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PubMed1991

Differential effects of cyclooxygenase inhibitors on the cardiovascular response to hyperosmotic mannitol.

The intravenous infusion of mannitol (1.37 mosm kg-1 min-1 during 4 min) to anesthetized, open-chest, intact dogs produced a hemodynamic response characterized by a positive inotropic effect and a decrease in total peripheral resistance. This response is attributable to a direct effect of hypertonicity (plasma osmolality raised from 309 +/- 4 to 332 +/- 5 mosm kg-1 H2O). Pretreatment with indomethacin (5 mg kg-1 i.v.) or meclofenamic acid (2 mg kg-1 i.v.) attenuated the mannitol-induced response but acetylsalycilic acid (10 mg kg-1 i.v.) was without effect. Indomethacin (5 mg kg-1 i.v.) did not change the decrease in canine hindlimb perfusion pressure produced by intra-arterial mannitol 5 mosm kg-1. Indomethacin (3 microM) did not alter the chronotropic and inotropic responses to mannitol (150 mosm above normal) in isolated rabbit atria. These results suggest that the cardiovascular response to hyperosmotic mannitol may be partly mediated in intact animals by prostaglandin release.

Animals↗

PubMed1983

Stimulation of ovine myometrial activity by 6-keto prostaglandin E1.

6-keto prostaglandin E1 (6KE) is a metabolite of PGI2, which we have shown previously inhibits spontaneous myometrial activity. In the present study we examined the effects of 6KE on uterine electrical and mechanical activity in non-pregnant ovariectomized sheep. 6KE stimulated uterine activity in a dose-dependent fashion. The effect was enhanced by pre-treatment with estradiol (E2). It was not influenced by pre-treatment with meclofenamic acid and was not associated with significant changes in the concentrations of 13,14 dihydro 15-keto PGF2 alpha in vena cava plasma. After E2 treatment, 6KE had 0.2-0.3 of the stimulatory activity of PGF2 alpha. In the absence of E2, the uterine response to both 6KE and PGF2 alpha was decreased. In animals in which spontaneous myometrial activity was inhibited by PGI2, the uterus remained responsive to 6KE. We conclude that in the ovariectomized non-pregnant sheep 6KE stimulates uterine activity, and that the effect is independent of endogenous PG production.

Alprostadil↗

PubMed1999

Non-steroidal anti-inflammatory drugs inhibit Helicobacter pylori-induced human neutrophil reactive oxygen metabolite production in vitro.

BACKGROUND: Helicobacter pylori infection is associated with increased production of gastric mucosal reactive oxygen metabolites which have been implicated in mucosal damage and carcinogenesis. In vitro, neutrophils produce reactive oxygen metabolites following activation by H. pylori. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neutrophil activation by several factors, e.g. N-formyl-methionyl-leucyl-phenyalanine (f-MLP). AIM: To examine the effect of NSAIDs on H. pylori-induced reactive oxygen metabolite production by human peripheral blood neutrophils. METHODS: Neutrophils were stimulated by H. pylori (NCTC 11637) water extract or f-MLP in the presence or absence of NSAIDs. Reactive oxygen metabolite activity was measured by luminol-enhanced chemiluminescence. RESULTS: H. pylori water extract stimulated a sevenfold increase in chemiluminescence which was inhibited dose-dependently by diclofenac. All six NSAIDs studied (at 10-4 M) significantly inhibited H. pylori-and f-MLP-stimulated neutrophil reactive oxygen metabolite production. Meclofenamic acid and diclofenac had the greatest inhibitory effects on both H. pylori and f-MLP-stimulated neutrophil reactive oxygen metabolite production. The inhibitory effects of other NSAIDs varied with the activation stimulus. NSAIDs did not quench reactive oxygen metabolites generated in a cell-free xanthine:xanthine oxidase assay. CONCLUSION: Several NSAIDs attenuate H. pylori-induced neutrophil reactive oxygen metabolites production in vitro. This may be relevant to a potential chemopreventative role in gastric cancer and to a possible lack of synergy between H. pylori and NSAID use regarding peptic ulceration.

Adult↗

PubMed1980

Do endogenous prostaglandins modulate noradrenergic transmission in the rat isolated perfused vas deferens?

The effects of the prostaglandin synthetase inhibitors aspirin, indomethacin and meclofenamic acid have been studied on the response of the rat isolated perfused vas deferens. None of these drugs, up to a concentration of 5 x 10(-5) M affected either phase of the biphasic constrictor response to 30 s periods of field stimulation. In the same preparations an inhibition of the response to field stimulation was seen in the presence of prostaglandin E1 at concentrations of 1 to 5 ng ml-1. All three prostaglandin synthetase inhibitors, at 5 x 10(-5) M, caused significant reduction of prostaglandin biosynthesis by homogenates of rat vas deferens. It is, therefore, suggested that stimuli which activate directly the noradrenergic nerves in the rat vas do not activate simultaneously a release of endogenous prostaglandins.

Animals↗

PubMed1985

Evidence for a possible role of the brain kallikrein-kinin system in the modulation of the cerebral circulation.

Experiments by others have shown that exogenous bradykinin dilates cerebral arterioles and that the brain contains kininogen and kallikrein, the latter being the enzyme which converts kininogen to bradykinin. The objective of these experiments was to determine if bradykinin produced from endogenous brain kininogen can affect the cerebral microcirculation. Rabbit pial arteriolar diameter was measured with a microscope using the closed cranial window technique. Topical application of bradykinin (10(-8)-10(-5) M) induced a dose-dependent vasodilation (8-46%) which was completely inhibited by the cyclooxygenase enzyme inhibitors indomethacin and meclofenamic acid. Topical application of 1 U of tissue kallikrein per milliliter of artificial cerebrospinal fluid induced 43% dilation, which could be prevented by local treatment with indomethacin or the proteinase inhibitor aprotinin. The action of aprotinin and indomethacin was specific, since aprotinin did not affect the dilation produced by bradykinin, and indomethacin did not affect dilation produced by adenosine. A second application of kallikrein had no effect on cerebral diameter, yet the arterioles still responded normally to exogenous bradykinin, indicating that the first application of kallikrein depleted brain kininogen. We suggest that activation of brain kallikrein and subsequent formation of kinin from brain kininogen may be important in modulation of cerebral blood flow or generation of cerebral edema.

Animals↗

PubMed1984

Effects of cyclooxygenase inhibitors and PGI2 on the adrenergic contractions of isolated rabbit arteries.

The effect of three cyclooxygenase inhibitors (indomethacin, suprofen, meclofenamic acid) and PGI2 on the contractile responses to noradrenaline (NA) and to nerve stimulation (TNS) of strips of rabbit coeliac-, pulmonary-, ear-, carotid-, femoral arteries and the aorta were studied. The equipotent concentration (0.1 X EC50) of NA were calculated from dose-response curves. The stimulation parameters (Hz, duration) varied according to the responsiveness of the tissue. Both NA and TNS caused 7-23% of maximum response. In the presence of cyclooxygenase inhibitors (COI's) NA and TNS produced significantly greater proportion (15-30%) of maximum contraction in coeliac-, ear-, and pulmonary arteries. Contractions of the other 3 vessels were not influenced by COI's. The inhibitory potency of PGI2 was determined on contractions produced by equipotent concentration (EC50) of NA. PGI2 was highly effective in coeliac arteries, it was less potent in pulmonary- and ear arteries and had no effect on the responses of the other vessels.

Animals↗

PubMed1996

Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody.

Aerosolized cysteinyl leukotrienes (CysLTs) elicit migration of eosinophils into guinea pig lungs and the airways of patients with asthma. The present studies were designed to analyze the concentration-response relationship, time course, and pharmacologic and histologic characteristics of leukotriene D4 (LTD4)-induced eosinophil influx into the airways of conscious guinea pigs. Animals were exposed to aerosols of 0.3 to 30 microg/ml LTD4 for 1 min, during which specific airway conductance (sGaw) was monitored. Bronchoalveolar lavages (BALs) of guinea pig airways were conducted at selected times from 4 h to 4 wk after LTD4 challenge. LTD4 produced maximal decreases in sGaw (70 to 90% reduction) at all concentrations tested and concentration-related increases in eosinophil levels in BALs, assessed 24 h after challenge. Increased numbers of eosinophils in the bronchial epithelium and subepithelium were confirmed histologically. Significant eosinophilia was maintained for up to 4 wk postchallenge. Pretreatment with the LTD4 receptor antagonist, pranlukast (ONO-1078, SB 205312) (20 mg/kg, intragastrically), significantly inhibited both the bronchoconstriction and the eosinophilia at 24 h, whereas the cyclooxygenase inhibitor, meclofenamic acid (5 mg/kg, intragastrically), had no effect on either parameter. Histologic observations were consistent with BAL results. Pretreatment with the rat anti-mouse antibody to interleukin-5 (IL-5), TRFK-5 (10-300 microg, intraperitoneally), produced dose-related inhibition of LTD4-induced eosinophilia, measured in 24 h or 3 wk BAL, but did not affect the acute bronchoconstriction. These results indicate that LTD4 elicits airway eosinophil influx in guinea pigs which persists as long as 4 wk after a single exposure, and provide the first evidence that IL-5 may have a role in LTD4-induced airways inflammation. This and other previously reported proinflammatory effects of LTD4 may contribute significantly to its overall influential role in the pathophysiology of asthma, and may underlie the therapeutic benefit of CysLT receptor antagonists, such as pranlukast, in this disorder.

Animals↗

PubMed2000

Different transporters for tri-iodothyronine (T(3)) and thyroxine (T(4)) in the human choriocarcinoma cell line, JAR.

We investigated transport systems for tri-iodothyronine (T(3)) and thyroxine (T(4)) in the human choriocarcinoma cell line, JAR, using a range of structurally similar compounds to determine whether these thyroid hormones are transported by common or different mechanisms. Saturable T(3) but not saturable T(4) uptake was inhibited by a wide range of aromatic compounds (nitrendipine, nifedipine, verapamil, meclofenamic acid, mefenamic acid, diazepam, phenytoin). Nitrendipine and diazepam were the most effective inhibitors of saturable thyroid hormone uptake. Nitrendipine decreased the K(m) for T(4) uptake from a control value of around 500 nM to around 300 nM (n=6). In contrast, the K(m) for T(3) uptake was increased from a control value of around 300 nM to around 750 nM (n=4). Diazepam had similar effects. This divergent shift in affinity for the uptake of T(3) and T(4) suggested that separate uptake systems exist for these two thyroid hormones. This provides evidence for at least two transporters mediating uptake of T(3) and T(4) in JAR cells: a specific T(4) transporter that does not interact with T(3) or structurally similar compounds; and a shared iodothyronine transporter that interacts with T(3), T(4), nitrendipine and diazepam.

Analysis of Variance↗

PubMed1984

Differential contractile responsiveness of isolated rabbit arteries from different vascular beds to cyclooxygenase inhibitors and PGI2.

The actions of three, structurally unrelated cyclooxygenase inhibitors and PGI2 on the contractile responses to electrical stimulation and to noradrenaline of strips of rabbit coeliac, ear, pulmonary, carotid, femoral arteries and the aorta were studied. Indomethacin (3 mumol/l), suprofen (0.8 mumol/l) and meclofenamic acid (0.2 mumol/l) potentiated the adrenergically induced contractions of coeliac arteries by 126-165%. The contractile responses of ear arteries were increased by these three substances by 87-91%, and the responses of pulmonary arteries by 26-33%. All of these changes were statistically significant. Prostacyclin produced a dose-related inhibition of the stimulation-induced contractions of the coeliac, ear and pulmonary arteries; its IC50 values were 10.4, 212 and 433 nmol/l, respectively. In contrast to effects in the above arteries, the evoked contractions of aortic and carotid strips were not affected by any of the prostaglandin synthesis inhibitors used; the responses of femoral vessels were reduced by all of the inhibitors (by 13-23%; P less than 0.05). Low concentrations of PGI2 did not affect the evoked contractions of aortic, carotid and femoral strips whereas higher concentrations increased baseline tone and potentiated contractions. The results indicate that there are considerable difference in the sensitivities of the arteries from different vascular beds to inhibitors of cyclooxygenase and to prostacyclin.

Animals↗

PubMed1976

Influence of nonsteroidal anti-inflammatory agents on myocardial ischemia in the cat.

Indomethacin, meclofenamic acid and acetylsalicylic acid are prostaglandin synthetase-inhibiting, nonsteroidal anti-inflammatory drugs. Their effects on hemodynamic and enzymatic responses to coronary artery occlusion were evaluated in the cat. The direct effects of these drugs on isolated tissue preparations (i.e., cat papillary muscle, aortic strip and liver lysosomes) were also studied. None of the drugs tested exhibited any significant hemodynamic or biochemical effects which would indicate protection against damage due to myocardial ischemia during the 5-hour experimental period. Furthermore, only indomethacin produced significant effects on the isolated tissues studied. Indomethacin increased the tension of aortic strips confirming a pressor effect seen in the intact animal and exerted a modest stabilization of isolated liver lysosomes. All three anti-inflammatory drugs inhibited prostaglandin F2alpha, release in heart homogenates by 82 to 87%. It is concluded that nonsteroidal anti-inflammatory drugs do not significantly influence the early course of myocardial ischemia in the cat, in contrast to the previously reported preservation of myocardial integrity afforded by dexamethasone and methylprednisolone.

Animals↗

PubMed1993

Prostaglandin F2 alpha mediates platelet-activating factor-stimulated atrial natriuretic factor release from the isolated rat heart.

Platelet-activating factor (PAF) and the prostaglandins have recently been shown to stimulate atrial natriuretic factor (ANF) secretion from the heart. As PAF also potentiates the release of cyclooxygenase products from isolated hearts, the role of these substances in PAF-induced ANF secretion was investigated. Using an isolated perfused rat heart preparation, cyclooxygenase inhibition by indomethacin or meclofenamic acid (10 microM for each) significantly attenuated the rise in ANF associated with PAF administration (2.5 nmol). Prostaglandin F2 alpha (PGF) produced an immediate and dose-dependent increase in ANF secretion, which was significant at 0.01 mumol and reached 348 +/- 66% over baseline values after a 1-mumol injection. Prostaglandin E2 (PGE) generated a much smaller 98 +/- 25% increase after a 1-mumol administration. Furthermore, PGF but not PGE was released from isolated hearts immediately after PAF administration. PGF release reached a maximum of 0.06 nmol/min g Heart-1 1 min after PAF stimulation and had returned to undetectable baseline values by 6 min. Cyclooxygenase inhibition abolished the release of PGF after PAF, in addition to attenuating (by 60-70%) the increased secretion of ANF after PAF injection. These results demonstrate very clearly that PGF is the major mediator for PAF-stimulated ANF secretion. Such an interaction may provide an alternative mechanism to atrial distension for the secretion of ANF in pathologies such as myocardial infarction, where autacoids such as PAF and the PGs are released from damaged cardiac muscle and elevated plasma levels of ANF are observed.

Animals↗

PubMed1985

Renal vasodilation with ureteral occlusion and prostaglandins: attenuation by histamine H1 antagonists.

We evaluated the effects of histamine receptor antagonists on the renal vasodilatory responses to ureteral occlusion (UO), to the intrarenal infusion of prostaglandins E2, I2, A2, D2 and E1, and to bradykinin. We also determined the effects of meclofenamic acid, a cyclooxygenase inhibitor, on histamine-induced renal vasodilation and the effects of 2-methylhistamine (2-MeH), and H1 agonist, on glomerular filtration rate (GFR) and renal blood flow (RBF). Experiments were performed on adult mongrel dogs anesthetized with pentobarbital sodium. RBF was measured with an electromagnetic flow probe. Neither UO-induced nor prostaglandin- (PG) induced renal vasodilation was affected by infusion of the histamine H2 receptor antagonist cimetidine into the renal artery at 10(-5) M/min. On the other hand, renal artery infusion of the H1 receptor antagonist chlorpheniramine (CP) at 10(-5) M/min blocked UO-induced renal vasodilation [RBF increased 34 +/- 4% (SE) prior to but only 2 +/- 2% during infusion of CP) and markedly attenuated PGI2-, PGA2-, and PGE2-induced increases in RBF (CP inhibited 64 +/- 9% of the PGE2-induced renal vasodilation). CP had less effect on the renal vasodilation associated with infusion of PGD2 or PGE1 and had no effect on the vasodilation induced by bradykinin. Infusion of exogenous histamine (1 micrograms X kg-1 X min-1) into the renal artery prior to ureteral occlusion resulted in a typical H1 + H2-mediated vasodilatory response (RBF increased 53 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1989

Prostacyclin and pathogenesis of hemodynamic abnormalities of diabetic ketoacidosis in rats.

The pathogenesis of the hemodynamic abnormalities of diabetic ketoacidosis (DKA) is not well understood. Previous studies suggest that prostacyclin (PGI2) production by adipose tissue is increased in DKA. We investigated the role of PGI2 in the pathogenesis of the reduced vascular resistance in DKA. Rats with streptozocin-induced DKA were anesthetized with pentobarbital sodium, and flow was measured with an electromagnetic probe on the infradiaphragmatic aorta. The plasma level of 6-keto-PGF1 alpha (stable derivative of PGI2) was higher (mean +/- SE 0.91 +/- 0.05 ng/ml) and vascular resistance lower (4.9 +/- 0.2 mmHg.ml-1.min-1.100 g-1 [resistance units, RU]) in 67 rats with DKA than in 21 normal rats (0.34 +/- 0.03 ng/ml, P less than .01, and 9.0 +/- 0.7 RU, P less than .01, respectively). Inhibition of cyclooxygenase activity with either indomethacin or meclofenamic acid reduced the plasma 6-keto-PGF1 alpha level but failed to raise vascular resistance. Infusions of PGI2 in rats with DKA demonstrated that the vasculature was responsive to PGI2. Inhibition of cyclooxygenase activity not only reduced PGI2 production but also suppressed renin release. When the effects of the renin-angiotensin system were excluded by bilateral nephrectomy, indomethacin caused a significant increase (P less than .05) in vascular resistance. Thus, the failure of cyclooxygenase inhibitors to raise vascular resistance in DKA was a result of concurrent suppression of vasodilator (PGI2) and vasoconstrictor (renin-angiotensin system) mechanisms that are activated in DKA. Insulin administration increased vascular resistance (P less than .01) and decreased the level of plasma 6-keto-PGF1 alpha (P less than .01). Combined administration of PGI2 and insulin did not alter vascular resistance, suggesting that the increase in vascular resistance with insulin was predominantly due to the reduction of circulating PGI2. Thus, vascular resistance is decreased in DKA primarily as a result of the vasodilator effects of PGI2 produced by adipose tissue. The activation of the renin-angiotensin system represents a partial compensation. The increase in PGI2 production may contribute to the hypotension and mortality of DKA.

6-Ketoprostaglandin F1 alpha↗

PubMed1980

Dissociation of aldosterone and prostaglandin biosynthesis in the rat adrenal glomerulosa.

The relationship between aldosterone production and prosta-glandin E2 synthesis was evaluated using the responses of isolated rat adrenal glomerulosa cells to angiotensin II, ACTH and potassium. Simultaneous PGE2 and aldosterone measurements were made during timed incubations with these stimuli, and in incubations with arachidonic acid, meclofenamate, indomethacin, and aminoglutethamide. PGE2 and aldosterone production were assessed by radioimmunoassay. We were not able to demonstrate stimulation of PGE2 by angiotensin II, ACTH, or potassium despite significant increments in aldosterone production with these stimuli. Arachidonic acid enhanced PGE2 synthesis, but had no effect on aldosterone realease. Indomethacin and meclofenamate inhibited aldosterone secretion. Aminoglutethimide depressed aldosterone production, but had little effect on PGE2 levels in the media. These studies demonstrate that dienoic prostaglandins play no direct role in aldosterone production stimulated by angiotensin II, ACTH, or potassium in rat adrenal glomerulosa cells. Since inhibitors of cyclo-oxygenase decreased aldosterone synthesis, it is possible that fatty acids other than arachidonic acid may be cyclo-oxygenated to products which regulate aldosterone production.

Adrenal Cortex↗

PubMed1998

Determination of flufenamic, meclofenamic and mefenamic acids by capillary electrophoresis using beta-cyclodextrin.

The possibility of separating flufenamic, meclofenamic and mefenamic acids by capillary electrophoresis was studied. The best approach involved combining a suitable pH of the carrier electrolyte (pH 12.0) with the host-guest complexation effects of beta-cyclodextrin. A running buffer consisting of 30 mM phosphate buffer (pH 12.0), 2 mM beta-CD and 10% (v/v) acetonitrile was found to provide a very efficient and stable electrophoresis system for the analysis of fenamic acids by capillary zone electrophoresis. Responses were linear from 0.4 to 40 microg/ml for the three drugs with detection limits of about 0.3 ng/ml. Intra- and inter-day precision values of about 1-2% R.S.D. (n = 11) and 3-4% R.S.D. (n = 30), respectively, were obtained. The method is highly robust and no breakdowns of the current or capillary blockings were observed for several weeks. The general applicability of this rapid CZE procedure (migration times less than 12 min) is demonstrated for several practical samples, including serum, urine and pharmaceuticals.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors.

Recent studies from our laboratory have shown that derivatization of the carboxylate moiety in substrate analogue inhibitors, such as 5,8,11,14-eicosatetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the arylacetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of the structurally diverse indomethacin esters and amides inhibited purified human COX-2 with ICo5 values in the low-nanomolar range but did not inhibit ovine COX-1 activity at concentrations as high as 66 microM. Primary and secondary amide analogues of indomethacin were more potent as COX-2 inhibitors than the corresponding tertiary amides. Replacement of the 4-chlorobenzoyl group in indomethacin esters or amides with the 4-bromobenzyl functionality or hydrogen afforded inactive compounds. Likewise, exchanging the 2-methyl group on the indole ring in the ester and amide series with a hydrogen also generated inactive compounds. Inhibition kinetics revealed that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound.

Animals↗

PubMedDate not supplied

Endothelium-independent relaxations to acetylcholine and A23187 in the human umbilical artery.

The effects of acetylcholine (ACh) and A23187 on ring preparations from the human umbilical artery (HUA) were investigated and compared with the rat aorta (RA). The results from the HUA demonstrate that: (1) At both high (pO2 > 600 mm Hg) and low O2 tension (pO2 < 55 mm Hg), ACh and A23187 relaxed precontracted rings in a concentration-dependent and endothelium-independent manner. Changes in pO2 did not influence the responses of the HUA to either relaxant. (2) Relaxation responses of the HUA to either ACh or A23187 were insensitive to methylene blue (50 microM), L-nitro-arginine methyl ester (100 microM), indomethacin (10 microM) and nordihydroguaiaretic acid (50 microM). Relaxations initiated by ACh were also atropine-resistant. (3) Meclofenamic acid (3 microM) suppressed the relaxations to A23187, but not ACh. (4) Regardless of pO2 superoxide dismutase (100 U/ml) potentiated the relaxant effects of ACh, whereas mannitol (60 mM) enhanced ACh-initiated relaxations at high but not low pO2. (5) Ouabain (30 nM), high potassium (HK+, 60 mM) and tetraethylammonium (20 mM) inhibited responses to ACh. (6) Na(+)-free physiological saline solution inhibited both relaxations and oscillations initiated by either ACh or A23187. (7) Both nitroglycerin and exogenous nitric oxide (NO) fully, and 8-bromoguanosine 3',5'-cyclic monophosphate partially, relaxed the HUA, and LY83583 (10 microM) reversed such relaxations. (8) In the RA, relaxation responses to ACh and A23187 were endothelium-dependent and sensitivity was reduced under high versus low pO2 conditions. We conclude that in the HUA, unlike in the RA, ACh and A23187 mediate their responses via an endothelium- and NO-independent process(es), perhaps involving the release of a muscle-derived relaxing factor. ACh-initiated relaxations are mediated by activation of Na+,K(+)-ATPase, and subsequent hyperpolarization via K+ efflux, whereas A23187-mediated relaxations result from the synthesis of an indomethacin-resistant cyclooxygenase product.

Acetylcholine↗

PubMed1989

Uptake of 3,5,3'-triiodothyronine by cultured rat hepatoma cells is inhibitable by nonbile acid cholephils, diphenylhydantoin, and nonsteroidal antiinflammatory drugs.

Cellular uptake of T3 was examined using rat H4 hepatoma cells. Uptake of [125I]T3 (10(-11) M) from serum-free medium was measured as the cell-associated counts retained by washed cells (2 X 10(6) per well). Displaceable uptake was 84% of total uptake at 2 min (2.9% of total counts). T4, tetraiodothyroacetic acid, triiodothyroacetic acid, rT3, and D-T3 were 2-5% as effective as T3 in displacing uptake. Nonequilibrium kinetics indicated a half-maximal uptake at 680 nM T3 with approximately 7 million sites per cell. Displaceable uptake was time and temperature dependent and was 73% inhibited by 2 mM KCN and 52% by 10 mM bacitracin but not by 2 mM ouabain or 10 microM cytochalasin B. Phloretin, 100 microM, inhibited uptake by 66%. T3 uptake was directly related to the free T3 concentration over the range of albumin concentrations, 0-10 g/liter. The nonbile acid cholephil compounds, bromosulfophthalein, iopanoic acid, and indocyanine green (all 100 microM) inhibited T3 uptake to 62%, 17%, and 5% of control, respectively. Taurocholate, methylaminoisobutyric acid, and oleic acid were noninhibitory. The half-inhibitory concentrations of reactive nonsteroidal antiinflammatory drugs were: meclofenamic acid (25 microM), mefenamic acid (45 microM), fenclofenac (69 microM), flufenamic acid (100 microM), and diclofenac (230 microM). Aspirin, ibuprofen, oxyphenbutazone, and phenylbutazone (all 100 microM) were noninhibitory. Diphenylhydantoin inhibited uptake to 50% at 75 microM. These findings suggest that T3 uptake by cultured rat hepatocytes is by an energy-dependent, saturable, stereo-selective mechanism that is dependent on cell membrane proteins. This mechanism appears to be shared by a number of other ligands, including nonbile acid cholephils and several nonsteroidal antiinflammatory drugs of the anthranilic and phenylacetic acid classes, as well as diphenylhydantoin. The bile acid taurocholate, oleic acid, and a probe for type A amino acid uptake were inactive. The extent to which these effects may modify expression of thyroid hormone action remains to be established.

Aminoisobutyric Acids↗