydroxysteroid Dehydrogenase after Chronic Indomethacin Administration in Rats Pretreated with Clomiphene-Citrate

Histochemical studies of testicular delta5-3beta-Hydroxysteroid Dehydrogenase and 17beta-Hydroxysteroid Dehydrogenase in sexually immature rats treated chronically with simultaneous Indomethacin and Clomiphene revealed greater inhibition in the enzyme activities when compared to Clomiphene treated animals alone. This suggests prostaglandin-inhibitors may be directly inhibitory to NAD-requiring enzymes involved in testicular steroid biosynthesis.     

Prostacyclin, indomethacin and the cerebral circulation

The effect of intracarotid prostacyclin (PGI2) on cerebral blood flow (CBF) was measured by the 133xenon intracarotid injection technique in 8 baboons. Intracarotid prostacyclin increased CBF by 22% at 10(-7) g/kg/min and by 71% at 5 x 10(-6) g/kg/min, accompanied by systemic hypotension and tachycardia. The effects of PGI2 (10(-7) g/kg/min) were not potentiated by transient opening of the blood-brain barrier with the intracarotid hypertonic urea technique. At hypercapnia, the vasoconstrictor effect of indomethacin on the cerebral circulation was reversed by PGI2. These results support our suggestion that a prostaglandin, in particular PGI2, is required for hypercapnia to produce full cerebral vasodilatation. In separate experiments, following craniectomy in 5 cats, PGI2, but not its stable metabolite 6-keto-PGF1 alpha, dilated pial arterioles when locally injected into the mock CSF overlying the arteriole.     

PARTICIPATION OF PROSTANOIDS IN CHEMICAL ACTIVATION OF THE PERICARDIAL PRESSOR REFLEX IN DOGS

1. Experiments were performed on anaesthetized, open-chest dogs to determine the reflex effects on systemic blood pressure and heart rate produced by stimulation of the parietal pericardium with bradykinin, prostacyclin, prostaglandin E₂ (PGE₂), prostaglandin D₂ (PGD₂) and arachidonic acid. 2. Pericardial application of bradykinin (1 μg) consistently elicited reflex increases in blood pressure and heart rate, whereas application of prostanoids or arachidonic acid in doses up to 10 μg failed to produce any cardiovascular responses. 3. Indomethacin, applied either directly to the parietal pericardium (1 μg/ml) or given intravenously (5 mg/kg) caused a long lasting reduction of the reflex responses to bradykinin. The reflex effects of bradykinin could be temporarily restored by treatment of the pericardium with either prostacyclin (0.1 μg/min) or PGE₂ (0.1 μg/min). PGD₂ (0.1-1 μg/min) did not influence the bradykinin induced pericardial reflex. 4. Superfusion of arachidonic acid (3 μg/min) over the pericardium amplified the reflex effects of bradykinin when given before, but not when given after indomethacin treatment. 5. The results indicate that locally formed prostanoids, specifically prostacyclin and PGE₂, can facilitate activation of the pericardial pressor reflex by bradykinin. The findings may be relevant to the changes in cardiovascular activity occurring during pericardial inflammation.     

Prostaglandin-mediated control of rat brain kynurenic acid synthesis – opposite actions by COX-1 and COX-2 isoforms

Summary. Kynurenic acid (KYNA), an endogenous glutamate-receptor antagonist preferentially blocking NMDA-receptors, has analgesic properties and has also been implicated in the pathophysiology of schizophrenia. Recently, the non-steroid anti-inflammatory drug (NSAID) diclofenac was found to increase rat brain KYNA. Here, we analyze whether cyclooxygenase (COX)-1 or COX-2 modulate the levels of rat brain KYNA. The non-selective COX-inhibitor diclofenac (50mg/kg, i.p.) or indomethacin (50mg/kg, i.p.), a non-selective inhibitor with a preferential selectivity for COX-1, produced an elevation in brain KYNA. In contrast, the COX-2 selective inhibitors parecoxib (25mg/kg, i.p.) or meloxicam (5mg/kg, i.p.) decreased brain KYNA. Both elevation and lowering of brain KYNA by indomethacin or parecoxib, respectively, were prevented by the prostaglandin E₁/E₂ agonist misoprostol (1mg/kg, s.c.). It is proposed that increased brain KYNA formation induced by NSAIDs displaying an inhibitory action on COX-1 contribute to their analgesic efficacy as well as to their psychiatric side effects.     

In situ inhibition of uterine activity by indomethacin: possible relevance to preterm labor prevention after fetal surgery

Purpose

This report is an analysis of the effects of local indomethacin delivery on uterine activity in vitro.

Methods

Isolated strips of time-dated pregnant rats’ myometrium were placed within controlled tissue baths. Spontaneous muscular activity was recorded by a force transducer connected to a polygraph at cumulative concentrations of indomethacin. Statistical analysis was by single-factor analysis of variance (ANOVA), with P values of less than .05 considered significant.

Results

Within a narrow concentration range, the effects of indomethacin on frequency and amplitude of myometrial contractions were nonmonotonic, with an increase in frequency at levels that began to depress amplitude. However, both amplitude and frequency were significantly depressed and eventually totally abolished at most concentrations studied (P < .05).

Conclusions

Indomethacin administered in situ consistently inhibits or completely arrests overall myometrial activity. The concept of local myometrial delivery of indomethacin, possibly via slow release systems, may prove clinically useful as an adjuvant to its systemic administration in preterm labor prevention after fetal surgery, warranting further trials in vivo.     

Indomethacin decreases particulate guanylyl cyclase activity in rat kidney

1. Effects of non-steroidal anti-inflammatory drugs on the local atrial natriuretic peptide (ANP) and nitric oxide (NO) systems in the kidney were investigated. 2. Male Sprague-Dawley rats were treated with indomethacin (5 mg/kg, every 12 h, i.p.) for 2 days. The expression of ANP and natriuretic peptide receptor-A (NPR-A) mRNA was determined in the kidney, as was that of endothelial NO synthase (NOS) proteins. Particulate and soluble guanylyl cyclase activities were determined separately. 3. Following treatment with indomethacin, urinary sodium excretion decreased significantly. Although the renal expression of ANP was not changed significantly, that of NPR-A decreased significantly. The expression of NOS increased significantly. Particulate guanylyl cyclase activity was decreased, whereas the activity of soluble guanylyl cyclase was increased. The catalytic activity of Na(+)/K(+)-ATPase was increased, with no significant changes in its expression. The expression of the type 3 Na/H exchanger and Na-K-2CL cotransporters increased significantly. 4. The indomethacin-induced decrease in urinary sodium excretion may be attributed, at least in part, to decreased activity of the local ANP/cGMP system. The increased activity of the NO/cGMP system may be a compensatory response to the diminished activity of the prostaglandin system.     

Improvement of vascular function by chronic administration of a cyclo-oxygenase inhibitor in cholesterol-fed rabbits

1. Atherosclerotic cardio- and cerebrovascular disease is a leading cause of mortality in Western countries. Aspirin-like drugs are widely used to prevent and treat these occlusive cardio- and cerebrovascular diseases. The beneficial effects of these drugs have been largely attributed to inhibition of platelet cyclo-oxygenase activity and thromboxane (TX) A2 production. We investigated the effect of an aspirin-like drug, namely indomethacin, on endothelial function, plaque and platelet aggregation and the formation of vasoactive substances during the development of atherosclerosis in cholesterol-fed rabbits. 2. Rabbits were fed 1% cholesterol (n = 8), 1% cholesterol plus 25 mg/day indomethacin (n = 8) or normal rabbit chow (control group; n = 8) for 12 weeks. Urinary excretion rates of 2,3-dinor-TXB2, 6-keto-prostaglandin (PG) F1alpha, 8-iso-PGF2alpha and nitrate were analysed at the beginning of dietary intervention and at 4 weekly intervals thereafter. At the end of the study period, platelet aggregation, aortic plaque formation and endothelium-dependent and -independent vascular functions of isolated aortic rings ex vivo were assessed. 3. Compared with control, in the cholesterol-fed group, urinary 2,3-dinor-TXB2, 6-keto-PGF1alpha and 8-iso-PGF2alpha excretion and platelet aggregation were significantly increased (P < 0.05), but urinary excretion of nitrate was decreased (P < 0.05). Treatment with indomethacin significantly reduced platelet aggregation, urinary 2,3-dinor-TXB2, 6-keto-PGF1alpha and 8-iso-PGF2alpha excretion (P < 0.05 vs the cholesterol-fed group) and attenuated the reduction in urinary nitrate excretion. 4. Cholesterol feeding progressively increased aortic intimal thickening and impaired endothelium-dependent vasodilator function (P < 0.05 vs control), whereas indomethacin partially prevented aortic plaque formation and restored endothelium-dependent vasodilation (P < 0.05 vs the cholesterol-fed group). 5. The present study demonstrates that indomethacin reduces the progression of atherosclerotic lesions and improves endothelium-mediated vascular responses ex vivo in cholesterol-fed rabbits. The beneficial effects of indomethacin may be due to its ability to prevent the elevation of platelet aggregation, TXA2 (measured as urinary 2,3-dinor-TXB2 excretion) and 8-iso-PGF2alpha formation and to retard the decrease in endogenous nitric oxide synthesis (assessed as urinary excretion of nitrate). Despite indomethacin treatment leading to the suppression of prostacyclin biosynthesis (assessed as urinary 6-keto-PGF1alpha excretion), according to our data, indomethacin appears to preserve endothelial function.