Cyclooxygenase inhibition prevents PMA-induced increases in lung vascular permeability

The effect of cyclooxygenase inhibition in phorbol myristate acetate (PMA)-induced acute lung injury was studied in isolated constant-flow blood-perfused rabbit lungs. PMA caused a 51% increase in pulmonary arterial pressure (localized in the arterial and middle segments as measured by vascular occlusion pressures), a 71% increase in microvascular permeability (measured by the microvascular fluid filtration coefficient, Kf), and a nearly threefold increase in perfusate thromboxane (Tx) B2 levels. Cyclooxygenase inhibition with three chemically dissimilar inhibitors, indomethacin (10(-7) and 10(-6) M), meclofenamate (10(-6) M), and ibuprofen (10(-5) M), prevented the Kf increase without affecting the pulmonary arterial pressure increase or resistance distribution changes after PMA administration. The specific role of TxA2 was investigated by pretreatment with OKY-046, a specific Tx synthase inhibitor, or infusion of SQ 29548, a TxA2 receptor antagonist; both compounds failed to protect against either the PMA-induced permeability or the vascular resistance increase. These results indicate that cyclooxygenase-mediated products of arachidonic acid other than TxA2 mediate the PMA-induced permeability increase but not the hypertension.     

Current concepts for a drug-induced inhibition of formation and action of thromboxane A2

Urinary and plasma metabolites of thromboxane A2 (TxA2) indicate an increased TxA2 synthesis in a number of diseases, whereby TxA2 is assumed to contribute to the underlying pathomechanisms by its profound effects on platelet aggregation and smooth muscle contraction. In some clinical situations the increment in TxA2 biosynthesis is accompanied by an increased formation of prostacyclin (PGI2) which is one of the most potent inhibitors of platelet activation and smooth muscle contraction. Therefore, drugs are being developed which suppress the formation or action of TxA2 without interfering with its functional antagonist PGI2. Low doses of acetylsalicyclic acid (ASA) preferentially inhibit cyclooxygenase activity in platelets and the synthesis of TxA2 in vivo. However, neither low doses (approximately 300 mg/day) nor very low doses spare the formation of PGI2 completely. Despite its limited selectivity, very low dose ASA (approximately 40 mg/day) provides an attractive perspective in TxA2 pharmacology. Although thromboxane synthase inhibitors selectively suppress TxA2 biosynthesis PGH2 can accumulate instead of TxA2 and substitute for TxA2 at their common TxA2/PGH2 receptors. Thromboxane synthase inhibitors can only exert platelet-inhibiting and vasodilating effects if PGH2 rapidly isomerizes to functional antagonists like PGI2 that can be formed from platelet-derived PGH2 by the vessel wall. TxA2/PGH2 receptor antagonists provide a specific and effective approach for inhibition of TxA2. These inhibitors do not interfere with the synthesis of PGI2 and other prostanoids but prevent TxA2 and PGH2 from activating platelets and inducing smooth muscle contractions. Most of the available TxA2/PGH2 receptor antagonists produce a competitive antagonism that can be overcome by high agonist concentrations. Since in certain disease states very high local TxA2 concentrations are to be antagonized, non-competitive receptor antagonists may be of particular interest. Some recent TxA2/PGH2 receptor antagonists produce such a non-competitive type of inhibition due to their low dissociation rate constant. As a consequence, agonists like TxA2 or PGH2 only reach a hemiequilibrium state at their receptors, previously occupied by those antagonists. A combination of a thromboxane synthase inhibitor with a TxA2/PGH2 receptor antagonist presents a very high inhibitory potential that utilizes the dual activities of the synthase inhibitor to increase PGI2 formation and of the receptor antagonist to antagonize PGH2 and TxA2. Such combinations or dual inhibitors, combining both moieties in one compound, prolong the skin bleeding time to a greater extent than thromboxane synthase inhibitors and even more than low dose ASA or TxA2/PGH2 receptor antagonists.     

Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI(2)), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI(2) biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1(-/-), and COX-2(-/-) mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI(2) biosynthesis were determined 1-7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI(2) biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1(-/-) mice with NS398 or COX-2(-/-) mice with SC560 restricted PGI(2) biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI(2) biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI(2) rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone.     

Cigarette smoking, cyclooxygenase-2 pathway and cancer

Cigarette smoking is a major cause of mortality and morbidity worldwide. Cyclooxygenase (COX) and its derived prostanoids, mainly including prostaglandin E2 (PGE2), thromboxane A2 (TxA2) and prostacyclin (PGI2), have well-known roles in cardiovascular disease and cancer, both of which are associated with cigarette smoking. This article is focused on the role of COX-2 pathway in smoke-related pathologies and cancer. Cigarette smoke exposure can induce COX-2 expression and activity, increase PGE2 and TxA2 release, and lead to an imbalance in PGI2 and TxA2 production in favor of the latter. It exerts pro-inflammatory effects in a PGE2-dependent manner, which contributes to carcinogenesis and tumor progression. TxA2 mediates other diverse biologic effects of cigarette smoking, such as platelet activation, cell contraction and angiogenesis, which may facilitate tumor growth and metastasis in smokers. Among cigarette smoke components, nicotine and its derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are the most potent carcinogens. COX-2 and PGE2 have been shown to play a pivotal role in many cancers associated with cigarette smoking, including cancers of lung, gastric and bladder, while the information for the role of TxA2 and PGI2 in smoke-associated cancers is limited. Recent findings from our group have revealed how NNK influences the TxA2 to promote the tumor growth. Better understanding in the above areas may help to generate new therapeutic protocols or to optimize the existing treatment strategy.     

Acetyltransferase p300 inhibitor reverses hypertension‐induced cardiac fibrosis

Epigenetic dysregulation plays a crucial role in cardiovascular diseases. Previously, we reported that acetyltransferase p300 (ATp300) inhibitor L002 prevents hypertension‐induced cardiac hypertrophy and fibrosis in a murine model. In this short communication, we show that treatment of hypertensive mice with ATp300‐specific small molecule inhibitor L002 or C646 reverses hypertension‐induced left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction, without reducing elevated blood pressures. Biochemically, treatment with L002 and C646 also reverse hypertension‐induced histone acetylation and myofibroblast differentiation in murine ventricles. Our results confirm and extend the role of ATp300, a major epigenetic regulator, in the pathobiology of cardiac hypertrophy and fibrosis. Most importantly, we identify the efficacies of ATp300 inhibitors C646 and L002 in reversing hypertension‐induced cardiac hypertrophy and fibrosis, and discover new anti‐hypertrophic and anti‐fibrotic candidates.     

Overview of physiological and pathophysiological effects of thromboxane A2

Thromboxane (Tx) A2 is a biologically potent and chemically unstable metabolite of prostaglandin endoperoxides. Recent developments in measurement techniques and the availability of both selective inhibitors of Tx synthetase and TxA2 receptor antagonists have facilitated the implication of TxA2 as a physiological modulator and as a mediator in thrombotic, vasospastic, and bronchospastic conditions. TxA2 is synthesized by platelets and contributes to platelet activation and irreversible platelet aggregation in physiological hemostasis and in thrombosis (e.g., unstable angina, stroke). TxA2 is also synthesized in intestinal, pulmonary, and renal tissues by cells other than platelets. Particularly in these tissues, TxA2 appears to act as a physiological modulator of changes in blood flow distribution and airway caliber. Strong stimuli for TxA2 release from these tissues may initiate ulcer, pulmonary hypertension, bronchoconstriction, and renal vasoconstriction. Evidence supports participation of TxA2 and/or TxA2 receptors in modulation of natural cytotoxic cell cytotoxicity, in tumor growth and metastasis, in complications of pregnancy (e.g., preeclampsia), and in the progression of ischemic injury after coronary artery occlusion. This evidence supports pivotal involvement of TxA2 in pathophysiology and provides a strong rationale for pursuing TxA2-blocking strategies in drug development.     

Selective inhibition of prostacyclin synthase activity by rofecoxib

The development of cyclooxygenase-2 (COX-2) selective inhibitors prompted studies aimed at treating chronic inflammatory diseases and cancer by using this new generation of drugs.Yet, several recent reports pointed out that long-term treatment of patients with COX-2 selective inhibitors (especially rofecoxib) caused severe cardiovascular complicances. The aim of this study was to ascertain whether, in addition to inhibiting COX-2, rofecoxib may also affect prostacyclin (PGI2) level by inhibiting PGI2 forming enzyme (prostacyclin synthase, PGIS). In order to evaluate if selective (celecoxib, rofecoxib) and non-selective (aspirin, naproxen) anti-inflammatory compounds could decrease PGI2 production in endothelial cells by inhibiting PGIS, we analyzed the effect of anti-inflammatory compounds on the enzyme activity by ELISA assay after addition of exogenous substrate, on PGIS protein levels by Western blotting and on its subcellular distribution by confocal microscopy. We also analyzed the effect of rofecoxib on PGIS activity in bovine aortic microsomal fractions enriched in PGIS. This study demonstrates an inhibitory effect of rofecoxib on PGIS activity in human umbilical vein endothelial (HUVE) cells and in PGIS-enriched bovine aortic microsomal fractions, which is not observed by using other anti-inflammatory compounds. The inhibitory effect of rofecoxib is associated neither to a decrease of PGIS protein levels nor to an impairment of the enzyme intracellular localization. The results of this study may explain the absence of a clear relationship between COX-2 selectivity and cardiovascular side effects. Moreover, in the light of these results we propose that novel selective COX-2 inhibitors should be tested on PGI2 synthase activity inhibition.     

Directed vascular expression of the thromboxane A2 receptor results in intrauterine growth retardation

Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis.     

Bacillus Calmette-Guérin and TLR4 agonist prevent cardiovascular hypertrophy and fibrosis by regulating immune microenvironment

Hypertension-induced cardiovascular hypertrophy and fibrosis are critical in the development of heart failure. The activity of TLRs has been found to be involved in the development of pressure overload-induced myocardial hypertrophy and cardiac fibrosis. We wondered whether vaccine bacillus Calmette-Guérin (BCG), which activated TLR4 to elicit immune responses, modulated the pressure overload-stimulated cardiovascular hypertrophy and cardiac fibrosis in the murine models of abdominal aortic constriction (AAC)-induced hypertension. Before or after AAC, animals received BCG, TLR4 agonist, IFN-gamma, or TLR4 antagonist i.p. BCG and TLR4 agonist significantly prevented AAC-induced cardiovascular hypertrophy and reactive cardiac fibrosis with no changes in hemodynamics. Moreover, TLR4 antagonist reversed the BCG- and TLR4 agonist-induced actions of anti-cardiovascular hypertrophy and cardiac fibrosis. BCG decreased the expression of TLR2 or TLR4 on the heart tissue but TLR4 agonist increased the expression of TLR2 or TLR4 on the immune cells that infiltrate into the heart tissue. This led to an increased expression ratio of IFN-gamma/TGF-beta in the heart. The cardiac protective effects of BCG and TLR4 agonist are related to their regulation of ERK-Akt and p38-NF-kappaB signal pathways in the heart. In conclusion, the activity of TLR4 plays a critical role in the mediation of pressure overload-induced myocardial hypertrophy and fibrosis. The regulation of immune responses by BCG and TLR4 agonist has a great potential for the prevention and treatment of hypertension-induced myocardial hypertrophy and cardiac fibrosis.     

Estrogen potentiates constrictor prostanoid function in female rat aorta by upregulation of cyclooxygenase-2 and thromboxane pathway expression

Estrogen potentiates vascular reactivity to vasopressin (VP) by enhancing constrictor prostanoid function. To determine the cellular and molecular mechanisms, the effects of estrogen on arachidonic acid metabolism and on the expression of constrictor prostanoid pathway enzymes and endoperoxide/thromboxane receptor (TP) were determined in the female rat aorta. The release of thromboxane A2 (TxA2) and prostacyclin (PGI2) was measured in male (M), intact-female (Int-F), ovariectomized-female (OvX-F), and OvX + 17beta-estradiol-replaced female (OvX + ER-F) rats. The expression of mRNA for cyclooxygenase (COX)-1, COX-2, thromboxane synthase (TxS), and TP by aortic endothelium (Endo) and vascular smooth muscle (VSM) of these four experimental groups was measured by RT-PCR. The expression of COX-1, COX-2, and TxS proteins by Endo and VSM was also estimated by immunohistochemistry (IHC). Basal release of TxA2 and PGI2 was similar in M (18.8 +/- 1.9 and 1,723 +/- 153 pg/mg ring wt/45 min, respectively) and Int-F (20.2 +/- 4.2 and 1,488 +/- 123 pg, respectively) rat aortas. VP stimulated the dose-dependent release of TxA2 and PGI2 from both male and female rat aorta. OvX markedly attenuated and ER therapy restored VP-stimulated release of TxA2 and PGI2 in female rats. No differences in COX-1 mRNA levels were detected in either Endo or VSM of the four experimental groups (P > 0.1). The expression of both COX-2 and TxS mRNA were significantly higher (P < 0.05) in both Endo and VSM of Int-F and OvX + ER-F, compared with M or OvX-F. Expression of TP mRNA was significantly higher in VSM of Int-F and OvX + ER-F compared with M or OvX-F. IHC revealed the uniform staining of COX-1 in VSM of the four experimental groups, whereas staining of COX-2 and TxS was greater in Endo and VSM of Int-F and OvX + ER-F than in OvX-F or M rats. These data reveal that estrogen enhances constrictor prostanoid function in female rat aorta by upregulating the expression of COX-2 and TxS in both Endo and VSM and by upregulating the expression of TP in VSM.     

Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II

Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)‐induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal‐regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II‐induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II‐induced EGFR activation is mediated by c‐Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c‐Src‐dependent EGFR activation may play an important role in Ang II‐induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II‐associated cardiac diseases.     

Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7)

Cardiac remodeling, which typically results from chronic hypertension or following an acute myocardial infarction, is a major risk factor for the development of heart failure and, ultimately, death. The renin-angiotensin system (RAS) has previously been established to play an important role in the progression of cardiac remodeling, and inhibition of a hyperactive RAS provides protection from cardiac remodeling and subsequent heart failure. Our previous studies have demonstrated that overexpression of angiotensin-converting enzyme 2 (ACE2) prevents cardiac remodeling and hypertrophy during chronic infusion of angiotensin II (ANG II). This, coupled with the knowledge that ACE2 is a key enzyme in the formation of ANG-(1-7), led us to hypothesize that chronic infusion of ANG-(1-7) would prevent cardiac remodeling induced by chronic infusion of ANG II. Infusion of ANG II into adult Sprague-Dawley rats resulted in significantly increased blood pressure, myocyte hypertrophy, and midmyocardial interstitial fibrosis. Coinfusion of ANG-(1-7) resulted in significant attenuations of myocyte hypertrophy and interstitial fibrosis, without significant effects on blood pressure. In a subgroup of animals also administered [d-Ala(7)]-ANG-(1-7) (A779), an antagonist to the reported receptor for ANG-(1-7), there was a tendency to attenuate the antiremodeling effects of ANG-(1-7). Chronic infusion of ANG II, with or without coinfusion of ANG-(1-7), had no effect on ANG II type 1 or type 2 receptor binding in cardiac tissue. Together, these findings indicate an antiremodeling role for ANG-(1-7) in cardiac tissue, which is not mediated through modulation of blood pressure or altered cardiac angiotensin receptor populations and may be at least partially mediated through an ANG-(1-7) receptor.     

Prostaglandins mediate tonic contraction of the guinea pig and human gallbladder

The gallbladder (GB) maintains tonic contraction modulated by neurohormonal inputs but generated by myogenic mechanisms. The aim of these studies was to examine the role of prostaglandins in the genesis of GB myogenic tension. Muscle strips and cells were treated with prostaglandin agonists, antagonists, cyclooxygenase (COX) inhibitors, and small interference RNA (siRNA). The results show that PGE2, thromboxane A2 (TxA2), and PGF(2alpha) cause a dose-dependent contraction of muscle strips and cells. However, only TxA2 and PGE2 (E prostanoid 1 receptor type) antagonists induced a dose-dependent decrease in tonic tension. A COX-1 inhibitor decreased partially the tonic contraction and TxB2 (TxA2 stable metabolite) levels; a COX-2 inhibitor lowered the tonic contraction partially and reduced PGE2 levels. Both inhibitors and the nonselective COX inhibitor indomethacin abolished the tonic contraction. Transfection of human GB muscle strips with COX-1 siRNA partially lowered the tonic contraction and reduced COX-1 protein expression and TxB2 levels; COX-2 siRNA also partially reduced the tonic contraction, the protein expression of COX-2, and PGE2. Stretching muscle strips by 1, 2, 3, and 4 g increased the active tension, TxB2, and PGE2 levels; a COX-1 inhibitor prevented the increase in tension and TxB2; and a COX-2 inhibitor inhibited the expected rise in tonic contraction and PGE2. Indomethacin blocked the rise in tension and TxB2 and PGE2 levels. We conclude that PGE2 generated by COX-2 and TxA2 generated by COX-1 contributes to the maintenance of GB tonic contraction and that variations in tonic contraction are associated with concomitant changes in PGE2 and TxA2 levels.     

Evidence for the involvement of the thromboxane synthase pathway in human natural cytotoxic cell activity

We and other investigators have recently shown that inhibitors of lipoxygenase reversibly inhibit natural cytotoxic (NC) or natural killer (NK) cell activity, whereas some inhibitors of cyclooxygenase enhance these functions. In addition, exogenous LTB4 augments NC and NK activity, whereas PGE2 depresses it. In the present studies, we sought to investigate the possible role of the TxA2 synthase pathway in NC function. Inhibition of this pathway by OKY-1581 or dazoxiben significantly inhibited NC activity against HSV-infected cells as well as NK function against K562 target cells. The inhibition was dose dependent, reversible, and not due to direct toxicity. NC activity was also significantly inhibited by the addition of PGE2 or PGI2 to the 4-hr assay, whereas addition of 6-keto-PGF1 alpha had no effect. Addition of PGH2, which could be converted to TxA2 or other PG, had no significant effect, but concomitant use of OKY-1581 produced a greater inhibition of NC function than by using OKY-1581 alone. U44069, a TxA2 analog, was inhibitory by itself and could not alter the inhibition caused by OKY-1581 or dazoxiben. In contrast, the TxA2 receptor blocker 13-APA significantly enhanced NC activity and even reversed the inhibitory effect of U44069 at equimolar (10(-7)M) concentrations. Taken together, these data suggest that most of the inhibitory effect of the TxA2 synthase inhibitors on NC and NK cell function derives from their ability to reorient cyclic endoperoxide metabolism toward more inhibitory compounds. In addition, TxA2 itself could exert a negative feedback on NC function through its receptor, as evidenced by the use of a TxA2 analog and a TxA2 blocker.     

Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to prevent or reverse hypertrophy of the LV in several models of left ventricular hypertrophy. The aim of the present study was to determine whether treatment with simvastatin can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) remodeling in NG-nitro-L-arginine methyl ester(L-NAME)-induced hypertension. Four groups of rats were investigated: control, simvastatin (10 mg/kg), L-NAME (40 mg/kg) and L-NAME + simvastatin (in corresponding doses). Animals were sacrificed and studied after 6 weeks of treatment. The decrease of NO-synthase activity in the LV, kidney and brain was associated with hypertension, LV hypertrophy and fibrosis development and remodeling of the aorta in the L-NAME group. Simvastatin attenuated the inhibition of NO-synthase activity in kidney and brain, partly prevented hypertension development and reduced the concentration of coenzyme Q in the LV. Nevertheless, myocardial hypertrophy, fibrosis and enhancement of DNA concentration in the LV, and remodeling of the aorta were not prevented by simultaneous simvastatin treatment in the L-NAME treated animals.We conclude that the HMG-CoA reductase inhibitor simvastatin improved nitric oxide production and partially prevented hypertension development, without preventing remodeling of the left ventricle and aorta in NO-deficient hypertension.     

Endothelin A Receptor Antagonist,Atrasentan, Attenuates Renal and Cardiac Dysfunction in Dahl Salt-Hypertensive Rats in a Blood Pressure Independent Manner

Proteinuria is a hallmark of chronic kidney disease (CKD) and cardiovascular disease (CVD), and a good predictor of clinical outcome. Selective endothelin A (ET_A) receptor antagonist used with renin-angiotensin system (RAS) inhibitors prevents development of proteinuria in CKD. However, whether the improvement in proteinuria would have beneficial effects on CVD, independent of RAS inhibition, is not well understood. In this study, we investigated whether atrasentan, an ET_A receptor antagonist, has renal and cardiovascular effects independent of RAS inhibition. Male Dahl salt sensitive (DSS) rats, at six weeks of age, received water with or without different doses of atrasentan and/or enalapril under high salt (HS) diet or normal diet (ND) for 6 weeks. At the end of 12th week, atrasentan at a moderate dose significantly attenuated proteinuria and serum creatinine without reducing mean arterial pressure (MAP), thereby preventing cardiac hypertrophy and improving cardiac function. ACE inhibitor enalapril at a dose that did not significantly lowered BP, attenuated cardiac hypertrophy while moderately improving cardiac function without reducing proteinuria and serum creatinine level. Nonetheless, combined therapy of atrasentan and enalapril that does not altering BP exerted additional cardioprotective effect. Based on these findings, we conclude that BP independent monotherapy of ET_A receptor antagonist attenuates the progression of CKD and significantly mitigates CVD independent of RAS inhibition.     

Enhanced microvascular permeability of PMA-induced acute lung injury is not mediated by cyclooxygenase products.

Products of cyclooxygenase activity have been proposed to mediate the pulmonary hypertension and increased microvascular permeability associated with phorbol myristate acetate- (PMA) induced acute lung injury. Previously, we reported that thromboxane (Tx) does not mediate PMA-induced pulmonary hypertension in intact anesthetized dogs. In the present study, PMA was administered to isolated canine lungs perfused with autologous blood at constant flow to investigate a possible role for Tx in the PMA-induced increase in microvascular permeability. Changes in permeability were assessed by determining changes in the capillary filtration coefficient (Kfc). In lobes pretreated with papaverine to prevent PMA-induced increases in pulmonary vascular resistance, Kfc increased from a baseline value of 0.2 +/- 0.03 to 1.5 +/- 0.29 ml.min-1.cmH2O-1.100 g wet lobe wt-1 (P < 0.01) 30 min after PMA (5.8 x 10(-8) M, n = 10). Concomitantly, TxB2, the stable metabolite of TxA2, increased from 138 +/- 44 to 1,498 +/- 505 pg/ml (P < 0.05) in the blood. Both the selective Tx synthase inhibitor, OKY-046 (7 x 10(-4) M, n = 6), and the cyclooxygenase inhibitor, indomethacin (10(-4) M, n = 7), prevented the PMA-induced increase in TxB2, but neither compound attenuated the PMA-induced increase in Kfc. ONO-3708 (10(-6) M), a selective prostaglandin (PG) H2/TxA2 receptor antagonist, prevented the vasoconstriction resulting from administration of U-46619, a stable PGH2/TxA2 receptor agonist, but it did not prevent the PMA-induced increases in Kfc (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic inhibition of chemokine receptor CXCR2 attenuates cardiac remodeling and dysfunction in spontaneously hypertensive rats

System hypertension is a major risk factor for cardiac hypertrophy and heart failure. Our recent findings reveal that the ablation or inhibition of C-X-C chemokine receptor (CXCR) 2 blocks this process in mice; however, it is not clear whether the pharmacological inhibition of CXCR2 attenuates hypertension and subsequent cardiac remodeling in spontaneously hypertensive rats (SHRs). In the present study, we showed that chemokines (CXCL1 and CXCL2) and CXCR2 were significantly upregulated in SHR hearts compared with Wistar–Kyoto rat (WKY) hearts. Moreover, the administration of CXCR2-specific inhibitor N-(2-hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)-urea (SB225002) in SHRs (at 2 months of age) for an additional 4 months significantly suppressed the elevation of blood pressure, cardiac myocyte hypertrophy, fibrosis, inflammation, and superoxide production and improved heart dysfunction in SHRs compared with vehicle-treated SHRs. SB225002 treatment also reduced established hypertension, cardiac remodeling and contractile dysfunction. Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002. Accordingly, the inhibition of CXCR2 by SB225002 deactivates multiple signaling pathways (AKT/mTOR, ERK1/2, STAT3, calcineurin A, TGF-β/Smad2/3, NF-κB-p65, and NOX). Our results provide new evidence that the chronic blocking of CXCR2 activation attenuates progression of cardiac hypertrophic remodeling and dysfunction in SHRs. These findings may be of value in understanding the benefits of CXCR2 inhibition for hypertensive cardiac hypertrophy and provide further support for the clinical application of CXCR2 inhibitors for the prevention and treatment of heart failure.     

Effect of prostaglandin E2 and prostaglandin I2 on PDGF-induced proliferation of LI90, a human hepatic stellate cell line

Hepatic stellate cells (HSC) are central to liver fibrosis. The eicosanoid pathway and cyclooxygenase-2 (COX-2) may be an important signaling mechanism in HSC. We investigated the role of COX-2, prostaglandin E(2) (PGE(2)) and prostaglandin I(2) (PGI(2)) in proliferation of LI90, an immortalized cell line of HSC. Our results showed that COX-2 was upregulated by platelet-derived growth factor (PDGF), a mitogen in HSC. COX-2 was responsible for the production of PGE(2) and PGI(2) in PDGF-stimulated LI90 cells. Furthermore, we demonstrated that COX-2 and PGE(2) mediated the proliferative response of LI90 to PDGF while synthetic analogue of PGI(2) exhibited anti-proliferative effect. Our findings suggest complex interactions of prostaglandins in liver fibrogenesis. In vivo studies using animal models are needed to elucidate the effect of COX-2 inhibition by non-steroidal anti-inflammatory drugs or COX-2 inhibitor in hepatic fibrosis.     

A pharmacological approach to thromboxane receptor antagonism

Thromboxane A2 (TxA2) appears to be an important mediator of ischemia and hypoxia. Despite its short half-life and the fact that it may not circulate in the blood until its values become quite high, TxA2 contributes to the pathogenesis of cardiopulmonary diseases (e.g., sudden death, myocardial ischemia, circulatory shock). It does so because it propagates its own formation by activating platelets and constricting blood vessels, thus activating more TxA2 and trapping it locally within an ischemic or hypoxic region. TxA2 concentrations in the extracellular fluid of lymph of ischemic regions may be much higher than that occurring in nonischemic, normally perfused regions. Specific and potent Tx receptor antagonists (TxRA) have recently become available for study. The TxRA are useful tools in the study of the pathophysiology of Tx-dependent disease processes and have been found to be effective in a variety of ischemic disorders including circulatory shock, myocardial ischemia, and sudden cardiopulmonary death. Moreover, inasmuch as early work indicates that these agents are both safe and effective in humans, Tx receptor antagonists may be employed as therapeutic agents in several cardiovascular disease states. Further investigation is necessary to clarify the role of TxRA as therapeutic agents.