Metformin reduces vascular production of vasoconstrictor prostanoids in fructose overloaded rats

1 Metformin is a hypoglycaemic drug currently used to increase insulin sensitivity in the treatment of type 2 diabetes and metabolic syndrome. Its main mechanism of action is through activation of AMP‐activated protein kinase, an enzyme that regulates cellular and whole organ metabolism. 2 The fructose‐overloaded rat is an experimental model with features that resemble human metabolic syndrome. We have previously reported alterations in vascular prostanoids (PR) in this model. 3 The aim of this study was to analyse the effects of metformin treatment on blood pressure, metabolic parameters and PR production in aorta and mesenteric vascular bed (MVB) from fructose‐overloaded animals. Four groups of male Sprague–Dawley rats were used: control, fructose overloaded (10% w/v fructose), metformin treated (50 mg kg^?1 day^?1) and fructose‐overloaded treated with metformin. 4 Rats with fructose overload had significantly elevated systolic blood pressure, glycaemia, triglyceridaemia, cholesterolaemia and insulinaemia compared with controls. Except for insulinaemia, metformin limited all these increases in fructose‐overloaded animals. 5 Fructose overload reduced prostacyclin levels in aorta and MVB, but prostaglandin E₂ levels were only reduced in MVB. Metformin treatment reduced the levels of the vasoconstrictor prostaglandins, PGF₂α and thromboxane, in both vascular preparations from fructose‐overloaded rats. PGF₂α levels were significantly reduced by metformin in controls. 6 In conclusion, one of the mechanisms by which metformin reduced blood pressure in this model is by decreasing vasoconstrictor prostaglandin production.     

Sodium molybdate prevents hypertension and vascular prostanoid imbalance in fructose‐overloaded rats

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Noradrenaline and angiotensin II modify vascular prostanoid release in fructose-fed hypertensive rats

1 A fructose-enriched diet induces hypertension, metabolic alterations and insulin resistance in rats, resembling human metabolic syndrome. Previously, we found that prostanoid production was altered in fructose-fed rats. 2 This study analysed the effects of incubation with noradrenaline (NA) and angiotensin II (Ang II) on prostanoid release in mesenteric vascular beds from control and fructose-fed rats. Animals which received fructose solution (10% w/v) for 22 weeks showed higher systolic blood pressure and triglyceridaemia. 3 In controls, NA increased 6-keto-prostaglandin (PG) F(1)alpha (prostacyclin metabolite) and thromboxane (TX) production. Ang II increased only TX release. In fructose-fed animals, NA increased 6-keto-PG F(1)alpha and TX. PGF(2)alpha (vasoconstrictor) was also elevated. Ang II also increased PGF(2)alpha and PGE(2) levels. 4 In conclusion, in fructose rats Ang II in vitro stimulates a vasoconstrictor prostanoid not stimulated in controls. This could be related to the observed in vivo blood pressure increase. In fructose-fed animals, NA and Ang II also augment vasodilator prostanoids, suggesting a compensatory mechanism because of long-term hypertension.     

Metformin prevents vascular prostanoid release alterations induced by a high‐fat diet in rats

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Long-term streptozotocin-induced diabetes alters prostanoid production in rat aorta and mesenteric bed

Vascular disease is a major cause of mortality and morbidity in chronic diabetes mellitus. Prostanoids, metabolites of arachidonic acid, include vasoactive substances produced and released from the vascular wall. Alterations in prostanoid production have been reported in the vasculature of diabetic humans and experimental animals. The aim of the present work was to study the influence of three different periods of long-term streptozotocin-induced diabetes, 30, 120 and 180 days in the production of prostanoids in the thoracic aorta and in the mesenteric vascular bed of the rat. The prostanoids released to the incubation medium by the tissues were extracted and measured by reversed-phase HPLC. In the diabetic groups, body weight was reduced and glycaemia was increased when compared with the corresponding non-diabetic controls. In the aorta, 30 days of diabetes did not modify the prostanoid release pattern, meanwhile 120 and 180 days of incubation decreased prostacyclin (PGI(2)) production. In the mesenteric bed, at 30 days the release of the vasodilators PGI(2) and prostaglandin (PGE(2)) and the vasoconstrictor thromboxane (TXA(2)) was reduced. At 120 days the vasodilators were reduced and at 180 days such reduction was joined by an increase of the release of vasoconstrictor metabolites. Thirty days of diabetes did not modify the PGI(2)/TXA(2) ratio in the aorta or mesenteric bed. On the other hand, 120 and 180 days of diabetes reduced significantly the ratio when compared with the corresponding controls. In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of diabetes on prostanoid production. The observed effects contribute to a displacement of the balance of prostanoid release in favour of the vasoconstrictor metabolites, a phenomenon that could be related to the vascular complications of diabetes mellitus.     

Oral treatment and in vitro incubation with fructose modify vascular prostanoid production in the rat

1.-- In the rat, a fructose-enriched diet induces hyperglycaemia, hypertriglyceridaemia, insulin resistance and hypertension; a model which resembles the human metabolic syndrome. 2.-- Prostanoids, metabolites of arachidonic acid, include vasoactive substances synthesized and released from the vascular wall that have been implicated in the increase of peripheral resistance, one of the mechanisms involved in the fructose-induced hypertension. 3.-- The aim of the present study was to: (i) analyse the effects of the in vitro incubation with fructose on the production and release of prostanoids in rat thoracic aorta and in rat mesenteric bed and (ii) compare the effects of incubation with those of the in vivo acute and chronic treatment of rats with fructose and with the combination of both in vivo and in vitro procedures. 4.-- Blood pressure, glycaemia and triglyceridaemia were significantly elevated in both 4- and 22-week fructose-treated groups. Meanwhile, body and heart weight as well as insulinaemia were similar between experimental animals and controls. 5.-- In aortae, 4 weeks of Fructose treatment did not modify the prostanoid pattern release, but in vitro incubation decreased prostacyclin (PGI(2)) production. However, after 22 weeks, fructose treatment and incubation exerted the same effect. 6.-- In mesenteric bed, after 4 weeks, the incubation and the combination of both procedures reduced the release of the vasodilators PGI(2) and PGE(2), while fructose treatment only diminished the PGE(2) release. On the contrary, the production of the vasoconstrictor thromboxane A(2) (TXA(2)) was enhanced by incubation and both the procedures. After 22 weeks, fructose treatment increased PGI(2) release, while it was reduced by incubation. The combination of both did not modify this peripheral resistance when compared with controls. Finally, incubation of tissues from treated rats increased the release of the vasoconstrictors, PGF(2alpha) and TXA(2). 7.-- In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of fructose on prostanoid production. This difference could be related to a more relevant role of resistance vessels in the regulation of peripheral resistance and consequently of blood pressure. The observed effects should contribute to a shift in the balance of the release of prostanoid in favour of vasoconstrictor metabolites. This phenomenon could be related to an increase in the peripheral resistance and the mild hypertension observed in the fructose-treated rats.     

Aldosterone alters the participation of endothelial factors in noradrenaline vasoconstriction differently in resistance arteries from normotensive and hypertensive rats

This study analyzed the effect of aldosterone (0.05 mg/kg per day, 3 weeks) on vasoconstriction induced by noradrenaline in mesenteric resistance arteries from WKY rats and SHR. Contraction to noradrenaline was measured in mesenteric resistance arteries from untreated and aldosterone-treatedrats from both strains. Participation of nitric oxide (NO), superoxide anions, thromboxane A₂ (TxA₂) and prostacyclin in this response was determined. 6-keto-prostaglandin (PG)F1alpha and thromboxane B₂ (TxB₂) releases were determined by enzyme immunoassay. NO and superoxide anion release were also determined by fluorescence and chemiluminiscence, respectively. Aldosterone did not modify noradrenaline-induced contraction in either strain. In mesenteric resistance arteries from both aldosterone-treated groups, endothelium removal or preincubation with NO synthesis inhibitor L-NAME increased the noradrenaline-induced contraction, while incubation with the superoxide anion scavenger tempol decreased it. Preincubation with either the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively) decreased the noradrenaline contraction in aldosterone-treated animals, while this response was not modified by COX-1 inhibitor SC-560. TxA₂ synthesis inhibitor (furegrelate), or TxA2 receptor antagonist (SQ 29 548) also decreased the noradrenaline contraction in aldosterone-treated animals. In untreated SHR, but not WKY rats, this response was increased by L-NAME, and reduced by tempol, indomethacin, NS-398 or SQ 29 548. Aldosterone treatment did not modify NO or TxB₂ release, but it did increase superoxide anion and 6-keto-PGF(1alpha) release in mesenteric resistance arteries from both strains. In conclusion, chronic aldosterone treatment reduces smooth muscle contraction to alpha-adrenergic stimuli, producing a new balance in the release of endothelium-derived prostanoids and NO.     

Endothelins: potent releasers of prostacyclin and EDRF

The isopeptides endothelin-1 (ET-1) and endothelin-3 (ET-3) are potent vasoconstrictor substances in pithed or chemically-denervated rats. However, when injected into anesthetized rats with a high resting blood pressure, these peptides have vasodepressor actions. In addition, the pressor effects were potentiated by indomethacin indicating that release of endogenous eicosanoids modulated the pressor responses. Endothelin-1 released eicosanoids from a number of perfused isolated organ preparations. Prostacyclin and thromboxane A2 were released from perfused guinea-pig lungs, prostaglandin E2, prostacyclin and thromboxane A2 from rabbit spleen and prostacyclin and thromboxane A2 from rabbit kidneys. The eicosanoids were identified both by bioassay and by radioimmunoassay. Injection of ET-1 or ET-3 into the mesenteric artery of the rat isolated perfused mesentery preparation caused dose-related reductions in perfusion pressure. These depressor effects could be abolished by removing the endothelium with deoxycholate or by perfusing with oxyhaemoglobin, indicating that they were caused by release of EDRF. Endothelin-1 also released EDRF, identified by bioassay, from the endothelium of a perfused rabbit aorta. Endothelin-1 and ET-3 injected into anesthetized rabbits inhibited ex vivo platelet aggregation by increasing cyclic AMP, presumably through the release of prostacyclin into the circulation. Thus, endothelins release prostacyclin and EDRF both in vitro and in vivo.     

A high‐fat plus fructose diet produces a vascular prostanoid alterations in the rat

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Protein kinase A increases electrical stimulation-induced neuronal nitric oxide release in rat mesenteric artery

The aim of this study was to analyse the possible influence of cyclic AMP-protein kinase A (cAMP-PKA) activation on neuronal nitric oxide (NO) release induced by electrical field stimulation in mesenteric arteries from Wistar Kyoto (WKY) rats. Western blot experiments demonstrated the expression of neuronal NO synthase (nNOS) in mesenteric artery from WKY rats; however, electrical field stimulation alone did not induce detectable NO release. Preincubation with forskolin allowed NO release induced by electrical field stimulation, which was abolished by: the neuronal toxine tetrodotoxin, the nNOS inhibitors 7-nitroindazole or N(omega)-propil-l-arginine (NPLA), and the PKA inhibitors N-(2-(p-Bromocinnamylamino) ethyl 5-isoquinolinesulfonamide hydrochloride (H-89) or (9R,10S,12S)-2,3,9,10,11, 12-Hexahydro-10-9-methyl-1-oxo-9,12-epoxy-1H-diindolo(1,2,3-fg:3,2,1k)pyrrolo(3,4-l)(1,6) benzodiazocine-10-carboxylic acid hexyl ester (KT-5720). Preincubation with prostacyclin also allowed the NO release induced by electrical field stimulation which was significantly decreased by: the neuronal toxine tetrodotoxin, the nNOS inhibitors 7-nitroindazole or NPLA, and the PKA inhibitors H-89 or KT-5720. The NOS inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) did not modify the vasoconstrictor response induced by electrical field stimulation. However, in the presence of forskolin or prostacyclin, l-NAME increased the vasoconstrictor response to electrical field stimulation. These results indicate that forskolin and prostacyclin allow neuronal NO release induced by electrical field stimulation through a mechanism involving cAMP-PKA activation in rat mesenteric arteries.     

Endogenous prostacyclin increases neuronal nitric oxide release in mesenteric artery from spontaneously hypertensive rats

The aim of this study was to analyse the possible influence of endogenous prostacyclin on neuronal nitric oxide (NO) release induced by electrical field stimulation in mesenteric arteries from spontaneously hypertensive rats (SHR). Preincubation with the prostacyclin synthesis inhibitor tranylcypromine decreased NO release induced by electrical field stimulation, which was reversed by exogenous prostacyclin. Preincubation with tranylcypromine increased basal and electrical field stimulation-induced [3H]noradrenaline release. The nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl esther (L-NAME) increased the vasoconstrictor response induced by electrical field stimulation. In the presence of tranylcypromine, L-NAME did not modify the vasoconstrictor response induced by electrical field stimulation. In the presence of tranylcypromine and prostacyclin, LNAME increased the vasoconstrictor response to electrical field stimulation. These results indicate that endogenous prostacyclin positively modulates the neuronal NO release induced by electrical field stimulation and that this neuronal NO participates in the regulation of the vasomotor response.     

Mechanical effects of some prostanoids on isolated human oesophageal submucosal veins.

The effects of prostaglandins E1, E2, F2 alpha, prostacyclin, and the thromboxane A2-mimic U46619 were investigated on isolated human oesophageal submucosal veins from the oesophageal body and the oesophagogastric junction. U46619 most potently, but also PGF2 alpha produced venocontraction without differences between preparations from the oesophageal body and the oesophagogastric junction. PGE1 and prostacyclin caused relaxation of vessels precontracted with U46619 (10(-9) M). PGE2 induced either contraction or relaxation, but biphasic effects in the same vessel segment were not seen. Indomethacin 10(-6) M inhibited the contractile responses to both noradrenaline and K+ (124 mM), suggesting that the agonists induced synthesis or release of vasoconstrictor prostanoids. Prostanoids exert potent mechanical effects in submucosal oesophageal veins and may be of physiological importance.     

Mechanical Effects of Some Prostanoids on Isolated Human Oesophageal Submucosal Veins

Abstract: The effects of prostaglandins E₁, E₂, F_2α, prostacyclin, and the thromboxane A₂-mimic U46619 were investigated on isolated human oesophageal submucosal veins from the oesophageal body and the oesophagogastric junction. U46619 most potently, but also PGF_2α produced venocontraction without differences between preparations from the oesophageal body and the oesophagogastric junction. PGE₁ and prostacyclin caused relaxation of vessels precontracted with U46619 (10^-9 M). PGE₂ induced either contraction or relaxation, but biphasic effects in the same vessel segment were not seen. Indomethacin 10^-6 M inhibited the contractile responses to both noradrenaline and K⁺ (124 mM), suggesting that the agonists induced synthesis or release of vasoconstrictor prostanoids. Prostanoids exert potent mechanical effects in submucosal oesophageal veins and may be of physiological importance.     

Fructose overload modifies vascular morphology and prostaglandin production in rats

1. A fructose (Fru)-enriched diet induces a mild increase in blood pressure associated with hyperglycaemia, hypertriglyceridaemia, and insulin resistance, resembling the human 'syndrome X', being an useful model to study hypertension and type 2 diabetes. 2. A sustained elevation of blood pressure is associated with cardiovascular structural modifications such as left ventricular hypertrophy and increased wall thickness:lumen diameter ratio in blood vessels. 3. Prostanoids (PR), metabolites of arachidonic acid through the cyclooxygenase pathway, include vasoactive substances synthesized and released by the vessel walls. 4. The aim of the present study was to analyse, in Fru-treated rats: (i) the morphology of mesenteric vessels and; (ii) the PR production in aorta and mesenteric vessels, in order to assess whether these parameters are related with the haemodynamic alterations observed in this experimental model. 5. Blood pressure, glycaemia and triglyceridaemia, were significantly elevated in both (4 and 22 weeks) Fru-treated groups. Meanwhile body and heart weight as well as insulinaemia were similar between experimental animals and controls. 6. The mesenteric vessels of Fru-treated rats (22 weeks) showed an increased thickness and area of the media when compared with the controls; meanwhile, the lumen diameter was similar in both groups. 7. The Fru treatment for 4 weeks did not modify PR production in aorta, whereas in the mesenteric bed it diminished prostaglandin (PG) E(2) release significantly compared with the controls. However, in the group treated for 22 weeks, Fru reduced PGI(2) production in the aorta, as assessed by 6-keto-PGF(1)alpha measurements. Meanwhile, in the mesenteric bed, the chronic Fru treatment decreased PGE(2) release but, rather surprisingly, increased the output of PGI(2) when compared with its corresponding controls. 8. In conclusion, the present study shows the existence of an alteration in the morphology of mesenteric vessels in Fru-treated rats, which could be related to an increase in peripheral resistance and the consequent mild hypertension observed in this model. However, a diminished release of vasodilator PRs, such as PGE(2) in mesenteric vessels at 4 and 22 weeks and PGI(2) in aorta at 22 weeks could further impair the vessel response. The increase in PGI(2) observed in the chronic group in mesenteric vessels could be attributed to a compensatory mechanism.     

The effects of nafazatrom in an acute occlusion-reperfusion model of canine myocardial injury

Summary The effects of the lipoxygenase enzyme inhibitor nafazatrom on infarct size, haemodynamics, and prostanoid release was studied in a canine occlusion-reperfusion model of ischaemic myocardial injury. Treatment was with 10 mg/kg nafazatrom i.d., starting before coronary occlusion, 2 h and 6 h thereafter, and was repeated in 6 h intervals. The left anterior descending (LAD) coronary artery was occluded for 6 h and reperfused for 42 h. Infarct size and anatomic area dependent on the occluded LAD were determined post mortem by the tetrazolium staining technique. Nafazatrom significantly reduced the extent of irreversible myocardial ischaemic damage whether it was expressed as g/100 g left ventricle (24 ± 4 vs. 46 ± 6 in controls;p<0.01; mean ± SEM) or as percentage of LAD risk region for infarcting (38 ± 8 vs. 65 ± 7% in controls;p<0.05). Nafazatrom did not affect peripheral haemodynamics but during drug vehicle treatment and LAD occlusion systemic blood pressure, left ventricular pressure anddP/dt _max decreased while filling pressure, heart rate, and the S-T segments of the ECG increased. The incidence of ventricular fibrillation was 8% during drug treatment and coronary ligature vs. 25% in controls (n.s.). During reperfusion, nafazatrom reduced the incidence of ventricular premature contractions and tachycardia. Ex vivo platelet aggregation in response to collagen was not inhibited by nafazatrom. Prostanoid release (thromboxane B₂ and 6-keto-prostaglandin F₁ as breakdown products of thromboxane A₂ and prostacyclin, respectively) remained unaltered in vehicle controls but nafazatrom treatment elevated prostacyclin release significantly at 4 and 5 h during LAD occlusion. We conclude, that inhibition of 5-lipoxygenase by nafazatrom may promote endogenous prostacyclin release and reduce infiltration of reparatory white blood cells with deleterious release of arachidonic acid products contributing to extension of infarction. This mechanism may reduce ultimate ischaemic damage to the heart.     

Endothelium-dependent and -independent vasodilator effects of eugenol in the rat mesenteric vascular bed

The possible involvement of the endothelium in the vasodilator action of eugenol was investigated in the mesenteric vascular bed (MVB) of the rat. Bolus injections of eugenol (0.2, 2 and 20 micromol) and acetylcholine (ACh; 10, 30 and 100 pmol) induced dose-dependent vasodilator responses in noradrenaline-precontracted beds that were partially inhibited by pretreatment of the MVB with deoxycholate (1 mg mL(-1)) to remove the endothelium (approximately 14% and approximately 30% of the control response remaining at the lowest doses of ACh and eugenol, respectively). The vasodilator effect of glyceryl trinitrate (1 micromol) was unaltered by deoxycholate. In the presence of either N(omega)-nitro-L-arginine methyl ester (300 microM) or tetraethylammonium (1 mM)the response to ACh was partially reduced, whereas eugenol-induced vasodilation was unaffected. Similarly the vasodilator effect of eugenol was not inhibited by indometacin (3 microM). Under calcium-free conditions the vasoconstrictor response elicited by bolus injections of noradrenaline (10 nmol) was dose-dependently and completely inhibited by eugenol (0.1-1 mM). Additionally, the pressor effects of bolus injections of calcium chloride in potassium-depolarized MVBs were greatly reduced in the presence of eugenol (0.1 mM), with a maximal reduction of approximately 71% of the control response. Our data showed that eugenol induced dose-dependent, reversible vasodilator responses in the rat MVB, that were partially dependent on the endothelium, although apparently independent of nitric oxide, endothelium-derived hyperpolarizing factor or prostacyclin. Furthermore, an endothelium-independent intracellular site of action seemed likely to participate in its smooth muscle relaxant properties.     

Inhibition by ethanol and mepacrine of phospholipase-dependent prostaglandin release from the isolated perfused rat lung

To investigate the possibility that millimolar concentrations of ethanol have a membrane-directed inhibitory effect on phospholipase A2 and prostanoid generation (suggested from previous platelet experiments), we studied the release of prostacyclin, thromboxane A2 and prostaglandin E2 from isolated perfused rat lung. Prostanoid release was evoked by arachidonic acid, bradykinin and ionophore A23187 and was measured after extraction by radioimmunoassay. In these experiments, prostanoid release is dependent upon biosynthesis from fatty acid precursors as there is no endogenous prostanoid storage pool. Arachidonic acid and bradykinin caused enhanced release of more prostacyclin than thromboxane A2 with much less prostaglandin E2 and no detectable prostaglandin F2 alpha, whereas A23187 released equal proportions of prostacyclin and thromboxane A2 with less prostaglandin E2. Ethanol at 50 mM resembled mepacrine (46 microM) in that prostanoid release in response to bradykinin and A23187 was highly significantly reduced with little effect on release induced by arachidonic acid. We suggest that ethanol, like mepacrine, interferes with prostaglandin generation by an action at the phospholipase step. This may be secondary to a physical effect on membrane configuration.     

Bradykinin-induced vasoconstriction of rat mesenteric arteries precontracted with noradrenaline.

1. Administration of bradykinin caused dose-dependent vasoconstriction in rat isolated perfused mesenteric arteries precontracted with noradrenaline. 2. The vasoconstrictor response was not mediated by BK1-bradykinin receptors. 3. Inhibition of cyclo-oxygenase with indomethacin, aspirin or meclofenamate abolished the vasoconstrictor effect of bradykinin, showing that a member of the arachidonic acid cascade may be involved. 4. Inhibitors of thromboxane synthesis (imidazole and UK 38485) did not affect or only reduced the bradykinin-induced vasoconstriction. 5. The endoperoxide H2/thromboxane A2 receptor antagonist SQ 29548 significantly reduced the vasoconstrictor effect of bradykinin, but did not affect the vasoconstrictor response to noradrenaline, adrenaline, vasopressin, 5-hydroxytryptamine or prostaglandins. 6. The eicosanoid(s) that mediate bradykinin-induced vasoconstriction appear to be synthesized outside the arterial endothelium. 7. The data suggest that the vasoconstrictor effect of bradykinin in the rat isolated mesenteric artery is mediated by vasoconstrictor arachidonic acid metabolites including the cyclic endoperoxides and/or the thromboxanes.     

Mechanisms underlying ATP-induced endothelium-dependent contractions in the SHR aorta

In mature spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats, acetylcholine, the calcium ionophore A 23187 and ATP release endothelium-derived contracting factor (EDCF), cyclooxygenase (COX) derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine have been identified as prostacyclin and prostaglandin (PG) H(2) while in response to A 23187 thromboxane A(2), along with the two other prostaglandins, contributes to the endothelium-dependent contractions. The purpose of the present study was to identify the EDCFs produced by ATP. Isometric tension and the release of prostaglandins were measured in isolated aortic rings of WKY rats and SHR. ATP produced the endothelium-dependent release of prostacyclin, thromboxane A(2) and PGE(2) (PGI(2)>TXA(2)> or =PGE(2)>PGF(2alpha)) in a similar manner in aorta from WKY rats and SHR. In SHR aortas, the release of thromboxane A(2) was significantly larger in response to ATP than to acetylcholine while that to prostacyclin was significantly smaller. The inhibition of cyclooxygenase with indomethacin prevented the release of prostaglandins and the occurrence of endothelium-dependent contractions. The thromboxane synthase inhibitor dazoxiben selectively abolished the ATP-dependent production of thromboxane A(2) and partially inhibited the corresponding endothelium-dependent contractions. U 51605, a non-selective inhibitor of PGI-synthase, reduced the release of prostacyclin elicited by ATP but induced a parallel increase in the production of PGE(2) and PGF(2alpha), suggestive of a PGH(2)-spillover, which was associated with the enhancement of the endothelium-dependent contractions. Thus, in the aorta of SHR, endothelium-dependent contractions elicited by ATP involve the release of thromboxane A(2) and prostacyclin with a possible contribution of PGH(2).     

Effects of cadmium on platelet thromboxane and vascular prostacyclin production

The interaction between cadmium and arachidonic acid metabolism in platelets and vascular tissue was evaluated, in ex vivo experiments, by determining the thromboxane levels in serum and the prostacyclin production by the aortic walls in cadmium-treated rabbits. Cadmium given parenterally for 4 days in doses of 0.25, 0.5, and 1 mg/kg/day produced a dose-dependent increase of serum thromboxane B₂ levels. The effect of cadmium on prostacyclin release was biphasic. The metal, in doses of 0.25 and 0.5 mg/kg/day, inhibited prostacyclin production in an inverse ratio with administered doses. At the higher dose (1 mg/kg/day) cadmium caused an increase in prostacyclin formation. The present results suggest that the vascular action of cadmium is due, in part at least, to the involvement of the vascular-wall and platelet prostaglandin systems.