Intravenous SRS-induced increases in tracheal mucous gel layer thickness: evidence for thromboxane involvement

Intravenous (IV) slow reacting substance (SRS) challenge produces bronchoconstriction that can be reduced by cyclooxygenase inhibitors. This report shows that IV SRS challenge also produces significant increases in tracheal mucous gel thickness and that the increases are inhibited by pretreatment with indomethacin (4 mg/kg, PO) or imidazole (10 mg/kg, IV). The increase in gel thickness is preceded by increases in plasma thromboxane B2 (TXB2) levels and the inhibition of gel thickening by imidazole is paralleled by decreases in plasma TXB2 levels. Aerosolized SRS produces increases in tracheal mucous gel thickness which are not inhibited by either indomethacin or imidazole, but are significantly inhibited by FPL-55712. These findings indicate that SRS acts, not only directly to stimulate mucous secretion but also indirectly through an indomethacin and imidazole sensitive mechanism.     

Intravenous SRS-induced increases in tracheal mucous gel layer thickness: Evidence for thromboxane involvement

Intravenous (IV) slow reacting substance (SRS) challenge produces bronchoconstriction that can be reduced by cyclooxygenase inhibitors. This report shows that IV SRC challenge also produces significant increases in tracheal mucous gel thickness and that the increases are inhibited by pretreatment with indomethacin (4 mg/kg, PO) or imidazole (10 mg/kg, IV). The increase in gel thickness is preceded by increases in plasma thromboxane B₂ (TXB₂) levels and the inhibition of gel thickening by imidazole is paralleled by decreases in plasma TXB₂ levels. Aerosolized SRS produces increases in tracheal mucous gel thickness which are not inhibited by either indomethacin or imidazole, but are significantly inhibited by FPL-55712. These findings indicate that SRS acts, not only directly to stimulate mucous secretion but also indirectly through an indomethacin and imidazole sensitive mechanism.     

Close-arterial administration of the thromboxane mimetic U-46619 induces damage to the rat gastric mucosa

The pro-ulcerogenic actions of the thromboxane mimetic, U-46619 on the rat gastric mucosa have been investigated, utilizing a novel technique which allows administration directly into the left gastric artery. Local intra-arterial infusion of U-46619 (100-500 ng/kg/min for 10 min) induced dose-dependent macroscopic damage in both the corpus and antral regions, characterized as vasocongestion, disruption and haemorrhage, with deep penetrating ulcers in the antral mucosa. Vascular congestion, epithelial cell and glandular disruption was observed histologically in both corpus and antral regions. Local intra-arterial infusion of lower doses of U-46619 (25-100 ng/kg/min) significantly disrupted the mucosa in the presence of 10% ethanol in a concentration which itself did not induce macroscopic damage. The damaging actions of U-46619 were substantially reduced by pretreatment with the thromboxane-receptor antagonist, BM 13,177 (5mg/kg i.v.) or 16,16-dimethyl PGE2 (5 micrograms/kg s.c.). These findings support the role of endogenous thromboxane A2 as a local mediator of gastric injury.     

Blockade of thromboxane responses in the airway of the cat by SQ 29,548

The effects of SQ 29,548, a thromboxane receptor antagonist, on airway responses were investigated in paralyzed, anesthetized, mechanically ventilated cats. Intravenous injections of the thromboxane and prostaglandin precursor, arachidonic acid (AA), and the thromboxane mimic, U 46619, produced dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance. After administration of SQ 29,548 (0.5 mg/kg iv), bronchoconstrictor responses to AA were reduced by approximately 50%, whereas responses to U 46619 were reduced by approximately 90%. The cyclooxygenase inhibitor, sodium meclofenamate (2.5 mg/kg iv), blocked the component of the airway response to AA remaining after treatment with SQ 29,548. The thromboxane receptor antagonist had no significant effect on bronchoconstrictor responses to prostaglandins F2 alpha, and D2, methacholine, 5-hydroxytryptamine, histamine, or BAY K 8644, an agent that promotes calcium entry. Reductions in systemic arterial pressure in response to AA were enhanced by the thromboxane receptor antagonist and abolished by meclofenamate. SQ 29,548 had no effect on terminal enzyme activity in microsomal fractions from cat lung. These data support the hypothesis that AA-induced bronchoconstriction in the cat is mediated in large part by the actions of thromboxane A2. These data also suggest that U 46619 and U 44069 stimulate the same airway receptor as thromboxane A2 and mimic the bronchomotor effects of this hormone, which has not yet been isolated as a pure substance. These data demonstrate that SQ 29,548 is a selective thromboxane receptor antagonist in the airways of the closed-chest cat and may be a useful probe for studying responses to thromboxane A2 in physiological and pathophysiological processes in the lung.     

Thromboxane induced red blood cell lysis

The two thromboxane A2 mimetics, carbocyclic thromboxane A2 (CTA2) and U-46619 (9,11-methanoepoxy PGH2) at concentrations of 400 ng/ml significantly enhanced the release of hemoglobin from both feline and human erythrocyte suspensions. This effect was significantly attenuated by the thromboxane receptor antagonist BM-13,505 indicating that the membrane leakiness is in some way receptor mediated. The effects also appear to be concentration-dependent over the range of 100-400 ng/ml. The membrane labilizing effect of thromboxane analogs is not due to a non-specific eicosanoid effect since iloprost, the stable prostacyclin analog, actually stabilized erythrocyte membranes. Moreover, synthetic thromboxane A2 exerted similar effects to that of the two TxA2-mimetics. This membrane labilizing action of thromboxanes may be important in propagating the other pathophysiologic effects of thromboxane A2 in cardiovascular disease states.     

Dietary n-3 fatty acids alter the contractile response to thromboxane A(2) agonists of porcine coronary arteries

Dietary supplementation with marine fish oils rich in n-3 fatty acids reduces circulating thromboxane A(2) (TxA(2)). However, the effects on thomboxane A(2) receptor mediated vascular reactivity are uncertain. The aim of this study was to test the hypothesis that dietary modification of TxA(2) levels alters vascular responsiveness to TxA(2) analogues. Juvenile female white pigs were fed a diet enriched in either 5% (w/w) fish oil or beef tallow for 6 weeks. Serum and myocardial tissue levels of eicosapentaenoic and docosahexaenoic acid reached a plateau during this period. Vascular responses were measured in isolated coronary arterial rings with intact endothelium by isometric tension measurement. Arteries from pigs fed fish oil produced a greater maximum vasoconstrictor tension to the TxA(2) analogue U46619 than did rings from pigs fed beef tallow (120 +/- 6% compared to 92 +/- 8%, values represented as a percentage relative to the maximum vasoconstrictor effect obtained to KCl, regression analysis, analysis of variance, P 相似文献   

Identification and functional characterization of thromboxane A2 receptors in Schwann cells

Previous reports have demonstrated the presence of functional thromboxane A2 (TP) receptors in astrocytes and oligodendrocytes. In these experiments, the presence and function of TP receptors in primary rat Schwann cells (rSC) and a neurofibrosarcoma-derived human Schwann cell line (T265) was investigated. Immunocytochemical and immunoblot analyses using polyclonal anti-TP receptor antibodies demonstrate that both cell types express TP receptors. Treatment with the stable thromboxane A2 mimetic U46619 (10 microM) did not stimulate intracellular calcium mobilization in rSC, whereas T265 cells demonstrated a calcium response that was inhibited by prior treatment with TP receptor antagonists. U46619 also stimulated CREB phosphorylation on Ser133 in T265 cells and, to a lesser extent, in rSC. To identify potential mechanisms of CREB phosphorylation in rSC, we monitored intracellular cAMP levels following U46619 stimulation. Elevated levels of cAMP were detected in both rSC (20-fold) and T265 (15-fold) cells. These results demonstrate that TP receptor activation specifically stimulates CREB phosphorylation in T265 cells, possibly by a calcium- and/or cAMP-dependent mechanism. In contrast, TP receptor activation in rSC stimulates increases in cAMP and CREB phosphorylation but does not elicit changes in intracellular calcium.     

Receptor-mediated effect of a synthetic thromboxane-analogue on cytosolic calcium in isolated proximal tubules.

The aims of this study were to measure cytosolic calcium concentration -[Ca2+]i- under resting conditions in isolated renal proximal tubules and to analyze the effect of U-46619 (stable analogue of thromboxane A2/PGH2 on [Ca2+]i in a mammalian epithelium. Proximal tubules were dissected out from male New Zealand rabbits (2.5 to 3.0 kg). After isolation they were washed twice and resuspended in 2 ml phosphate buffer solution (PBS). Tubules were loaded with Quin 2-AM (25 microM) for 15 min. After washing with PBS to eliminate the excess of extracellular Quin 2, fluorescence was measured at 340 nm excitation and 490 emission, under resting conditions and after stimulation. U 46619 (from 10 nm to 10 mM) increased [Ca2+]i in a concentration-dependent pattern. Exposure to an antagonist of the thromboxane receptor (S-145) blocked the response to U-46619. Removal of external calcium abolished the response to U-46619. Change of PBS for Ringer-choline blunted the response to thromboxane analogue. Our results indicate that U-46619 increases cytosolic calcium through a receptor-mediated mechanism that requires external calcium to operate. Blockade of the response in the absence of external sodium suggests that Na+/Ca2+ exchanger participates in this response.     

Chronic exposure to TXA2 increases expression of ROCKI in human myometrial cells

Increased expression of RhoA-associated protein kinase (ROK) in human pregnant myometrial tissue is due to increased expression of the p160ROKI isoform. Expression and proteolysis of p160ROKI was investigated in cultured primary human uterine smooth muscle cells stimulated with the stable thromboxane A2 (TXA2) analogue U46619. Acute exposure to U46619 showed no change in protein expression or cleavage of p160ROKI. Chronic exposure to U46619 resulted in a concentration-dependent increase in protein expression of p160ROKI that was inhibited by pre-treatment of the cells with the C3-exotoxin. Pre-incubation with the thromboxane receptor antagonist SQ29548 also blocked the U46619-mediated increase in p160ROKI protein expression but at the same time promoted increased proteolysis of pre-existing p160ROKI to p130ROKI. Pre-treatment of the cells with the caspase 3 inhibitor Z-DEVD-FMK blocked the cleavage of p160ROKI. These findings show that ROKI is an inducible isoform whose aberrant expression and cleavage needs to be controlled to prevent contractile dysfunction.     

The effect of chronic alcohol inhalation on blood pressure and the pressor response to noradrenaline and the thromboxane-mimic U46619

Rats were exposed to alcohol vapor for 6 days and the mean blood ethanol concentration (BEC) was obtained for each subject. Blood pressure and its reactivity to noradrenaline and a thromboxane-mimic U46619 were directly measured on day 6 via a catheter implanted in the tail artery of normal and ethanol-treated animals. The mean BEC for each subject correlated with mean arterial blood pressure (MAP); an increase in BEC was associated with a decrease in MAP (p less than 0.02). The mean MAP of subjects with BEC less than 168 mg% was 8% higher than normal (not significant), whereas, the mean MAP of subjects with BEC greater than 182 mg% decreased 27 +/- 4% (p less than 0.01). Conversely, the pressor response to U46619 was markedly enhanced (p less than 0.005) in rats with mean BEC greater than 182 mg% at all doses investigated (12.5-3200 ng per rat). Increases in the pressor response to noradrenaline in ethanol-treated rats were significant only when maximally stimulated by 400 and 800 ng doses (p less than 0.03). A 3-fold increase in sensitivity for U46619 was seen in subjects with high mean BEC, however, sensitivity for noradrenaline did not significantly change. Vasoreactivity was not effected in rats with mean BEC less than 168 mg%. These data demonstrate that a moderate mean BEC for 6 days induces a tendency towards a mild hypertension, whereas, high mean BEC induces marked hypotension which is associated with hyperreactivity. Long-term exposure to high blood ethanol concentrations may predispose the alcohol-dependent rats to hypertensive disease and vasospastic disorders, at least partially, as a result of enhanced sensitivity to prostaglandins such as thromboxane.     

Inhibition of platelet aggregation by unsaturated fatty acids through interference with a thromboxane-mediated process

cis- and trans-unsaturated fatty acids with 18 carbon atoms (oleic, linoleic, elaidic and linolelaidic acid) inhibited aggregation of washed rabbit platelets stimulated with collagen, arachidonic acid and U46619 when in the same concentration ranges. Thrombin-induced aggregation was not affected by any of them. Saturated fatty acid (stearic acid) had no effect on this response. The inhibition is independent of the induced change in membrane fluidity, since trans-isomers could not induce the change in fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. Unsaturated fatty acids, except linoleic acid, did not interfere with the formation of thromboxane B2 from exogenously added arachidonic acid. All the unsaturated fatty acids only slightly inhibited the arachidonic acid liberation by phospholipase A2 in platelet lysate. This indicates that the unsaturated fatty acids may block a process after formation of thromboxane A2 in response to collagen and arachidonic acid. The increase in phosphatidic acid formation stimulated with U46619 was inhibited dose dependently by each of the unsaturated fatty acids but that stimulated with thrombin was not affected by any of them. Phospholipase C activity measured by diacylglycerol formation in unstimulated platelet lysate was not inhibited by the fatty acids. The elevation of cytosolic free Ca2+ induced by arachidonic acid or U46619 and Ca2+ influx by collagen were inhibited almost completely at the same concentration as that which inhibited their aggregation. These data suggest that the unsaturated fatty acids were intercalated into the membrane and inhibited collagen- and arachidonic acid-induced platelet aggregation by causing a significant suppression of the thromboxane A2-mediated increase in cytosolic free Ca2+, probably due to interference with the receptor-operated Ca2+ channel.     

Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo.

Although (-)-(S)-trimetoquinol [1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Receptor-mediated effect of a synthetic thromboxane-analogue on cytosolic calcium in isolated proximal tubules

The aims of this study were to measure cytosolic calcium concentration -[Ca²⁺]i- under resting conditions in isolated renal proximal tubules and to analyze the effect of U-46619 (stable analogue of thromboxane A₂/PGH₂ on [Ca²⁺]i in a mammalian epithelium. Proximal tubules were dissected out from male New Zealand rabbits (2.5 to 3.0 kg). After isolation they were washed twice and resuspended in 2 ml phosphate buffer solution (PBS). Tubules were loaded with Quin 2-AM (25 μM) for 15 min. After washing with PBS to eliminate the excess of extracellular Quin 2, fluorescence was measured at 340 nm excitation and 490 emission, under resting conditions and after stimulation. U 46619 (from 10 nm to 10 mM) increased [Ca²⁺]i in a concentration-dependent pattern. Exposure to an antagonist of the thromboxane receptor (S-145) blocked the response to U-46619. Removal of external calcium abolished the response to U-46619. Change of PBS for Ringer-choline blunted the response to thromboxane analogue. Our results indicate that U-46619 increases cytosolic calcium through a receptor-mediated mechanism that requires external calcium to operate. Blockade of the response in the absence of external sodium suggests that Na⁺/Ca²⁺ exchanger participates in this response.     

Effects of thromboxane A2 on lymphocyte proliferation

The main cyclooxygenase-dependent arachidonic acid derivatives produced by monocytes and macrophages have been shown to be thromboxane A2 and prostaglandin E2. The immunomodulatory effects of thromboxane A2 were examined using a specific thromboxane synthase inhibitor (dazoxiben), a thromboxane A2 analog (U46619), and a thromboxane A2 receptor blocker (BM13.177). Dazoxiben inhibited lymphocyte proliferation in response to mitogens (PHA and OKT3), but also reoriented cyclic endoperoxide metabolism towards the production of prostaglandin E2. Prostaglandin E2 has been shown previously to inhibit mitogen-induced lymphocyte proliferation. U46619, a stable thromboxane A2 analog, slightly enhanced lymphocyte responses to mitogens in the presence of dazoxiben and in the presence of a cyclooxygenase inhibitor (indomethacin). This occurred at concentrations of U46619 which are probably supraphysiological in view of the short half-life of natural thromboxane A2. Finally, the thromboxane A2 receptor blocker BM13.177 did not have any effect on mitogen-induced lymphocyte proliferation. It is concluded that thromboxane A2 has no or minimal modulatory effects on lymphocyte proliferative responses to mitogens and that the effect of thromboxane A2 synthase inhibition is rather due to reorientation of cyclic endoperoxide metabolism, resulting in increased prostaglandin E2 production.     

Measurement of thromboxane A2-induced elevation of ionized calcium in collagen-stimulated platelets with the photoprotein, aequorin

Using aequorin-loaded rat platelets stimulated with collagen, we found two phases of Ca2+ mobilization, one coinciding with a shape change and the other with aggregation, which have not yet been detected in quin2-loaded platelets. U46619, a stable analogue of prostaglandin H2, induced only a shape change and a concomitant rapid rise in the cytoplasmic ionized calcium concentration ([Cai2+]). However, upon addition of U46619 to platelets previously stimulated with collagen in the presence of indomethacin, a rapid increase in [Cai2+] and a shape change occurred, and, after about 1 min, second increase in [Cai2+] and aggregation occurred. The actions of U46619 were inhibited by an antagonist for the thromboxane A2 (TXA2) receptor. These results suggest that the collagen-induced shape change is initiated by TXA2-induced Ca2+ mobilization, and aggregation is induced by the secondary Ca2+ mobilization induced by TXA2 and the occupation of the receptor by collagen.     

Stimulation of glycogenolysis and vasoconstriction in the perfused rat liver by the thromboxane A2 analogue U-46619

Infusion of the thromboxane A2 analogue U-46619 into isolated perfused rat livers resulted in dose-dependent increases in glucose output and portal vein pressure, indicative of constriction of the hepatic vasculature. At low concentrations, e.g. less than or equal to 42 ng/ml, glucose output occurred only during agonist infusion; whereas at concentrations greater than or equal to 63 ng/ml, a peak of glucose output also was observed upon termination of agonist infusion coincident with relief of hepatic vasoconstriction. Effluent perfusate lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios increased significantly in response to U-46619 infusion. Hepatic oxygen consumption increased at low U-46619 concentrations (less than or equal to 20 ng/ml) and became biphasic with a transient spike of increased consumption followed by a prolonged decrease in consumption at higher concentrations. Increased glucose output in response to 42 ng/ml U-46619 was associated with a rapid activation of glycogen phosphorylase, slight increases in tissue ADP levels, and no increase in cAMP. At 1000 ng/ml, U-46619 activation of glycogen phosphorylase was accompanied by significant increases in tissue levels of AMP and ADP, decreases in ATP, and slight increases in cAMP. In isolated hepatocytes, U-46619 did not stimulate glucose output or activate glycogen phosphorylase. Reducing the perfusate calcium concentration from 1.25 to 0.05 mM resulted in a marked reduction of the glycogenolytic response to U-46619 (42 ng/ml) with no efflux of calcium from the liver. U-46619-induced glucose output and vasoconstriction displayed a similar dose dependence upon the perfusate calcium concentration. Thus, U-46619 exerts a potent agonist effect on glycogenolysis and vasoconstriction in the perfused rat liver. The present findings support the concept that U-46619 stimulates hepatic glycogenolysis indirectly via vasoconstriction-induced hypoxia within the liver.     

Platelet aggregation increases cholinergic neurotransmission in canine airway

To determine whether thromboxane A2 released from aggregating platelets increases the contractile response of airway smooth muscle to cholinergic nerve stimulation and, if so, what the mechanism of action is, we studied in vitro bronchial segments from dogs under isometric conditions. The contractile responses to electrical field stimulation at 30 s and 1 min after the addition of autologous platelets were increased by 11.1 +/- 3.2 (SD) and 20.7 +/- 5.4%, respectively, and were accompanied by the release of thromboxane A2. These effects were inhibited either by pretreatment of platelets with indomethacin or by addition of the thromboxane A2 receptor antagonist SQ 29548. Likewise, the thromboxane A2 mimetic U 46619, in subthreshold doses (i.e., insufficient to increase base-line tension), increased electrical field stimulation-induced contraction by 18.7 +/- 4.8%. The increase was greater in the presence of a concentration of physostigmine that did not cause spontaneous contraction and was blocked by SQ 29548 but not by hexamethonium or by phentolamine. Methacholine-induced contractions were unaffected by U 46619. These results indicate that aggregating platelets, by releasing thromboxane A2, increase the airway contractile response to neural stimulation probably by the accelerated release of acetylcholine.     

Extracellular signal-regulated kinase1/2 in contraction of vascular smooth muscle

Smooth muscle contractility is regulated by both intracellular Ca2+ concentration ([Ca2+]i) and Ca2+ sensitivity of the contractile apparatus. Extracellular signal-regulated kinases1/2 (ERK1/2) have been implicated in modulating Ca2+ sensitivity of smooth muscle contraction but mechanisms of action remain elusive. This study investigated the roles of ERK1/2 in modulating [Ca2+]i, calcium sensitivity and the 20-kDa myosin light chain (MLC20) phosphorylation during contraction activated by alpha1-adrenoceptor agonist phenylephrine and thromboxane A2 mimetic U46619 in rat tail artery strips. A specific inhibitor for ERK1/2 activation, U0126, inhibited phenylephrine- and U46619-induced contraction, shifting both concentration-response curves rightward. During phenylephrine-stimulated contraction, U0126 exhibited concentration-dependent inhibition towards force but significant decreases in [Ca2+]i were detected only at higher concentration. Both phenylephrine and U46619 induced a transient activation of ERK1/2 which was abolished by U0126 but unaffected by a general tyrosine kinase inhibitor genistein or Rho kinase inhibitor Y27632 at concentrations inhibiting more than 50% force. Interestingly, U0126 had no effect on steady-state MLC20 phosphorylation levels stimulated by both receptor agonists. These results indicated that during contraction of rat tail artery smooth muscle activated by alpha1-adrenoceptor agonist or thromboxane A2 analogue, ERK1/2 increase Ca2+ sensitivity that does not involve the modulation of MLC20 phosphorylation.     

Differential effects of losartan and candesartan on vasoconstrictor responses in the rat

Losartan has been reported to have inhibitory effects on thromboxane (TP) receptor-mediated responses. In the present study, the effects of 2 nonpeptide angiotensin II (AT1) receptor antagonists, losartan and candesartan, on responses to angiotensin II, the thromboxane A2 mimic, U46619, and norepinephrine were investigated and compared in the pulmonary and systemic vascular beds of the intact-chest rat. In this study, intravenous injections of angiotensin II, U46619, and norepinephrine produced dose-related increases in pulmonary and systemic arterial pressure. Losartan and candesartan, in the doses studied, decreased or abolished responses to angiotensin II. Losartan, but not candesartan, and only in a higher dose, produced small, but statistically significant, reductions in pressor responses to U46619 and to norepinephrine in the pulmonary and systemic vascular beds. Furthermore, losartan significantly reduced arachidonic acid-induced platelet aggregation, whereas candesartan had no effect. Pressor responses to angiotensin II were not changed by thromboxane and alpha-adrenergic receptor antagonists, or by cyclooxygenase and NO synthase inhibitors. These results show that losartan and candesartan are potent selective AT1 receptor antagonists in the pulmonary and systemic vascular beds and that losartan can attenuate thromboxane and alpha-adrenergic responses when administered at a high dose, whereas candesartan in the highest dose studied had no effect on responses to U46619 or to norepinephrine. The present data show that the effects of losartan and candesartan on vasoconstrictor responses are different and that pulmonary and systemic pressor responses to angiotensin II are not modulated or mediated by the release of cyclooxygenase products, activation of TP receptors, or the release of NO in the anesthetized rat.     

Potentiation of vagal contractile response by thromboxane mimetic U-46619

We studied the effect of the thromboxane mimetic U-46619 on tracheal smooth muscle contraction caused by bilateral stimulation of the vagus nerves in 14 mongrel dogs in situ. The parasympathetic contractile response was studied isometrically after beta-adrenergic blockade with 2 mg/kg iv propranolol plus 20 micrograms X kg-1 X min-1 continuous intravenous infusion and blockade of endogenous prostaglandin synthesis with 5 mg/kg iv indomethacin. An initial frequency-response curve was generated by electrical stimulation of the caudal ends of cut cervical vagi over the range of frequencies 2-25 Hz (constant 25 V) at 15-s intervals. In five dogs, 10(-10) to 10(-8) mol of the thromboxane mimetic (15S)-hydroxyl-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U-46619) was injected selectively into the tracheal arterial circulation, causing a transient contractile response (less than or equal to 10 g/cm). Additional frequency response studies were generated 7 min before and 1, 15, 30, 45, and 60 min after U-46619. Substantial augmentation of tracheal contraction to efferent vagal stimulation was observed after U-46619 for all frequencies greater than 4 Hz (P less than 0.02). Augmentation of vagally mediated contraction was not observed in four other dogs after equivalent tracheal contraction was elicited without U-46619. Similarly, in four separate dogs, augmentation of tracheal contraction was not observed when acetylcholine was given instead of vagal stimulation after U-46619. We conclude that the thromboxane analogue, U-46619, causes augmentation of tracheal contractile response induced by efferent vagus nerve stimulation. Potentiation is caused by a prejunctional action of U-46619 and is not induced by nonspecific precontraction with another agonist.