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PubMed1983

Prevention of the luteolytic action of oxytocin in the goat by inhibition of prostaglandin synthesis.

Oxytocin-induced luteolysis in goats was associated with significant increases in peripheral plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F2alpha (PGFM). Oral administration of the prostaglandin (PG) synthetase inhibitor meclofenamic acid (l g/day) prevented both the luteolytic action of oxytocin and the increase in PGFM concentrations. These results confirm that the luteolytic effect of oxytocin is mediated via the production and release of PGF2alpha.

Journal Article↗

PubMed1983

Studies on the mechanisms by which 2-chloroadenosine stimulates bone resorption in tissue culture.

The effect of 2-chloroadenosine on bone resorption was studied in calvarial bones from 6-7-day-old mice in organ culture. 2-Chloroadenosine stimulated the mobilization of minerals (40Ca, 45Ca) and increased the degradation of matrix ([3H]proline) from the bones. The nucleoside also caused an increased release of beta-glucuronidase, a lysosomal enzyme. In doses above 30 microM 2-chloroadenosine was cytotoxic, as evidenced by an increased release of lactate dehydrogenase. 2-Chloroadenosine-stimulated resorption could be inhibited by calcitonin, increased concentration of phosphate in culture medium, cortisone, dexamethasone, indomethacin, naproxen, meclofenamic acid and 5,8,11,14-eicosatetraynoic acid. 2-Chloroadenosine was much more sensitive to inhibition by dexamethasone than was parathyroid hormone. The response to the maximal dose of 2-chloroadenosine could not be enhanced by parathyroid hormone, 1 alpha-hydroxyvitamin D-3 and prostaglandin E2. An exposure to 2-chloroadenosine for 12 h was not sufficient to produce prolonged resorption. The results suggest that 2-chloroadenosine stimulated bone resorption by a process which is dependent on osteoclastic activity. The possibility that the effect of 2-chloroadenosine, either directly or indirectly, is related to formation of prostaglandins is discussed in the light of the above data.

2-Chloroadenosine↗

PubMed2004

Roles for prostaglandins in the steroidogenic response of human granulosa cells to high-density lipoproteins.

In human granulosa-lutein cells, high-density lipoproteins (HDL) can stimulate progesterone synthesis. The objective of the present study was to establish whether prostaglandins (PGs) participate in the steroidogenic response to HDL. Both HDL and apolipoprotein AI (ApoAI) stimulated concentration-dependent increases in PGE2, cAMP and progesterone accumulation. The minimum concentrations of HDL and ApoAI required to elevate PGE2 production were the same as those required to stimulate cAMP accumulation and progesterone synthesis. Concentrations of PGE2 were elevated within 10 min in cells exposed to HDL and rose progressively over 24 h, whereas cAMP and progesterone were only increased significantly after 24 h of treatment with HDL. Co-treatment with prostaglandin H synthase inhibitors (meclofenamic acid and indomethacin) abolished the cAMP and progesterone responses to both HDL and ApoAI. Hence, the ability of HDL to stimulate progesterone synthesis can be mimicked by ApoAI and appears to involve increased generation of one or more luteotrophic PGs, possibly acting via cAMP.

Apolipoprotein A-I↗

PubMed1997

Pharmacologic inhibition of transglutaminase-induced cross-linking of Alzheimer's amyloid beta-peptide.

The brain of Alzheimer's disease (AD) patients contains deposits of amyloid beta-peptide (A beta). Recent studies have shown that A beta is a substrate for tissue transglutaminase (TGase), which induces the formation of cross-linked dimers and polymers, and that tacrine, indomethacin and deferoxamine, which have widely different chemical structures, attenuate the progression of symptoms of AD. This report evaluated the potential of a total of ten different pharmacological agents to inhibit TGase-induced cross-linking of A beta, including known TGase inhibitors (dansylcadaverine, spermine), non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid, diflunisal, salicylic acid), monoamine oxidase inhibitors (tranylcypromine, phenelzine), an acetylcholinesterase inhibitor (tacrine), and an iron chelating agent (deferoxamine). All but one (salicylic acid) of these ten agents had an inhibitory effect on TGase-induced A beta cross-linking. These results suggest that inhibition of TGase-induced cross-linking of A beta is a potential pharmacologic target for the treatment of AD. A method is also presented for the determination of percent inhibition of TGase-induced A beta cross-linking based on the separated monomer, dimer and polymer bands on SDS-PAGE gels.

Amyloid beta-Peptides↗

PubMed1999

Analgesia.

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.

Adrenergic alpha-Agonists↗

PubMed1995

Cardioselective anti-ischemic ATP-sensitive potassium channel openers. 3. Structure-activity studies on benzopyranyl cyanoguanidines: modification of the cyanoguanidine portion.

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.

Adenosine Triphosphate↗

PubMed1986

The increase in testicular vascular permeability induced by human chorionic gonadotrophin involves 5-hydroxytryptamine and possibly oestrogens, but not testosterone, prostaglandins, histamine or bradykinin.

Possible intermediates in the response of the rat testicular vasculature to human chorionic gonadotrophin (hCG) have been investigated. Ketanserin, an antagonist of 5-hydroxytryptamine, significantly reduced the increase in 1-h albumin space seen 20 h after hCG, as did one aromatase inhibitor (1,4,6-androstatriene-3,17-dione), but the effect of another (testolactone) did not reach significance. Aminoglutethimide, which inhibits overall steroid synthesis as well as aromatase, reduced the albumin space in both control and hCG-injected rats but the hCG response, as judged by the ratio between treated and control rats, was unaffected. Inhibitors of overall steroid synthesis (WIN 32,729), prostaglandin synthesis (meclofenamic acid or indomethacin) and angiotensin converting enzyme (captopril) and blockers of H1 and H2 histamine receptors (mepyramine, cimetidine or ranitidine) were without effect. The time course of the vascular response to hCG is quite different from the response in testosterone secretion by the testis. Considerable numbers of mast cells were found in the vicinity of the testicular artery in the testicular capsule, and these may be a source of 5-hydroxytryptamine.

Aminoglutethimide↗

PubMed1979

Cooxygenation by prostaglandin cyclooxygenase from rabbit inner medulla.

The renal inner medulla may be exposed to high concentrations of organic compounds which are excreted into the urine. This report examines the capacity of the inner medulla to metabolize organic compounds both in vitro and in vivo. The compounds used were 1,3-diphenylisobenzofuran (DPBF), luminol, and benzidine. The inner medulla was shown to possess the capacity to oxidize each of these compounds. Microsomal oxygenation did not require NADPH. Cytochorome P-450 inhibitors carbon monoxide and metyrapone did not reduce DPBF metabolism. Lipoxygenase activity was not detected in inner medullary microsomes. Oxygenation of DPBF was demonstrated in inner medullary slices and was inhibited by indomethacin. The product of DPBF metabolism in renal slices and microsomes was identified as O-dibenzoylbenzene. In vivo experiments demonstrated benzidine metabolism, which was blocked by meclofenamic acid. On the basis of substrate specificity and inhibitor studies, it was concluded that oxygenation of DPBF, luminol, and benzidine was mediated by prostaglandin cyclooxygenase. These results are compatible with cooxygenation being a mechanism of inner medullary drug metabolism.

Animals↗

PubMed1997

Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability.

1. The responses of wide dynamic range spinal dorsal horn neurones to noxious mechanical stimulation of the ankle or knee joint were tested before and after spinal administration of the non-selective cyclooxygenase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of these drugs altered the responses of these neurones to noxious mechanical stimulation. 2. Wind-up of a spinal nociceptive reflex evoked by electrical stimulation of the sural nerve at C-fibre strength was dose-dependently inhibited by intravenous administration of indomethacin, a non-selective COX inhibitor, and SC58125, a selective COX-2 inhibitor. Intrathecal administration of indomethacin also reduced the wind-up of this nociceptive reflex. 3. Western blot analysis of proteins extracted from normal rat spinal cord revealed the presence of both cyclo-oxygenase (COX)-1 and COX-2 proteins. 4. Immunocytochemistry of sections of normal rat spinal cord with specific COX-1 antiserum revealed little specific COX-1-like immunoreactivity in the grey matter. With the same antiserum, intense COX-1-like immunoreactivity was observed in the cytoplasm, nuclear membrane and axonal processes of small to medium sized (< 1000 microns2) dorsal root ganglion (DRG) cell bodies. 5. Immunocytochemistry of sections of normal rat spinal cord incubated with specific COX-2 antiserum showed intense COX-2-like immunoreactivity (COX-2-li) in the superficial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX-2-li was also observed in some neurones in deep dorsal horn and in individual motor neurones in ventral horn. COX-2-li was not observed in the cell bodies of DRG. 6. Superfusion of the lumbar spinal cord of normal rats with artificial CSF and subsequent radioimmunoassay revealed the presence of prostaglandin D2 (PGD2) < PGE2, but not PGI2 (determined by measurement of the stable metabolite, 6-keto-PGF1 alpha) or PGF2 alpha. 7. These data suggest that eicosanoids synthesized by an active COX pathway in the spinal cord of normal animals may contribute to nociceptive processing, but only when the spinal cord neurones are rendered hyperexcitable following C-fibre stimulation. Selective inhibition of one or both of the COX isoforms in normal animals may represent a novel target for spinal analgesia.

Animals↗

PubMedDate not supplied

Angiotensin-induced release of a prostacyclin-like substance from the lungs.

Intravenous infusions of angiotensins I and II into anesthetized dogs caused release of a prostacyclin-like substance into arterial blood: prostacyclin (PGI2) was detected by direct bioassay on bovine coronary artery, rat stomach strip, and rat colon, all of which were treated with phenoxybenzamine, propranolol, and Sar1-Ile8-angiotensin II. This effect of angiotensin I, but not of angiotensin II, was abolished by captopril (1 mg/kg, i.v.), and the effect of angiotensin II was abolished by Sar1-Ala8-angiotensin II (0.5 micrograms/kg/min, i.v.). The PGI2-like substance disappeared during incubation of arterial blood for 6 min, and much less appeared in mixed venous blood withdrawn from the right atrium of pulmonary artery, indicating that it originates from the lungs. Neither arterial nor mixed venous blood contained measurable amounts of prostaglandin E2; infusions of noradrenaline did not release the PGI2-like substance. Release of the PGI2-like substance by angiotensin II was reduced after intravenous administration of indomethacin (2, 5, or 10 mg/kg), aspirin (100 mg/kg), aspirin (100 mg/kg), and meclofenamic acid (2 mg/kg), but was not completely eliminated by any of the above inhibitors. In indomethacin-treated dogs the residual relaxation of the bovine coronary artery induced by intravenous angiotensin II was not further reduced by treating the tissues with hyoscine, mepyramine, cimetidine, and methysergide. Either the pulmonary site of PGI2 biosynthesis, which is stimulated by angiotensin, is partly resistant to inhibition by nonsteroidal anti-inflammatory drugs, or the PGI2-like substance is an unknown substance with similar biological properties.

Angiotensin II↗

PubMed2003

Endothelium-dependent, vasopressin-induced contractions in rabbit renal arteries.

OBJECTIVES: To identify and quantify the stimulatory and inhibitory activity of endothelial factors on Arginine vasopressin (AVP)-induced contractions. METHODS: In a standard organ bath set-up for isometric force recording, rabbit isolated renal artery rings were exposed to cumulative concentrations of AVP. Experiments were performed in the presence or absence of functional endothelium, or in the presence of N-Nitro-L-Arginine 10 microM (L-NNA) (NO-synthase inhibitor). RESULTS: Arginine vasopressin induced a maximal contractile response of 6.5 +/- 0.1 mN in vessels with and 6.3 +/- 0.3 mN in vessels without endothelium. The preincubation with l-NNA resulted in an enhanced response to AVP of 12.6 +/- 0.8 mN (P < 0.05). The augmentation of the AVP induced contractile response by NOS inhibition, which was not seen in preparations after the removal of the endothelium, suggests an endothelium dependent factor that is co-released with NO. The unknown nature of this endothelium dependent contractile factor was not influenced by indomethacin 100 microM (cyclooxygenase inhibitor), meclofenamic acid 20 microM (cyclooxygenase and lipoxygenase inhibitor), or bosentan 100 microM (endothelin antagonist). Charybdotoxin 0.1 microM (inhibitor of Ca2+ -activated K+ channels) specifically increased the contractile force in preparations with and without endothelium, or in the presence of l-NNA to 11.2 +/- 0.4 mN, 14.0 +/- 0.8 mN, and 19.0 +/- 0.8 mN, respectively (P < 0.05 compared with the experiments without charybdotoxin). SR 49059 (vasopressin 1 receptor (V1) antagonist) antagonized the effects of AVP, whereas SR 121463 B (V2 antagonist) was ineffective. In contrast to the results obtained with AVP, desmopressin (V2 agonist) showed no effect. CONCLUSION: The completely V1 dependent AVP-induced contraction is partly inhibited by the stimulated release of NO. This was only demonstrable in endothelium intact vessels in the presence of l-NNA and not after removal of the endothelium. This strongly suggests the involvement of an unknown endothelium V1 receptor dependent contractile factor that is not influenced by inhibition of the prostaglandin, lipoxygenase, or endothelin pathway, or by blockade of the V2 receptor.

Animals↗

PubMed1996

Potentiation by bradykinin and substance P of purinergic neurotransmission in urinary bladder.

PURPOSE: The higher than normal levels of substance P (SP) and the kinins in patients suffering from interstitial cystitis suggest that they may contribute to the complex symptoms of the condition. The purpose of our experiments was to determine whether SP and bradykinin (BK) influence the excitatory motor innervation of the urinary bladder. MATERIALS AND METHODS: Strips of guinea pig urinary bladder were placed in isolated tissue baths, and the influence of SP and BK on contractions induced by transmural electrical stimulation and cholinergic and purinergic agonists was evaluated. RESULTS: Substance P and BK potentiated responses to the purinergic component of the neurogenic stimulation (that part of the contractile response that remains after treatment with atropine) and potentiated responses to exogenously applied adenosine triphosphate (ATP). The peptides did not potentiate the response to the cholinergic component of the nerve-induced contraction (that part of the neurogenic response that remains after desensitization of purinoceptors with alpha, beta-methylene ATP) nor responses to carbachol. The potentiating actions of SP and BK were reduced but not abolished by treatment with meclofenamic acid. CONCLUSIONS: Substance P and BK potentiate the neurogenic response of the bladder by influencing the purinergic component of the excitatory motor innervation, apparently at a postjunctional site. Prostaglandins may be involved in mediating some of the actions of these peptides.

Adenosine Triphosphate↗

PubMed1996

Exogenous endothelin-1 causes renal vasodilation in the fetal lamb.

PURPOSE: Endothelin-1 is known to be a potent vasoconstrictor. We investigated the effects and mechanisms of action of endothelin-1 and its receptors in regulating renal vascular tone in the fetal lamb. MATERIALS AND METHODS: We observed the in vivo effects of endothelin-1, an endothelin-b receptor agonist (4-alanine-endothelin-1), endothelin-a receptor antagonists (BQ-610 and BQ-123), and the inhibition of prostaglandin and nitric oxide synthesis on the response of the renal circulation to endothelin-1 in a chronic preparation in third trimester fetal lambs. RESULTS: After injection of 250 ng./kg. endothelin-1 into the descending aorta proximal to the renal arteries in 8 fetal animals, renal blood flow increased (4.4 +/- 0.7 ml. per minute per kg., p < 0.001 versus vehicle), as did mean arterial blood pressure (3.0 +/- 0.3 mm. Hg,p < 0.001 versus vehicle). Calculated renal vascular resistance decreased (-1.1 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001 versus vehicle). After injection of 1,725 ng./kg. 4-alanine-endothelin-1 in 5 animals renal blood flow increased (3.8 +/- 0.4 ml. per minute per kg., p < 0.05 versus vehicle) and mean arterial blood pressure was unchanged (1.6 +/- 1.7 mm. Hg). Calculated renal vascular resistance decreased (-0.8 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.05 versus vehicle). After injection of 0.5 mg./kg. BQ-610 in 6 animals renal blood flow increased (2.3 +/- 0.7 ml. per minute per kg., p < 0.05) and mean arterial blood pressure decreased (-2.7 +/- 0.3 mm. Hg, p < 0.05 versus vehicle). Calculated renal vascular resistance decreased but this difference was not statistically significant (-0.7 +/- 0.3 mm. Hg per minute per kg./ml., p < 0.07). A dose of 1 mg./kg. BQ-123 in 2 animals decreased renal vascular resistance markedly. Infusion of a prostaglandin synthesis inhibitor (1 mg./kg. per minute meclofenamic acid) did not alter the decrease in renal vascular resistance after endothelin-1 (-0.7 +/- 0.4 mm. Hg per minute per kg./ml). In contrast, during infusion of a nitric oxide synthesis inhibitor (1.5 mg./kg. per minute N-omega-nitro-L-arginine) endothelin-1 increased renal vascular resistance (1.2 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001). CONCLUSIONS: Endothelin-1 is a vasodilator in the fetal renal circulation, which acts primarily via endothelin-b receptors. Ongoing activity of endothelin-a receptors contributes to renal vascular tone in fetal lambs. The vasodilatory effects of endothelin-1 in the fetal lamb renal circulation are mediated via the nitric oxide system and not via prostanoids.

Animals↗

PubMed1992

Bioavailability and bioequivalence of veterinary drug dosage forms, with particular reference to horses: an overview.

The route of administration and formulation of the dosage form affect the bioavailability (rate and extent of absorption) of a drug and may thereby influence the intensity and duration of the pharmacological effect. Location of injection site may affect the plasma concentration profile of drugs administered as aqueous suspensions or sustained release parenteral preparations (procaine penicillin G). When absorption influences the rate of elimination ('flip-flop' phenomenon), the apparent half-life of the drug will be increased (cefazolin sodium, i.m.; meclofenamic acid, p.o.). Absorption generally approximates a first-order process and either the absorption half-life or the mean absorption time (statistical moment term) will provide an estimate of the rate of absorption. The method of corresponding areas is the usual technique employed in estimating the extent of absorption (systemic availability). Inherent in this technique is the assumption that clearance of the drug remains unchanged. In horses, the time of feeding relative to oral dosing has been shown to affect systemic availability (rifampin, trimethoprim) and pattern of absorption (phenylbutazone). Oral paste formulations (trimethoprim-sulphadiazine, ivermectin) are convenient to administer, allow precision in dosage compared with powders or granules added to feed, and could provide sustained release. Assessment of bioequivalence is based on relative bioavailability, using a reference dosage form, together with a measure of the uncertainty (variance) of the estimate. Bioequivalence relies on the concept that preparations of a drug which provide essentially equivalent plasma concentration profiles should produce the same therapeutic effect.

Absorption↗

PubMed1980

Failure of anti-inflammatory steroids to inhibit prostaglandin production by rat polymorphonuclear leucocytes.

1 Like rabbit polymorphonuclear (PMN) leucocytes, rat peritoneal glycogen-induced PMN leucocytes produced much greater amounts of prostaglandin when incubated with killed bacteria than in the absence of phagocytosable material. 2 Rat PMN leucocytes mainly prostaglandin E2 (PGE2), in amounts up to 17 ng/10(6) cells in 90 min incubation, some 25 times the amount produced by resting cells. 3 Indomethacin and meclofenamic acid inhibited prostaglandin production by resting and phagocytosing cells, the IC50 being of the order of 10(-6) to 10(-7) M for both drugs. 4 Hydrocortisone and dexamethasone at concentrations up to 10(-4) M did not cause significant dose-related inhibition of prostaglandin production in this system. 5 It is suggested that the phagocytosing PMN leucocyte is insensitive to the action of anti-inflammatory steroids with respect to prostaglandin production.

Animals↗

PubMed1988

Effect of sulfidopeptide leukotrienes D4 and E4 on ileal ion transport in vitro in the rat and rabbit.

Effects of leukotrienes D4 and E4 (LTD4 and LTE4) on electrolyte transport were examined, employing stripped segments of rat and rabbit ileum mounted in Ussing chambers. Addition of LTD4 or LTE4 to the serosal but not the mucosal bathing solution elicited a transient increase in short-circuit current (Isc) with maximal responses seen at 10(-5) M and 10(-8) M in rat and rabbit respectively and a sustained decrease in transepithelial conductance (Gt) in the rat only. In the rat, Cl replacement, reduction of bathing solution [Ca2+] to 1 microM or pretreatment with 1 microM indomethacin or meclofenamic acid inhibited the LTD4- or LTE4-induced Isc changes with no effect on the decrease in Gt. LTD4 (10 microM) transiently increased net Cl secretion and produced a sustained decrease in both unidirectional and net Na transport and mucosal-to-serosal Cl flux in rat ileum. The decrease in unidirectional Na fluxes is accounted for predominantly by a change in the potential independent flux of Na. These results suggest that the increase in Isc in both rat and rabbit is mediated by arachidonic acid metabolites, whereas the decrease in Gt and net Na absorption in rat ileum is mediated by a cyclooxygenase-independent pathway.

Animals↗

PubMed1992

Characterization of the antigen-induced contraction of colonic smooth muscle from sensitized guinea pigs.

To study the potential of inflammatory mediators to alter colonic motility, we characterized the response of distal colonic smooth muscle to antigen challenge. Addition of ovalbumin to isolated segments of circular smooth muscle obtained from sensitized guinea pigs produced a biphasic contraction. The initial response consisted of a rapid contraction followed by a late response, which was a more sustained but smaller increase in tone and phasic activity. Interestingly, these two responses could be antagonized differentially. Pretreatment with mepyramine (10 microM) inhibited the initial response, whereas the leukotriene antagonist WY 48252 (10 microM) inhibited the late response. The mast cell stabilizer doxantrazole (0.1 microM) reduced only the late response. Inhibition of cyclooxygenase with meclofenamic acid (1 microM) potentiated both responses, whereas blocking neuronal activity with tetrodotoxin (1 microM) only enhanced the initial response. These data indicate clear differences between the inflammatory mediators important in the initial vs. the late response. The initial response is probably mediated by the release of histamine, with enteric neuronal interactions important in attenuating the magnitude of this response. In contrast, the late response appears to be mediated by the release of peptidyl leukotrienes. In this system, cyclooxygenase products apparently function to decrease the response of the smooth muscle to these mediators. These results suggest that release of mediators during an inflammatory response could profoundly alter colonic motility and that these alterations may be important in the pathophysiological manifestations associated with colonic inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles.

Arteriolar dilation to endothelium-derived relaxing factor (EDRF) is suppressed early in diabetes mellitus. The purpose of this study was to determine whether acute exposure to a hyperglycemic media can suppress EDRF function of normal arterioles. Dilation of intestinal arterioles to iontophoretically applied acetylcholine (ACh) and nitroprusside was measured in normoglycemic rats before and after 1 h of topical exposure to isotonic solutions containing D-glucose concentrations of 200, 300, and 500 mg/100 ml. Exposure to a D-glucose concentration of 200 mg/100 ml had no effect on vasodilation to ACh. D-Glucose concentrations of both 300 and 500 mg/100 ml caused significant suppression of the responses: for example, at the approximate 50% effective dosage (100 nA), the dilatory response was decreased by 60% at a D-glucose concentration of 300 mg/100 ml and 55% at a D-glucose concentration of 500 mg/100 ml. Responses to nitroprusside were not significantly (P < 0.05) impaired after exposure to D-glucose concentrations of 200, 300, or 500 mg/100 ml. Exposure to an isotonic L-glucose concentration of 500 mg/100 ml for 1 h had no significant (P > 0.05) effect on responses to ACh. Pretreatment with superoxide dismutase, catalase, indomethacin, or meclofenamic acid preserved EDRF-mediated vasodilation during exposure to a D-glucose concentration of 500 mg/100 ml at almost all the ACh dosages tested. These results indicate that oxygen radicals formed in part by increased eicosanoid synthesis during exposure to D-glucose hyperglycemia interfere with the EDRF mechanism before its action on the microvascular smooth muscle.

Acetylcholine↗