Vascular Eicosanoids Research Articles

Eicosanoid blood vessel regulation in physiological and pathological states.

Arachidonic acid can be metabolized in blood vessels by three primary enzymatic pathways; cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 (CYP). These eicosanoid metabolites can influence endothelial and vascular smooth muscle cell function. COX metabolites can cause endothelium-dependent dilation or constriction. Prostaglandin I2 (PGI2) and thromboxane (TXA2) act on their respective receptors exerting opposing actions with regard to vascular tone and platelet aggregation. LO metabolites also influence vascular tone. The 12-LO metabolite 12S-hydroxyeicosatrienoic acid (12S-HETE) is a vasoconstrictor whereas the 15-LO metabolite 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA) is an endothelial-dependent hyperpolarizing factor (EDHF). CYP enzymes produce two types of eicosanoid products: EDHF vasodilator epoxyeicosatrienoic acids (EETs) and the vasoconstrictor 20-HETE. The less-studied cross-metabolites generated from arachidonic acid metabolism by multiple pathways can also impact vascular function. Likewise, COX, LO, and CYP vascular eicosanoids interact with paracrine and hormonal factors such as the renin-angiotensin system and endothelin-1 (ET-1) to maintain vascular homeostasis. Imbalances in endothelial and vascular smooth muscle cell COX, LO, and CYP metabolites in metabolic and cardiovascular diseases result in vascular dysfunction. Restoring the vascular balance of eicosanoids by genetic or pharmacological means can improve vascular function in metabolic and cardiovascular diseases. Nevertheless, future research is necessary to achieve a more complete understanding of how COX, LO, CYP, and cross-metabolites regulate vascular function in physiological and pathological states.

Abstract 250: 20-HETE is Increased and EETs are Decreased in the Renal Vasculature of a Rat Model of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women during their reproductive years. Enlarged ovaries containing numerous small cysts, elevated circulating androgens, modest increases in blood pressure, and insulin resistance, are among the main symptoms of PCOS. However, the mechanisms responsible for higher blood pressure have not been elucidated. We have characterized a rat model of PCOS, the hyperandrogenemic female (HAF) rat that exhibits characteristics of PCOS in women. The present study was performed to test the hypothesis that 20-HETE and EET levels and expression of the cytochrome P450 (CYP) 4A ω-hydroxylases are different in HAF and placebo rats. Dihydrotestosterone (DHT) (7.5 mg/90 days) or placebo pellets were implanted subcutaneously in female SD rats (n = 6/group) at 4 weeks of age. Kidneys were removed at 12 weeks of age, preglomerular vessels isolated, and 20-HETE, EETs, and ω-hydroxylase activity were measured by liquid chromatography-mass spectroscopy; CYP 4A protein was measured by western blot. The basal renal microvascular level of 20-HETE (0.15± 0.02 vs. 0.81± 0.08 pmol/mg; p<0.001) and renal vascular ω-hydroxylase activity (0.20± 0.04 vs. 0.69± 0.14 pmol/min/mg; p<0.01) were higher in HAF compared to placebo controls. In addition, CYP4A protein expression was increased by 79% (0.31 vs. 0.40 AU; p<0.005) in HAF rats. In contrast, the basal renal microvascular level of EETs was reduced in HAF rats (40.80± 11.96 vs. 2.33± 1.74 pmol/mg; p<0.005). The data suggest that renal production of 20-HETE is increased in HAF, and may contribute to renal vascoconstriction, whereas EETs are decreased which may contribute to reduced vasodilation of preglomerular vasculature. These data suggest that androgens may affect intrarenal vascular eicosanoids in women with PCOS to mediate their increases in blood pressure.

Eicosanoids and renal vascular function in diseases

Arachidonic acid metabolites are vital for the proper control of renal haemodynamics and, when not properly controlled, can contribute to renal vascular injury and end-stage renal disease. Three major enzymatic pathways, COX (cyclo-oxygenase), CYP450 (cytochrome P450) and LOX (lipoxygenase), are responsible for the metabolism of arachidonic acid metabolites to bioactive eicosanoids. These eicosanoids can dilate or constrict the renal vasculature and maintain vascular resistance in the face of changing vasoactive hormones. Renal vascular generation of eicosanoids is altered in pathophysiological conditions such as hypertension, diabetes, metabolic syndrome and acute renal failure. Experimental evidence supports the concept that altered eicosanoid metabolism contributes to renal haemodynamic alterations and the development and progression of nephropathy. The possible beneficial renal vascular actions of enzymatic inhibitors, eicosanoid analogues and receptor antagonists have been examined in hypertension, diabetes and metabolic syndrome. This review highlights the roles of renal vascular eicosanoids in the pathogenesis of nephropathy and therapeutic targets for renal disease related to hypertension, diabetes, metabolic syndrome and acute renal failure.

Production of eicosanoids and angiotensin II in resistance vessels in spontaneously hypertensive rats.

1. Angiotensin II (AngII) and eicosanoids may be important in vascular remodelling and the pressor response via autocrine and paracrine mechanisms. We evaluated the influences of ageing and beta-adrenoceptor stimulation on the production of vascular AngII and eicosanoids in male spontaneously hypertensive rats (SHR), aged 5, 17 and 30 weeks, and age-matched Wistar-Kyoto (WKY) rats. 2. All rats were weighed and their systolic blood pressure (SBP) was measured by the tail-cuff method. Mesenteric arteries were isolated and perfused with Krebs'-Henseleit solution. The outflows of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, thromboxane B2 (TxB2) and AngII were measured by specific radioimmunoassays. 3. The SBP was higher in SHR than in WKY rats in the 17- and 30-week-old groups and increased with age. Basal levels of PGE2 were significantly lower in SHR than in WKY rats. The ratios of 6-keto-PGF1 alpha to TxB2 and PGE2 to TxB2 were significantly lower in 17-week-old SHR compared with age-matched WKY rats. Basal AngII release did not differ between SHR and WKY rats and decreased with age. Isoproterenol stimulated the release of AngII; the magnitude of the increment was greater in WKY rats than in age-matched SHR. These results show that there is an imbalance in the production of vasodilator and vasoconstrictor eicosanoids in the resistance vessels of SHR at ages at which hypertension developed. 4. This imbalance may contribute to the increased vasoconstrictor response and vascular remodelling in SHR. Our findings suggest that vascular AngII plays a role in the ageing process and that beta-adrenoceptor-stimulated release of vascular AngII is impaired in SHR.

Arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) exert systemic effects when applied topically in the mouse.

We studied the systemic actions of topically applied arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) in the mouse. AA or TPA-induced ear edema, increases in vascular permeability, eicosanoid levels, neutrophil and mononuclear influx were determined in both phlogogen-treated and contralateral vehicle-treated ear of each mouse and were compared with vehicle-treated ears from control mice. Edema and vascular permeability increases appeared only in AA- or TPA-applied ears. Moreover, in contralateral ears from AA-treated mice an increase in 6-keto-PGF1 alpha and LTB4 was found. Only LTB4 increased in the contralateral ear after TPA. Contralateral ears from AA- or TPA-treated mice also showed a significant increase in MPO levels. The increased levels of 6-keto-PGF1 alpha but not those of LTB4 in contralateral ears were reduced by indomethacin applied simultaneously with the phlogogen. AA also increased plasma and serum levels of LTB4, but not those of 6-keto-PGF1 alpha. In contrast, TPA increased plasma and serum levels of 6-keto-PGF1 alpha and LTB4. The results show that both AA and TPA applied topically exert systemic effects.

25-Hydroxycholesterol enhances eicosanoid production in cultured bovine coronary artery endothelial cells by increasing prostaglandin G/H synthase-2

Oxidized derivatives of cholesterol, the oxysterols, have been implicated in the development of atherosclerosis. We have found that the oxysterol, 25-hydroxycholesterol (25OHC), is a potent stimulator of eicosanoid production in endothelial cells. Confluent monolayers of bovine coronary artery endothelial cells (BCAECs) were treated with 25OHC (10 μg/ml) or interleukin-1 β (IL-1 β, 1 ng/ml), a known prostaglandin G/H synthase-2 (PGHS-2) inducer, for 48 h at 37°C. Following incubation with [ 14C]arachidonic acid, the 14C-labeled metabolites of arachidonic acid were extracted and resolved using both normal and reverse phase high-performance liquid chromatography (HPLC) systems. 25OHC-treated cells had a five-fold increase in their prostaglandin production when compared to untreated cells. Eicosanoid production in IL-1 β treated cells was not as pronounced. The major component in both sets of cells comigrated with 6-ketoPGF 1 α . Other PGHS metabolites, 15- and 11-hydroxyeicosatetraenoic acids (HETEs) and 12-hydroxyheptadecatrienoic acid (HHT) were also identified and increased following 25OHC treatment. Epoxyeicosatrienoic acids, metabolites of cytochrome P 450, were not effected. Enhanced production of 6-ketoPGF 1 α , 15-HETE, 11-HETE and HHT were inhibited by indomethacin. Thus, all eicosanoids induced by 25OHC treatment were PGHS products. Western immunoblot analysis of lysates from 25OHC, IL-1 β, or vehicle treated cells using anti-PGHS-1 and -2 antibodies revealed a significant increase in PGHS-2, but not PGHS-1, in both 25OHC and IL-1 β treated cells. The notion that oxysterols can modulate vascular eicosanoid production through enzyme induction may be important in ultimately understanding their role in the pathogenesis of atherosclerosis.

Role of catecholamines in platelet function: pathophysiological and clinical significance

Platelets are involved in the pathogenesis of vascular damage in both atherosclerosis and arterial hypertension. Their reactivity in vivo is influenced by different factors, including sympathoadrenal activation, plasma levels of atherogenic lipoproteins and haemorrheological changes. In the present review, we examine the modulation of platelet function by the sympathoadrenal system and concentrate on the role of circulating catecholamines in the control of platelet responses. Human platelets exhibit both adrenergic and dopaminergic receptors that are influenced by different catecholamines. alpha(2)-Adrenoceptors of alpha(2A) subtype prevail on platelet membrane; through their stimulation, catecholamines potentiate the effects of other agonists and, at higher concentrations, initiate platelet responses, including aggregation, secretion and arachidonate pathway activation. Physiological and pathological conditions causing sympathoadrenal activation in vivo, i.e. physical activity, mental stress, insulin-induced hypoglycaemia, acute coronary ischaemia and heart failure, modify the circulating platelet populations and modulate platelet reactivity through an increase in circulating catecholamines. A sympathoadrenal hyperactivation modifies the function of circulating platelets through direct catecholamine effects, catecholamine-induced changes of haemodynamic factors and lipid pattern and inhibition of the vascular eicosanoid synthesis. The catecholamine effects on platelet function can be involved in the interplay among stress, adrenomedullary system activation and cardiovascular diseases.

Effect of high potassium diets on the vascular and renal prostaglandin system in stroke-prone spontaneously hypertensive rats

High potassium (K) diets are known to have a protective effect on the endothelium and the kidney against hypertensive injury independent of blood pressure change. Vasodepressor prostaglandins (PGs) have been shown to be cytoprotective in various tissues. This study investigated the effect of high K diets on the vascular and renal eicosanoid system in stroke-prone spontaneously hypertensive rats (SHRsp). Eicosanoid production by the aorta and eicosanoid content in the renal cortex were examined in SHRsp rats fed high NaCl diets containing either 0.5% K (normal) or 2.1% K (high). Although the high K diet did not affect the blood pressure, SHRsp on the high K diet had less thickening of the aortic wall than SHRsp on the normal K diet (−15%, p < 0.001). The aortic strip of the high K SHRsp produced less vasodepressor PG than that of the normal K SHRsp when they were incubated in a medium (PGI 2 −45%, p < 0.003; PGE 2 −34%, p < 0.001). Furthermore, when the aorta was perfused in a chamber at hypertensive pressure, again the high K aorta showed reduced PGI 2 production as compared with the normal K aorta (intravascular side −52%, p < 0.01). Eicosanoid content in the renal cortex was not significantly different between the normal K and the high K SHRsp (PGI 2 79 vs 87 ng/g dry weight; PGE 2 214 vs 233 ng/g dry weight). Thus, the high K diet reduced vascular eicosanoid production but did not alter eicosanoid content in the renal cortex. The reduced vascular eicosanoid production in the high K SHRsp may reflect the reduced necessity for cytoprotective vasodepressor PG against vascular injuries.

Endotoxic shock has differential effects on renal and splanchnic eicosanoid synthesis

This study examined the differential effects of endotoxin on renal and splanchnic vascular (SV + SI) eicosanoid synthesis. Dogs were anesthetized and subjected to a challenge of 1 mg/kg (i.v.) bolus of B-lipopolysaccharide endotoxin followed by a 3 h infusion of endotoxin at 0.5 mg/kg/h. The kidney and SV + SI were cannulated and perfused in vitro with Krebs buffer. The venous effluent from the kidney and SV + SI were assayed for 6-keto-PGF 1a (PGI 2), PGE 2, Leukotriene B 4 (LTB 4), LTC 4, and thromboxane B 2 (TXB 2) by enzyme immunoassay. Endotoxin treatment markedly increased splanchnic PGI 2 release (splanchnic vasodilator) two fold and decreased release of all other measured eicosanoids. Endotoxin treatment markedly increased renal PGE 2 (renal vasodilator) but did not significantly increase PGI 2. These data showed that endotoxin treatment stimulated both the splanchnic vascular bed and kidney to increase synthesis and release of their major endogenous vasodilator eicosanoids.

Direct vascular actions of hydrochlorothiazide and indapamide in isolated small vessels

The mechanism by which thiazides lower peripheral resistance is unresolved. The aim of this study was to investigate the mechanisms of the acute vasodilator action of hydrochlorothiazide and the ‘thiazide-like’ diuretic indapamide on human, guinea pig and rat small arteries. Vessels were mounted on a myograph and the relaxation profile of both drugs and interactions with K + channels and the vascular eicosanoid system were studied. Neither drug had any relaxant effect in rat mesenteric vessels and indapamide did not relax human arteries. Hydrochlorothiazide in both human and guinea pig vessels produced significantly more relaxation of noradrenaline than K +-constricted vessels (P < 0.001). Relaxation to hydrochlorothiazide was reduced in the presence of charybdotoxin. Maximal-induced hydrochlorothiazide relaxation was reduced by 64% in human arteries (P < 0.001) and by 91% in guinea pig vessels (P < 0.001). Incubation with glibenclamide and indomethacin had no effect on the relaxant activity of hydrochlorothiazide and indapamide. Indapamide-induced relaxation was unaffected in the presence of charybdotoxin. These results show marked differences in the acute vasodilator action of hydrochlorothiazide and indapamide. There appears to be involvement of Ca 2+-activated K + channels in the acute vasorelaxant activity of hydrochlorothiazide.

Vascular eicosanoids and platelet-aortic wall interactions in spontaneously hypertensive rats

We studied the aggregation of collagen and ADP-stimulated platelet-rich plasma (PRP) and the formation of thromboxane B 2 (TxB 2) by collagen-stimulated PRP in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto control rats (WKY). In addition, we evaluated the inhibition of the aggregation of PRP following homologous or heterologous perfusions through isolated aortas, the release of 6-keto-prostaglandin (PG)F 1α from these arteries perfused with PRP, and the sensitivity of PRP to the antiaggregatory activity of the stable PGI 2 analogue, iloprost, in both SHR and WKY. The lower activities (aggregation induced by ADP and collagen, collagen-stimulated TxB 2 production) of SHR platelets, were not accompanied by morphological differences from WKY platelets. These changes were associated with a greater release of arterial 6-keto-PGF 1α, with greater platelet antiaggregatory activity of the arterial wall and with higher sensitivity of platelets to iloprost. The lower reactivity of platelets to aggregating agents, and the greater sensitivity to prostacyclin, associated with a greater production of arterial prostacyclin were the major changes observed in SHR animals These alterations in the SHR vs. normotensive WKY may lead to an enhanced risk of hemorrhngc in the hypertensive state.

Vascular eicosanoid production in experimental hypertensive rats with different mechanisms

This study investigated the release of prostacyclin (PGI 2) and thromboxane A 2 (TXA 2) from the aortic walls of various experimental hypertensive rats, e.g. spontaneously hypertensive rats (SHR), Dahl salt-sensitive (Dahl S) rats, deoxycorticosterone (DOCA)-salt hypertensive rats and renovascular (2-kidney, 1-clip (2K1C) and 1-kidney, 1-clip (1K1C) hypertensive rats. The PGI 2 generation was increased significantly in these hypertensive models, irrespective of the hypertensive mechanisms, when they developed established hypertension. Dahl S rats, having an impaired PGI 2 production on a low salt diet, restored PGI 2 generating capacity to the control level of Dahl salt-resistant rats when they were fed a high salt diet and developed salt-induced hypertension. On the other hand, the TXA 2 generation in the vascular walls was enhanced particularly in rat models for genetic hypertension, and this system was unaltered in the models for secondary hypertension, e.g. DOCA-salt and renovascular hypertension. Thus, it is suggested that the elevation of blood pressure is associated with an increase in vascular PGI 2 production, and that the increased vascular TXA 2 production is a characteristic feature of genetic hypertension.

Radical scavengers of indapamide in prostacyclin synthesis in rat smooth muscle cell.

Indapamide, a nonthiazide diuretic, exhibits direct vasodilator action as well as natriuretic and diuretic effects. Although calcium antagonist-like activity has been addressed so far, the mechanisms for vasodilator effect are still uncertain. To understand the wide range of indapamide actions, we examined the effects of indapamide on the vascular eicosanoid generation and investigated its mechanisms by using rat vascular smooth muscle cells in culture. Indapamide uniquely increased the prostacyclin generation in the vascular smooth muscle cells in a dose-dependent manner, whereas it did not affect the vasoconstrictor thromboxane A2. Thiazide diuretics lowered the prostacyclin generation, while nonthiazide derivatives did not affect the biosynthesis. Enzymatic analysis revealed that indapamide affected neither [14C]arachidonate liberation nor prostacyclin synthase of the smooth muscle cells. Indapamide eliminated a stable free radical in a cell-free system, lowered the formation of malondialdehyde from lipid peroxides in rat brain homogenate, and reduced lipid peroxidation by the free radical generating system of xanthine-xanthine oxidase. Indeed, the scavenging action of indapamide significantly attenuated the inhibitory activity of 15-hydroperoxy-arachidonate to prostacyclin synthase activity. These results indicate that indapamide diuretic increases prostacyclin generation in the vascular smooth muscle cells possibly through antioxidant effects and that the enhanced prostacyclin generation is partly responsible for its direct vasodilator action.

Renal vascular responses and eicosanoid release in diabetic rats

Changes in renal perfusion pressure and eicosanoid release in response to arginine vasopressin (AVP; 1-10 ng) and angiotensin II (ANG II; 1-10 ng) were determined 5 days, 2 wk, and 8-12 wk after the induction of diabetes with streptozotocin (STZ) in male Wistar rats. Renal perfusion pressure responses to AVP and ANG II were reduced at 2 and 8-12 wk, but not at 5 days, after the induction of diabetes. However, AVP- and ANG II-stimulated release of prostaglandins into the renal venous effluent was depressed at all times tested. Inhibition of cyclooxygenase with indomethacin did not significantly influence the perfusion pressure responses to ANG II and AVP. Likewise, raising perfusate glucose levels to 400 mg/dl or adding insulin (180 microU/ml) to the perfusate failed to modify responses to ANG II. In contrast, administration of 0.3 microgram arachidonic acid (AA), a dose approaching threshold in control rat kidneys, to the kidney of the diabetic rat resulted in a marked increase in perfusion pressure. Associated with the increase in renal perfusion pressure to AA in the diabetic rat were significant increases in renal venous efflux of prostaglandin E2 and prostacyclin compared with control. These data suggest a defect in renal deacylation-reacylation of AA associated with an increase in cyclooxygenase activity in the diabetic rat.

Effects of thiazide diuretic on vascular eicosanoid system of spontaneously hypertensive rats.

To assess the role of the vascular eicosanoid system in thiazide therapy, we examined the aortic eicosanoid system of spontaneously hypertensive rats (SHR) treated with trichloromethiazide for 2 weeks. The blood pressure reduction caused by the thiazide treatment was associated with a significant decrease in vascular vasodepressor prostacyclin (PGI2) generation, whereas neither nifedipine nor captopril treatment lowered vascular PGI2 generation. The thiazide diuretic directly lowered PGI2 synthase activity in cultured vascular smooth muscle cells (VSMC), thereby decreasing PGI2 generation in the VSMC and probably in the aortic wall. This direct inhibitory effect on vascular PGI2 generation was not observed with either furosemide or indapamide. Thus, vascular PGI2 generation is reduced with trichloromethiazide, partly through its direct inhibition of PGI2 synthase; this has possible relevance to the non-beneficial effects of thiazide diuretics on the vascular sclerotic changes.

The effects of ketanserin on vascular eicosanoid system in spontaneously hypertensive rats and their implications

We designed experiments to reveal the effects of a S2 serotonergic receptor antagonist, ketanserin, on the vascular eicosanoid system and the relevance to medial hyperplasia in spontaneously hypertensive rats (SHR). 2-week ketanserin treatment (5 mg/kg/day) significantly decreased systolic blood pressure by 7% when compared to untreated SHR. The blood pressure reduction was associated with a significant decrease in vascular thromboxane A2 (TXA2) generation and sustained prostacyclin (PGI2) production, thereby shifting PGI2/TXA2 ratio toward vasodilatation. In contrast, the trichlormethiazide treatment, which achieved blood pressure reduction to almost the same extent, significantly decreased PGI2/TXA2 ratio. Vasodilator eicosanoids, e. g. PGI2, PGE2 and PGD2, dose-dependently decreased (3H)-thymidine uptake by vascular smooth muscle cells in culture whereas vasoconstrictor TXA2 enhanced (3H) thymidine uptake in a dose dependent manner. Indeed 2 x 10(-5) M ketanserin significantly decreased (3H) thymidine uptake by vascular smooth muscle cells by 48% although the same dose of methysergide, nonspecific serotonin inhibitor, did not affect the uptake by vascular smooth muscle cells. These results clearly indicate that the blood pressure reduction in ketanserin treatment is uniquely associated with a decrease in vascular thromboxane generation, and that it is possibly beneficial to protect vascular wall against medial hyperplasia of vascular smooth muscle cells, an integral component of arterial sclerotic changes in hypertension.

Effects of thiazide diuretic on vascular eicosanoid system of spontaneously hypertensive rats and their mechanisms

Effects of thiazide diuretic on vascular eicosanoid system of spontaneously hypertensive rats and their mechanisms

Alterations of vascular prostacyclin and thromboxane A 2 in Dahl genetical strain susceptible to salt-induced hypertension

To assess the implications of vascular eicosanoids system in the hypertension of Dahl salt-sensitive (Dahl S) strain, we investigated the production of vascular vasodepressor and vasoconstrictor eicosanoids in Dahl S rats. 14-week-old Dahl S rats on a 0.11% NaCl diet (normotension) or a 0.3% NaCl diet (borderline hypertension) had a significantly lowered generation of vascular prostacyclin (PGI 2), compared with Dahl salt-resistant (Dahl R) rats. The impairment of vascular PGI 2 in Dahl S rats was restored to the normal level of Dahl R rats with the elevation of blood pressure induced by a high salt diet (4% NaCl). The production of vascular PGI 2 was closely related to the height of blood pressure. The deterioration of vascular PGI 2 was also found in 4-week-old Dahl S rats with normotension. Conversely, vascular thromboxane A 2 (TXA 2) was significantly enhanced in 14-week-old Dahl S rats in all of the feeding groups. Thus, it seems possible that the proved alterations of the vasodepressor and vasoconstrictor eicosanoids partially contribute to the genesis of salt hypertension. Although the exact mechanisms remain obscure, the adaptation of vascular PGI 2 on a high salt diet may be suitable to compete with the high blood pressure and to protect against the vascular damage.

Influences of Cardiovascular Drugs on Leukotriene D4 Action

In anesthetized dogs, the effects of intracoronary leukotriene D4 (LTD4) (0.5 micrograms/kg) were studied on hemodynamics, the electrocardiogram (ECG) (lead II), flow in the left circumflex (LCX) coronary artery, and resistance in the absence or presence of intravenously administered cardiovascular drugs: nifedipine (10 micrograms/kg), nitroglycerin (5 micrograms/kg/min), isosorbide dinitrate (100 micrograms/kg), molsidomine (500 micrograms/kg), propranolol (500 micrograms/kg), and phentolamine (250 micrograms/kg). LTD4 increased left ventricular end-diastolic pressure (LVEDP) by 126% (p less than 0.01), the S-T segments of the ECG from 0.3 to 2.4 mV (p less than 0.001), and coronary resistance from 3.5 to 35.7 mm Hg X min X ml-1 (p less than 0.001). LCX blood flow fell from 33.8 to 3 ml/min (p less than 0.001), and LV dP/dtmax decreased by 51% (p less than 0.05). Nitroglycerin and isosorbide dinitrate were ineffective on cardiovascular LTD4 actions. Nifedipine and molsidomine inhibited the coronary flow reduction with LVEDP and S-T segment elevation by the LTD4 vasoconstriction. Negative inotropic LTD4 effects were counteracted by molsidomine. Phentolamine augmented the degree and duration of coronary constriction after LTD4. Propranolol weakened the coronary and circulatory eicosanoid actions. Indomethacin (5 mg/kg, i.v.) neither abolished the LTD4-caused hemodynamic and electrocardiographic consequences, nor attenuated beneficial nifedipine or molsidomine antagonism. Thus, it can be considered that nifedipine may inhibit the Ca2+ influx required for the effects of exogenously administered LTD4. LTD4 apparently does not act over cardiac alpha- or beta-receptor activation. Molsidomine effects on cardiohemodynamics with platelet and coronary vascular eicosanoid actions may protect the heart against LTD4 induced derangement.

Pharmacological modulation of vascular eicosanoids in rat brain cortex

Pharmacological modulation of vascular eicosanoids in rat brain cortex