Effect of sodium loading and depletion on vascular reactivity and prostacyclin generation

In order to estimate the modulatory activity of Prostacyclin (PGI2) to the vascular reactivity, pressor responses to angiotensin II (A II) and noradrenaline (NA) and PGI2 generation aorta were measured using the rats of sodium loading or of sodium depletion. On the sodium loading, the blood pressure increased gradually and plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were decreased. The pressor responses to A II and NA were enhanced by sodium loading. The PGI2 generation of aorta was enhanced at the initial stage of sodium loading and decreased thereafter. The increased generation of PGI2 may represent the adaptive mechanism for the attenuation of the sustained elevation in blood pressure. It sodium depletion, the pressor responses to A II and NA were decreased, and PRA and PAC were elevated. PGI2 generation of aorta was also increased. These findings suggested that PGI2 could participate in blood pressure control mechanism on sodium loading and depletion.     

Fasting and diabetes mellitus elicit opposite effects on agonist-stimulated prostacyclin synthesis by the rat aorta

The effects of prolonged fasting and experimental nonketonuric diabetes on rat aortic prostacyclin (PGl2) synthesis were compared. Whereas fasting (for 48 hours or longer) resulted in a marked increase in trauma-, adrenaline-, and U46619-stimulated aortic PGI2 synthesis, prolonged experimental (streptozotocin-induced) nonketonuric diabetes caused a marked decrease in aortic PGI2 synthesis stimulated by the above agonists. Arachidonic acid (AA)-stimulated aortic PGI2 synthesis in fasted and diabetic rats, however, was not different from that in controls. The reduction in adrenaline- and U46619-stimulated, but not AA-induced, PGI2 synthesis in the diabetic rat suggests that the diminished production of PGI2 in diabetes may be due to diminished phospholipase A2 (or of the phospholipase C-diglyceride lipase system) activity, diminished AA stores, or both. The opposite effects of prolonged fasting and diabetes on aortic PGI2 synthesis suggest that caution should be exercised when comparing the metabolic consequences of starvation with those of diabetes.     

Ethyl icosapentate (omega-3 fatty acid) causes accumulation of lipids in skeletal muscle but suppresses insulin resistance in OLETF rats. Otsuka Long-Evans Tokushima Fatty

Ethyl icosapentate (EPA) is known to improve insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM); however, its mechanism is unclear. In this study, we attempted to determine the mechanism of EPA's effects on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Administration of EPA caused a reduction in plasma cholesterol and triglycerides, but increased cholesterol and triglyceride contents in skeletal muscle. EPA did not have an effect on glucose or insulin levels. EPA accelerated the glucose infusion rate (GIR) and improved the endothelium-dependent relaxation of OLETF rat the thoracic aorta caused by addition of acetylcholine. However, the improvement observed in endothelium-dependent relaxation disappeared after addition of N(w)-nitro-L-arginine (L-NA). Furthermore, when L-NA and indomethacine were added to the medium, relaxation of the aorta in EPA-treated rats was weaker than that in control rats. These actions may cause NO induction in the endothelium and an increase in prostaglandin I(2) (PGI(2)) and prostaglandin I(3) (PGI(3)) action, which in turn may result in improvement of insulin resistance.     

Prostacyclin (prostaglandin I2, PGI2) inhibits platelet adhesion and thrombus formation on subendothelium.

Prostaglandin I2 (prostacyclin, PGI2), a substance synthesized in the wall of blood vessels, has been previously shown to inhibit the aggregation of platelets in stirred platelet-rich plasma. We used a method in which segments of deendothelialized rabbit aorta are perfused at arterial shear rates with human blood and found that both platelet adhesion and thrombus formation on subendothelium was inhibited in blood containing 10 nM PGI2. PGI2 appears to reduce adhesion by inhibiting platelet spreading. These findings suggest that PGI2 could regulate the deposition of platelets on vascular surfaces.     

Comparison of prostaglandin synthesis by endothelial cells from blood vessels originating in the rat, baboon, calf and human

The synthesis of prostaglandins (PGs) was determined in endothelial cells obtained from various vessels from baboon, human and rat both by radioimmunoassay and prelabel of the cells with [3H] arachidonate. Cells were stimulated with bradykinin, ionophore A23187 or 10 microM arachidonate. Although prostacyclin (PGI2) has proven to be the major prostaglandin product of human umbilical vein and calf pulmonary artery endothelial cells, our results show that PGI2 is frequently not the major prostaglandin product of endothelial cells from other vessels. For example baboon endothelial cells lining the large vessels, aorta and cephalic vein produce mainly PGF2a with only small amounts of PGE2 and PGI2. Human endothelial cells from saphenous vein also produce mainly PGF2a. Baboon, human and rat adipose capillary endothelial cells make predominantly PGE2 and PGI2 with rat making significant amounts of PGF2a in addition. Endothelial cells from the rat aorta produced predominantly prostacyclin.     

Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats.

OBJECTIVE: The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). METHODS: Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar-Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1 alpha, the main metabolite of PGI2, was also measured. RESULTS: Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. CONCLUSIONS: These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR.     

Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administration of prostaglandin I2 analogue

We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high d-glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I(2) (PGI(2)) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI(2) analogue in the regulation of the local HGF system using DM rats. A PGI(2) analogue (beraprost sodium; 300 and 600 micro g/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0.01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI(2) treatment in a dose-dependent manner (P<0.01), whereas N(omega)-nitro-l-arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI(2) as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI(2) treatment. Overall, this study demonstrated that treatment with a PGI(2) analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI(2) analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.     

Stimulation and inhibition of PGI2 synthetase activity by phospholipids (PL), cholesterol esters (CE), unesterified fatty acids (UFA) and lipoproteins (LDL and HDL)

We investigated the influence of different lipids on the transformation of PGH2 to PGI2 by the microsomal fraction of pig aorta. Phospholipids and cholesterol esters obtained from animals fed prenatally a linoleic acid rich diet stimulated the PGI2 formation. However, when obtained from animals fed prenatally a linoleic acid deficient diet, phospholipids and cholesterol esters inhibited PGI2 production. Unesterified fatty acids are potent inhibitors at 1 mM. The degree of inhibition was dependent on the length of the carbon chain and the number of double bonds in the UFA molecule. We found further that lipoproteins modified the PGI2 formation at physiological concentrations. The amount of hig density lipoprotein cholesterol had a positive correlation with the activity of PGI2 synthetase, whereas the amount of low density lipoproteins cholesterol had a negative one.     

Differentiation of cyclooxygenase 1- and 2-derived prostanoids in mouse kidney and aorta

Accumulating evidence indicates cyclooxygenase (COX) 1 and COX2 differentially regulate cardiovascular and renal function. We have demonstrated previously in mice that COX2 inhibition enhances angiotensin II-induced hypertension, and COX1 inhibition attenuates the pressor effect of angiotensin II. To further elucidate the mechanism underlying the functional difference of COX1 versus COX2 inhibition, the present studies examined the prostaglandin (PG) profiles derived in COX1- or COX2-inhibited mouse kidney and aorta using gas chromatographic/mass spectrometric assays. PGE2 is the most abundant prostanoid in both renal cortex and medulla in normal C57BL/6J mice, followed by PGI2, PGF2alpha and thromboxane A2. In contrast PGI2 was most abundant in aorta followed by thromboxane A2, PGE2, and PGF2alpha. PGD2 was undetectable in control kidney or aorta. At baseline, inhibition of COX1 decreased total prostaglandins in renal cortex, medulla, and aorta, whereas COX2 inhibition decreased total prostaglandins only in renal medulla. Angiotensin II infusion significantly increased COX2-dependent/COX1-independent PGE2 and PGI2 in renal cortex and medulla. Angiotensin II also significantly increased renal PGF2alpha in cortex, but not in medulla, through both COX1- and COX2-dependent mechanisms. These studies demonstrate that although COX1 primarily contributes to basal prostanoid production in the kidney and aorta, angiotensin II increases renal vasodilator prostanoids predominately via COX2 activity. These effects may contribute to the specific effect of COX2 inhibitors to increase blood pressure.     

Failure of epoprostenol (prostacyclin, PGI2) to inhibit platelet aggregation and to prevent restenosis after coronary angioplasty: results of a randomised placebo controlled trial.

OBJECTIVE--To study the effect of epoprostenol (prostacyclin, PGI2) given before, during, and for 36 h after coronary angioplasty on restenosis at six months and to evaluate the transcardiac gradient of platelet aggregation before and after percutaneous transluminal coronary angioplasty (PTCA) in treated and placebo groups. DESIGN--Double blind placebo controlled randomised study. PATIENTS--135 patients with successful coronary angioplasty. METHODS--Intravenous infusion of PGI2 (4 ng/kg/ml) or buffer was started before balloon angioplasty and continued for 36 hours. Platelet aggregation was measured in blood from the aorta and coronary sinus before and after PTCA in each group. Routine follow up was at six months with repeat angiography and there was quantitative assessment of all angiograms (those undertaken within the follow up period and at routine follow up). PRESENTATION OF RESULTS--Restenosis rates in treated and placebo groups determined according to the National Heart, Lung and Blood Institute definition IV. Comparison at follow up between the effect of treatment on mean absolute luminal diameter and mean absolute follow up diameter in the placebo group. Comparison of acute gain and late loss between groups. RESULTS--Of 125 patients available for assessment 23 were re-admitted because of angina within the follow up period. Quantitative angiography showed restenosis in 15 (10 in the PGI2 group and five in the placebo group). Of 105 patients evaluated at six month angiography there was restenosis in nine more in the PGI2 group and 18 more in the placebo group. Total restenosis rates (for patients) were 29.2% for PGI2 and 38.3% for placebo (NS). The mean absolute gain in luminal diameter was 1.84 (0.76) mm in the PGI2 group and 1.58 (0.56) mm in the placebo group (p = 0.04); the late loss in the PGI2 group was also greater (0.65 (0.94) mm vs 0.62 (0.89) mm (NS) and there was no significant difference in final luminal diameter at follow up between the two groups (1.83 (0.88) mm v 1.59 (0.60) mm). The transcardiac gradient of quantitative platelet aggregation increased after PTCA in both groups, indicating that PGI2 in this dose did not affect angioplasty-induced platelet activation. Mean (SD) platelet activation indices in the PGI2 group were pre PTCA aorta 8.4 (4.1) v coronary sinus 8.8 (4.0) (p = 0.001) and post PTCA aorta 8.9(3.0) v coronary sinus 12.9 (5.7) (p = 0.001). In the placebo group the values were pre PTCA aorta 7.6 (3.3) v coronary sinus 7.4 (3.6) (p = 0.001) and post PTCA aorta 7.6(2.8) v coronary sinus 11.2(4.3) (p = 0.001). CONCLUSION--The dose of PGI2 given was designed to limit side effects and as a short-term infusion did not significantly decrease the six month restenosis rate after PTCA. The sample size, which was determined by the original protocol and chosen because of the potency of the agent being tested, would have detected only a 50% reduction in restenosis rate. There was, however, no effect in the treated patients on the increased platelet aggregation seen in placebo group as a result of angioplasty. Angioplasty is a powerful stimulus to blood factor activation. Powerful agents that prevent local platelet adhesion and aggregation are likely to be required to reduce restenosis.     

Comparison of prostaglandin biosynthetic activity between porcine aortic endothelial and smooth muscle cells in culture

Prostaglandin biosynthetic activity of miniature-pig aortic endothelial cells was compared with that of smooth muscle cells in culture. When used as homogenates, endothelial cells produced mainly PGE2 and 6-ketoPGF1 alpha (degradated product of PGI2) from arachidonic acid, while they produced a large amount of PGF2 alpha in addition to these when used as intact cells. Intact smooth muscle cells and their homogenates produced PGE2 as a major product. 6-KetoPGF1 alpha was produced by smooth muscle cells in the first few generations and became undetectable after several cultivations. 6-KetoPGF1 alpha and PGE2 were produced by intact or endothelium-depleted aortas. Our results suggest that both endothelial cells and smooth muscle cells in porcine aorta possess PGI2 and PGE2 biosynthetic activities. The subcultivation of smooth muscle cells, but not endothelial cells, in vitro resulted in the rapid disappearance of PGI2 synthetase activity. The PGI2 biosynthetic activity of endothelial cells was several fold higher than that of smooth muscle cells. Porcine smooth muscle cells' low ability to produce PGI2 may offer a reason why atherosclerosis is easily developed in pigs.     

Actions of prostaglandin I2 and thromboxane A2 on vascular smooth muscle tissues

Actions of prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) on vascular smooth muscles were investigated in relation to the function of the endothelium. In intact vascular smooth muscle tissues of the thoracic aorta, PGI2-Na, used as a substitute substrate of PGI2, relaxed the precontracted tissue, in a dose dependent manner, in intact tissues and also after mechanical ablation of the endothelium. Acetylcholine (ACh) relaxed the tissue precontracted by noradrenaline, in the presence or absence of indomethacin; however, the relaxation required the presence of an intact endothelium. On the other hand, increased amounts of PGI2 with the application of acetylcholine, as estimated from the amount of 6-keto-PGF1 alpha, were markedly attenuated by indomethacin. In smooth muscles of this tissue without the endothelium, ACh synthesized lesser amounts of PGI2, while PGI2-Na increased the amount of cyclic AMP. Thus, PGI2 was synthesized in both the endothelium and smooth muscles. The former produces a larger amount of PGI2 than the latter, but the PGI2 synthesized in smooth muscles may act more potently on the smooth muscle than does that synthesized in the endothelium. In the canine coronary artery, mechanical responses induced by TXA2, as estimated from actions of 9, 11,-epithio-11, 12-methano-thromboxane A2 (STA2) were enhanced after ablation of the endothelium. The minimum concentration of STA2 required to produce the contraction was above 1 nM and the maximum amplitude was evoked with 30 nM. The amplitude of the STA2-induced contraction was reduced in Ca-free solution or with the application of nifedipine. However, prazosin, propranolol or atropine had no effect on the STA2-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced serum-stimulatory activity on prostacyclin production by cultured aortic endothelial cells in diabetes mellitus

Reduced prostacyclin (PGI2) production by the vascular wall has been proposed as a possible cause of macro- or microangiopathy in diabetes mellitus. In the present study, we confirmed the stimulatory activity on PGI2 (PSA) production in plasma-derived serum (PDS) by cultured aortic endothelial cells. Furthermore, the abnormality of PSA was examined in diabetic PDS. PSA in PDS from non-insulin-dependent diabetics significantly decreased as compared with that in PDS from age-matched control subjects. There was no difference in PSA in PDS between diabetic patients with and without vascular complications such as retinopathy and nephropathy. In addition, after treatment with dialysis, PSA in diabetic PDS was still not restored to that in normal PDS. These findings suggest that relatively heat-stable (56 degrees C, 30 min) and nondialyzable PGI2 stimulatory substance(s) may decrease in diabetic PDS. It is concluded that a reduction in PDS-stimulated PGI2 production by the vascular wall can play an important role in the pathogenesis of vascular lesions in diabetes mellitus.     

Intracoronary infusion of prostaglandin I2 attenuates arterial baroreflex control of heart rate in conscious dogs

Prostaglandin I2 (PGI2) is known to stimulate ventricular C fiber receptors resulting in a Bezold-Jarisch-like reflex. Also, cardiac receptor stimulation is known to interact with the expression of arterial baroreflexes. Therefore, experiments were performed to determine the effects of left circumflex coronary artery infusion of PGI2 on the baroreflex control of heart rate in conscious instrumented dogs. Dogs were instrumented chronically with an aortic catheter for the measurement of mean aortic pressure, hydraulic occluder cuffs on the descending aorta and inferior vena cava, a left ventricular catheter for the measurement of left ventricular pressure and heart rate, and a nonocclusive catheter in the left circumflex coronary artery. At the time of experimentation, arterial pressure was altered randomly in steps by partially inflating the occluders. Mean arterial pressure-heart curves (baroreflex curves) were constructed by fitting the data to a logistic curve by nonlinear regression. PGI2 infused into the left circumflex coronary artery at doses of 10, 20, and 50 ng/kg/min caused significant (p less than 0.05) inhibition of the maximum heart rate, heart rate range, and maximum slope of the curve compared to the control baroreflex curve obtained during intracoronary infusion of PGI2 vehicle. PGI2 had no significant effect on the minimum heart rate during hypertension. Since PGI2 is known to stimulate left ventricular receptors, these effects were most likely produced via stimulation of cardiac receptors. In additional experiments using beta 1-blockade with metoprolol or cholinergic blockade with atropine methyl bromide, it was shown that PGI2 attenuates baroreflex-mediated tachycardia by preventing parasympathetic withdrawal completely and by attenuating sympathetic stimulation by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet interactions with the endothelium and the subendothelium: the role of thrombin and prostacyclin.

The adherence of 51Cr-labeled platelets to rabbit aortae everted on probes rotated in platelet-red cell suspensions has been measured. Platelet adherence to the subendothelium exposed by passage of a balloon catheter before everting the aortae was inhibited by compounds that increase platelet cyclic AMP levels (PGE1, PGI2 or dipyridamole). These agents, however, did not abolish platelet adherence to the subendothelium. Aspirin treatment of the vessel wall was used to block PGI2 production; platelet adherence to the surface of the 'undamaged' aorta and the subendothelium was studied following this treatment. Since aspirin treatment of the 'undamaged' vessel wall did not cause platelets to adhere to it, it seems unlikely that PGI2 formation by the vessel wall is the mechanism that prevents platelet adherence to normal endothelium. In addition, PGI2 formation by the vessel wall does not appear to influence platelet adherence to the subendothelium, since adherence was not increased by aspirin treatment of the damaged wall. Thrombin treatment of the 'undamaged' vessel wall increased platelet adherence to the surface, but the adherent platelets were seen to be adherent only to small areas where the endothelium was lost or damaged. Heparin reversed the effect of thrombin. Similar results were found when the subendothelium was exposed to thrombin or thrombin and heparin.     

Stimulation of vascular prostacyclin and inhibition of platelet function by oral defibrotide in cholesterol-fed rabbits

The effect of chronic oral defibrotide on platelet function, vascular PGI2 generation, atherosclerotic plaque formation and serum lipids was studied in rabbits. The animals were fed for 4 months a standard laboratory diet (150 g/day) with or without defibrotide (60 mg/kg/day) or a cholesterol-rich (1%) diet with or without defibrotide. Defibrotide significantly reduced the platelet reactivity ex vivo against collagen and ADP. This included a reduced aggregation response, thromboxane release and ATP secretion. Furthermore, the inhibition of platelet function and stimulation of platelet cAMP by iloprost, were significantly improved by defibrotide treatment. This was associated with an increased number of prostacyclin binding sites and enhanced PGI2 affinity in platelet membranes from these animals. Bradykinin stimulated PGI2 generation of segments of the thoracic aorta about 2-fold above control in both normo- and hypercholesterolemic rabbits. There was no difference in basal values between these groups but a more than 2-fold increase in either group by defibrotide treatment. Atherosclerotic plaque formation, determined by a subjective score, was found to be significantly reduced by defibrotide although the compound did not alter serum cholesterol levels. The data suggest potent and potentially valuable antiatherosclerotic effects of oral defibrotide: (i) normalization of platelet function by reduction of platelet hyperreactivity and improvement of the sensitivity towards prostacyclin, and (ii) stimulation of vascular PGI2 production.     

Functional alterations in NO, PGI2 and EDHF pathways in the aortic endothelium after myocardial infarction in rats

BACKGROUND: Previous work on endothelial dysfunction in post-MI heart failure has shown conflicting results. AIM: To analyze gender related alterations in NO-, PGI(2)- and EDHF-dependent endothelial function in the thoracic aorta 7 and 42 days after myocardial infarction (MI). METHODS AND RESULTS: MI was induced by coronary artery ligation in female and male Sprague-Dawley rats. There was no gender related difference in infarct-size or in the impairment of fractional shortening of the left ventricle 42 days after coronary ligation. Neither acetylcholine-induced (Ach) vasodilation nor basal PGI(2) production in the aorta was modified by coronary ligation. Interestingly, 7 days after MI, basal NO production was impaired and the EDHF component of Ach-induced vasodilation was up-regulated, in both male and female rats. However, 42 days post-MI, basal NO was only impaired in male rats, while EDHF was only up-regulated in female rats. CONCLUSION: MI induced impairment of functional activity of basal NO production and adaptive up-regulation of the EDHF component of Ach-induced relaxation. The above alterations in endothelial function in the aorta were gender-specific at 42 days but not 7 days after MI. Some of the previously reported discrepancies in the development of endothelial dysfunction in the post-MI period may be gender related differences.     

Prostaglandin I2 does not contribute to the hypotensive effect of the superoxide dismutase mimetic Tempo in rats with aortic coarctation-induced hypertension

This study was designed to investigate the contribution of prostaglandins to the vasodepressor effect of the superoxide dismutase mimetic Tempo in rats made hypertensive by ligation of the abdominal aorta at a point between the left and right renal arteries. Rings of thoracic aorta taken from rats with aortic coarctation released more 6-keto-PGF1alpha (a non-enzymatic product of PGI2 degradation) in the presence than in the absence of Tempo (1 mmol/L; 35.3 +/- 10.1 versus 13.6 +/- 2.6 pg/mg tissue). However, Tempo administered intravenously (2 mg/kg bolus injection plus infusion at 3 mg/kg/h) to rats with aortic coarctation did not increase significantly the concentration of 6-keto-PGF1alpha in vena cava blood. Treatment with Tempo did not affect the arterial pressure of un-operated normotensive rats but promptly decreased the arterial pressure of rats with aortic coarctation-induced hypertension (from 178 +/- 2 to 125 +/- 6 mmHg). The vasodepressor effect of Tempo in hypertensive animals was not affected by pretreatment with indomethacin to inhibit prostaglandin synthesis. These data argue against the hypothesis that PGI2 contributes to the acute hypotensive effect of Tempo in rats with aortic coarctation.     

Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction

The relevance of prostanoids to inflammation, thrombosis, and cardiovascular diseases is well known. The present study attempts to explore age effects on prostanoids and their biosynthesis cascade. Results from comparing prostanoid levels between young (6 months) and old (24 months) Fischer 344 rats showed rises of prostaglandin E2 (PGE2), PGI2, and thromboxane A2 (TXA2) levels in the old rats. Correlating evidence showed gene expression up-regulation of several prostanoid synthase enzymes in old rat aorta. Further, we found that expression of the antioxidant enzyme glutathione peroxidase was raised by age in the aorta, while superoxide dismutase and catalase expression showed no significant change during aging in the aorta. Moreover, calorie restriction (CR) was found to attenuate age-related prostanoid changes by suppressing inflammatory activities. In conclusion, the data from this study indicated that age-related increases in prostanoids and their biosynthesis might be closely associated with a weakened antioxidant capacity.     

Expression of Adhesion Molecules on the Surface of Activated Platelets is Diminished by PGI(2)-analogues and an NO (EDRF)-Donor: A Comparison Between Platelets of Healthy and Diabetic Subjects

Adhesion molecules such as P-selectin (CD 62), glycoprotein (CP) 53 (CD63) and thrombospondin play a decisive role in the thrombogenic transformation of platelets. Here we present evidence obtained using flow cytometric analysis that the PGI(2)-mimetics iloprost and taprostene, and an NO (EDRF)donor (SIN-1) are able to inhibit the expression of P-selectin, GP 53 and thrombospondin on human platelets activated by submaximal concentrations of thrombin. Since the half-maximal concentrations for inhibition of antigen expression (0.15 nM for iloprost, 3.0-5.3 nM for taprostene) are much lower than for activation of adenylate cyclase (1.4 nM for iloprost and 29.4 nM for taprostene) our data suggest that the occupation of a small number of PGI(2)-receptors is sufficient to inhibit the thrombogenic transformation and that spare PGI(2)-receptors are present on human platelets. In diabetes, the EC(50) for inhibition of expression of platelet antigens is shifted to higher concentrations suggesting that platelets from type 1 diabetic patients are partly resistant to PGI(2). Since the dose dependent increase in c-AMP by iloprost is not changed and intraplatelet c-AMP is elevated in platelets of diabetic patients, we assume that steps in the activation cascade subsequent to activation of adenylate cyclase are disturbed in diabetes.