Prostaglandin F2 Alpha-induced Contractions Research Articles

Erythromycin inhibits prostaglandin F2alpha-induced contractions of myometrium isolated from non-pregnant rats.

The aim of this study was to investigate the effects of erythromycin on prostaglandin F2alpha (PGF2alpha)-induced contractions of isolated myometrial strips from non-pregnant rats. In vitro pharmacological study. Firat University Faculty of Medicine. Myometrium samples were taken from 55 adult Wistar rats. Myometrial strips were isolated from mature, non-pregnant Wistar rats. Isometric contractions of these strips were induced with 1 microM PGF2alpha. Effects of 0.01, 0.1, 0.2, 0.5 and 1 mM erythromycin on the frequency and amplitude of these PGF2alpha-induced contractions were recorded. The inhibition of prostaglandin F2alpha-induced contractions in vitro. Application of 0.01 mM erythromycin had no effect on either amplitude or frequency of contractions. However, 0.1, 0.2, 0.5 and 1 mM erythromycin decreased the frequency and amplitude of PGF2alpha-induced contractions. The inhibitory effect of erythromycin on amplitude was 27%, 38%, 54% and 83% (P < 0.05), and that on frequency was 10%, 16%, 32% and 61% (P < 0.05) at 0.1, 0.2, 0.5 and 1 mM concentrations, respectively. The results of this study demonstrate that erythromycin inhibits PGF2alpha-induced contractions in rat myometrium. Because PGF2alpha-induced contractions have been suggested to be involved in the pathogenesis of primary dysmenorrhoea, effects of erythromycin in this clinical entity may present a new approach for the treatment.

Differential regulation of norepinephrine- and prostaglandin F2alpha-induced contraction by extracellular Na+ in rat aorta.

The purpose of this study was to test whether extracellular Na+ differentially regulates agonist-induced contraction in vascular smooth muscle. Exposure of rat aorta to 20 nM extracellular Na+ by substitution of 123 mM Na+ with N-methyl-D-glucamine or choline, inhibited norepinephrine-induced contraction to a greater magnitude than contraction to prostaglandin F2alpha. In the absence of extracellular Ca2+ and in 20 mM Na+ solution containing 123 mM N-methyl-D-glucamine, the norepinephrine and prostaglandin F2alpha contraction remained unaltered. In contrast, in the absence of extracellular Ca2+ and in 20 mM Na+ solution containing 123 mM choline, the norepinephrine and prostaglandin F2alpha contraction were decreased and increased, respectively. Contraction to the phorbol ester, phorbol dibutyrate, was inhibited in 20 mM extracellular Na+ solution containing N-methyl-D-glucamine. Removal of extracellular Ca2+ inhibited the phorbol dibutyrate contraction, and 20 mM extracellular Na+ solution containing N-methyl-D-glucamine did not inhibit the phorbol dibutyrate contraction elicited in the absence of extracellular Ca2+. Complete replacement of extracellular Na+ with choline, and concomitant treatment with nifedipine to reduce the elevated basal tone after Na+ replacement, also resulted in greater inhibition of norepinephrine- as compared with prostaglandin F2alpha-induced contraction. Ethylisopropylamiloride, a Na+/H+ exchange inhibitor, did not alter norepinephrine contraction, as determined in the presence of nifedipine to reduce the elevated basal tone due to ethylisopropylamiloride. Acidification, which may result from decreased Na+/H+ exchange, inhibited the prostaglandin F2alpha-induced contraction to a greater magnitude than contraction to norepinephrine. These results demonstrate that extracellular Na+ selectively regulates agonist-induced contraction. The study further suggests that the selectivity may be related to an extracellular Na+-dependent process that is activated by protein kinase C, such as Na+/Ca2+ exchange, and is unrelated to the release of intracellular Ca2+ and Na+/H+ exchange.

Endothelium-dependent potentiation of prostaglandin F2alpha-induced contractions by (+/-)-[6]-gingerol is inhibited by cyclooxygenase- but not lipoxygenase-inhibitors in mouse mesenteric veins.

The mechanism of potentiation of prostaglandin (PG) F2alpha-induced contraction of mouse mesenteric veins by (+/-)-[6-gingerol was investigated in vitro. (+/-)-[6]-Gingerol (0.3mM) potentiated the maximal contraction response elicited by PGF2alpha (0.28 mm) in the presence of intact vascular endothelium, but not in its absence (de-endothelialized preparations). The potentiating effect was completely inhibited by cyclooxygenase inhibitors (0.2 mm aspirin and 0.2 mm indomethacin) and partly by calcium antagonists (2 microM verapamil, 8 nM nitrendipine and 1 microM ryanodine), but not inhibited by nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor and ONO-3708, a thromboxane (TX) A2 antagonist. The potentiation by (+/-)-[6]-gingerol is also observed in mesenteric veins of streptozotocin-diabetic mice where the enhancement of PGF2alpha-induced contraction is caused mainly by activation of lipoxygenase. The potentiation of PGF2alpha-induced contraction by (+/-)-[6]-gingerol may be caused by a cyclooxygenase-dependent release of vasoconstrictors, other than PGF2alpha and TXA2, or by inhibiting vasorelaxants released from endothelial cells of mouse mesenteric veins.

Long-term observations of uterine contractions in nonpregnant dogs.

Uterine contractile activity in nonpregnant conscious dogs was investigated based on 2- to 6-mo-long continuous recording by means of a chronically implanted force transducer. We found that nonpregnant uterine contractile activity could be classified into six major patterns: sporadic contractions, weak and strong tonic contractions, weak and strong phasic contractions, and phasic contraction bursts. The contractile patterns during proestrus and estrus were the most active, with strong phasic and tonic contractions and phasic contraction bursts. The phasic and tonic contractions were inhibited dose-dependently by a beta 2 adrenergic agonist, ritodrine, and reproduced by an alpha 2 adrenergic agonist, clonidine. In contrast, the cholinergic inhibitors atropine and hexamethonium did not affect the spontaneous occurrence of these contractions, although bethanechol evoked uterine contractions. Oxytocin and prostaglandin F2 alpha-induced contractions were phasic during estrus, whereas they showed tonic increases with phasic contractions during proestrus, diestrus, and anestrus, and these contractions did not resemble the spontaneous contractions. In conclusion, the nonpregnant uterus contracts continuously in harmony with the estrous cycle phases, and its contractile activity is enhanced by alpha adrenergic receptors and inhibited by beta 2 adrenergic receptors.

Effect of the vascular endothelium on contractions induced by prostaglandin F2 alpha in isolated pregnant guinea pig uterine artery.

The purpose of this study was to examine the influence of endothelium on prostaglandin F2 alpha-mediated contractions in pregnant guinea pig uterine artery. Consequently, the effects of prostaglandin F2 alpha on pregnant guinea pig uterine arterial rings with both intact and denuded endothelium were studied. In vessels with denuded endothelium prostaglandin F2 alpha (0.1-10 microM) induced contraction (pD2 = 6.17) with greater potency than in vessels with intact endothelium (pD2 = 5.68). NG-Monomethyl-L-arginine (10 microM) did not affect the concentration-response curve for prostaglandin F2 alpha, regardless of endothelial condition. In contrast, in both types of preparation, indomethacin (10 microM) increased the maximal response value obtained with prostaglandin F2 alpha, but this effect was significantly greater in preparations with intact than in those with denuded endothelium (128.3 versus 206.5%). Moreover, indomethacin shifted the concentration-response curve for prostaglandin F2 alpha to the left only in preparations with intact endothelium. The pKA values for prostaglandin F2 alpha itself did not differ between preparations: 5.41 and 5.52 for pregnant guinea pig uterine artery with and without endothelium, respectively. The receptor reserve expressed as KA/EC50 was significantly greater in rings with denuded (4.44) compared to those in rings with intact endothelium (1.86). We conclude that prostaglandin-F2 alpha-induced contraction in pregnant guinea pig uterine artery is modulated by the vascular endothelium. It is probable that cyclooxygenase products relating to vasodilatation and derived from endothelium mediate this effect, acting as a functional endogenous antagonist and thereby reducing the apparent efficacy and potency of prostaglandin F2 alpha.

Effects of PKC downregulation on norepinephrine- and prostaglandin F2 alpha-induced contraction in rat aorta

The purpose of this study was to investigate, through phorbol ester-induced protein kinase C (PKC) downregulation, the role of PKC in the regulation of alpha-adrenergic agonist- and prostaglandin (PG) F2 alpha-induced contraction in vascular smooth muscle. In rat aorta, long-term phorbol ester exposure (10 microM phorbol dibutyrate for 17 h), a procedure that decreased PKC activity by > 95%, and maximal phorbol myristate acetate (PMA)-induced contraction by approximately 75%, decreased tissue sensitivity to norepinephrine (NE) and PGF2 alpha 2.8- and 4.6-fold, respectively, while maximal contraction was not significantly decreased. In contrast, long-term phorbol ester exposure did not alter tissue sensitivity to KCl, while maximal KCl contraction was decreased by 40%. Long-term phorbol ester exposure, as well as short-term phorbol ester exposure (1 microM PMA for 1 h), abolished the initial transient NE contraction elicited in Ca(2+)-free solution. In contrast, long-term phorbol ester exposure did not alter the plateau NE or PGF 2 alpha contraction elicited in Ca(2+)-free solution. Short-term phorbol ester exposure of PKC-downregulated tissues potentiated the plateau PGF2 alpha contraction elicited in Ca(2+)-free solution, although the magnitude of potentiation was less than that observed in non-PKC downregulated tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation by hypoxia of contractions caused by angiotensin II in dog and monkey cerebral arteries.

Hypoxia alters the responsiveness to endogenous substances of cerebral arteries, possibly resulting in the modulation of blood supply to ischemic brain regions. The present study was undertaken to analyze the mechanism of potentiation by hypoxia of angiotensin II-induced cerebroarterial contractions. Monkey and dog cerebral arterial strips with endothelium were suspended for isometric tension recording in Ringer-Locke solution aerated with 95% O2-5% CO2 (partial pressure, 570-600 mm Hg) or 95% N2-5% CO2 (approximately 10 mm Hg). Contractions induced by angiotensin II and substance P were potentiated by exposure to hypoxia, whereas contractile responses to prostaglandin F2 alpha were not influenced. Treatment with cyclooxygenase inhibitors abolished the peptide-induced contraction but did not alter the prostaglandin F2 alpha-induced contraction. Relaxations induced by arachidonic acid were suppressed by indomethacin and hypoxia, whereas those caused by a prostaglandin I2 analogue were unaffected. The potentiation by hypoxia of cerebroarterial contractions caused by angiotensin II and substance P appears to be due to an interference with the synthesis of prostaglandin I2 from arachidonic acid and a resultant increase in the production of vasoconstrictor prostaglandins.

OXYGEN MODULATES CONTRACTILE RESPONSES TO POTASSIUM AND PROSTAGLANDIN F2α IN HUMAN PIAL ARTERIES

Oxygen may modulate cerebrovascular resistance, but its direct influence on human pial arteries is unknown. We have investigated the effects of varying oxygen tension (73, 30 and 8 kPa) in depolarized (potassium) and receptor stimulated (prostaglandin F2 alpha) isolated human pial arteries. Control responses were obtained at an oxygen tension of 30 kPa. Contractions induced by prostaglandin F2 alpha and potassium showed no significant difference in potency (unaffected EC50 values) at the different oxygen concentrations. In contrast, the maximum contractions (Emax) were dependent on the oxygen tension. Potassium-induced contractions were enhanced (Emax = 107 (SE 3)% of control contractions (P less than or equal to 0.01)) at an oxygen tension of 73 kPa, whereas a reduction in tension to 8 kPa had no significant effect (97 (2)%). Prostaglandin F2 alpha-induced contractions were enhanced at 73 kPa (115 (6)%) (P = 0.02) and depressed at 8 kPa (96 (2)%) (P = 0.02). Reduction in oxygen tension induced a relaxation in depolarized and in receptor stimulated arteries, regardless of whether or not oxygen was replaced by nitrogen or by helium. Low oxygen tension relaxed arteries despite pretreatment with 2,4-dinitrophenol, an agent which blocks oxidative phosphorylation. It is concluded that a reduction in oxygen tension exerted a direct, although small, depressant effect on human pial arteries, and that this effect was not mediated exclusively by hyperpolarization or by inhibition of oxidative phosphorylation.

Peptide leukotriene antagonistic activity of AS-35, a new antiallergic drug.

The effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (AS-35), a newly synthesized compound, on leukotrienes (LTs) antagonistic activities were investigated in vitro and in vivo. In isolated guinea pig preparations, AS-35 antagonized LTC4-, LTD4- and LTE4-induced contractions of the ileum with IC50 values of 8 nM, 4 nM and 3 nM, respectively. In the trachea, the agent also antagonized LTD4- and LTE4-induced contractions with IC50 values of 10 nM and 20 nM, respectively. However, LTC4-induced tracheal contraction in the presence of L-serine borate was not antagonized by AS-35. Histamine-, acetylcholine-, serotonin- and bradykinin-induced contractions of the ileum, carbachol-, prostaglandin D2-, prostaglandin F2 alpha-induced contractions of the trachea and LTB4-induced chemotaxis of rat polymorphonuclear leukocytes were not inhibited by AS-35. As to the in vivo models, AS-35 (i.v.) dose-dependently antagonized bronchoconstriction induced by i.v.-injection of LTC4 and LTD4 in anesthetized guinea pigs, but did not inhibit histamine-induced bronchoconstriction. Oral administration of AS-35 also antagonized LTD4- as well as antigen-induced LT-mediated bronchoconstriction. In addition, LTD4-induced increase in the cutaneous vascular permeability of guinea pig was inhibited by the drug (p.o.). These results indicate that AS-35 is an orally effective, potent and selective peptide LT antagonist.

Characterization of contraction‐mediating prostanoid receptors in human hand veins: effects of the thromboxane receptor antagonists BM13, 505 and AH23848

The effects of prostaglandin F2 alpha, prostaglandin E1, prostaglandin E2 and the thromboxane A2 analogue U46619 were determined in ring segments of human hand veins. All prostanoids except prostaglandin E1 elicited contraction. The order of potency was U46619 greater than prostaglandin F2 alpha greater than prostaglandin E2. The thromboxane receptor antagonists BM13,505 and AH23848 both caused a parallel rightward displacement of the concentration-response curve for U46619 without depression of the maximum contraction, suggesting competitive antagonism. Schild plots for both antagonists yielded regression lines with slope indices not significantly different from unity. The pA2 values for BM13,505 and AH23848 were 7.9 and 8.4 respectively. Both antagonists also effectively inhibited prostaglandin F2 alpha-induced contractions. However, AH23848 significantly reduced the maximum response, and the results with BM13,505 gave no clear indication of the type of inhibition. In vein segments submaximally contracted by 5-hydroxytryptamine, prostaglandins E1 and E2 produced a biphasic response with a relaxation at low and a contraction at high concentrations. Prostaglandin F2 alpha and U46619 failed to elicit relaxation under these conditions. However, in the presence of either thromboxane receptor antagonist, prostaglandin F2 alpha but not U46619 produced a relaxation. The results are compatible with the presence of at least two prostanoid receptors in human hand veins, a contraction-mediating thromboxane receptor and an as yet unclassified receptor eliciting relaxation. U46619 was a potent agonist at the thromboxane receptor and prostaglandin E1 and E2 preferentially stimulated the relaxation-mediating receptor, whereas prostaglandin F2 alpha appeared to be active at both receptor sites.

Chemical structural requirement in gingerol derivatives for potentiation of prostaglandin F2 alpha-induced contraction in isolated mesenteric veins of mice.

We have previously reported that (+/-)-[6]- and (+/-)-[8]-gingerols potentiate prostaglandin (PG) F2 alpha-induced muscle contraction, and that other gingerol-related derivatives do not necessarily produce the same effect. The moiety necessary for potentiation was therefore investigated. 1) (+/-)-[8]-Gingerol potentiated PGF2 alpha-induced contraction to a greater extent than (+/-)-[6]-gingerol and (+/-)-hexahydrocurcumine (HHC), but [6]-shogaol produced inhibition; 2) Noradrenaline (NA)-induced contraction was inhibited in the following order: [6]-shogaol greater than (+/-)-[8]-gingerol greater than [6]-gingerdione greater than (+/-)-[6]-gingerol greater than S-(+)-[6]-gingerdiacetate (GDA) greater than [6]-dehydrogingerdione (DHG), whereas (+/-)-HHC had no significant inhibitory action; 3) [6]-gingerdione had different effects on PGF2 alpha-induced contraction, indicating inhibition just after preparation of the solution, no effect apparent after 2 h, and potentiation after 5 h; 4) [6]-gingerdione showed a change in its chemical structure after 5 h as measured by the FeCl3 reaction, and ultraviolet and 1H nuclear magnetic resonance spectra. It was concluded that the aliphatic hydroxyl group present in gingerol derivatives is necessary for potentiation of PGF2 alpha- and the keto group for inhibition of NA-induced contraction.

Peptide‐containing nerve fibers in human cerebral arteries: Immunocytochemistry, radioimmunoassay and in vitro pharmacology

Nerve fibers containing neuropeptide Y, vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) were seen in the adventitia or at the adventitia-media border of human cerebral arteries obtained during neurosurgical procedures. Radioimmunoassay of human cerebral arteries, removed at autopsy, revealed that the levels of the four peptides did not differ among the major cerebral arteries. There was, however, a gradual decline in peptide concentrations with increasing age of the patients, as measured in the proximal part of the middle cerebral artery. Pharmacological experiments on fresh segments of cerebral (pial) arteries in vitro revealed that neuropeptide Y caused vasoconstriction per se but did not potentiate the contractile response of noradrenaline. VIP, peptide histidine methionine-27 (PHM-27), SP, neurokinin A (NKA), and human CGRP potently relaxed vessels precontracted by prostaglandin F2 alpha, the relative potency being human CGRP greater than SP greater than VIP greater than NKA greater than PHM-27. The amount of relaxation varied between 55% (SP) and 96% (human CGRP) of the prostaglandin F2 alpha-induced contraction. The peptide effects were not antagonized by propranolol, atropine, or cimetidine, suggesting an action that does not involve adrenergic, cholinergic, or histaminergic receptors.

Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene–related peptide in human temporal arteries

Nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) were seen in the adventitia or at the adventitia-media border of the human temporal artery. Pharmacological experiments on isolated temporal artery segments revealed that NPY potentiated the vasoconstrictor responses to noradrenaline, but had no vasoconstrictor ability or only a small vasoconstrictor ability per se. VIP, peptide histidine methionine 27 (PHM-27), SP, neurokinin A (NKA), and CGRP potently relaxed vessels precontracted by prostaglandin F2 alpha, the relative potency being CGRP greater than SP greater than NKA = VIP = PHM-27. The amount of relaxation varied between 67 and 91% of the prostaglandin F2 alpha-induced contraction. The peptide effects were not antagonized by classic adrenergic or cholinergic blockers, suggesting interactions via separate receptor sites.

Contractions of the canine coronary artery in calcium-free solution.

Prostaglandin F2 alpha, but not norepinephrine, augments the maximal contractile response to potassium. To examine the mechanism underlying this augmentation, rings of canine coronary artery were studied isometrically in physiological salt solutions of various composition. The contractions evoked by prostaglandin F2 alpha were larger in high-potassium, calcium-free solution than in calcium-free solution. Similar results were obtained using canine saphenous vein and femoral artery. Isoproterenol, but not nimodipine, relaxed the contractions produced by prostaglandin F2 alpha in high-potassium, calcium-free solution. Unlike prostaglandin F2 alpha, norepinephrine failed to constrict rings in high-potassium, calcium-free solution. In calcium-free solution, prostaglandin F2 alpha-induced contractions increased with increasing potassium concentrations, but no enhancement occurred when lithium was substituted for potassium. Rings of coronary artery incubated with calcium-45 did not show changes in prostaglandin F2 alpha-induced calcium-45 efflux following changes in potassium concentration. These results suggest that potassium enhances coronary vascular smooth muscle contraction to prostaglandin F2 alpha, but not norepinephrine, independently of calcium entry.

Effects of relaxin on in vivo uterine contractions in conscious and unrestrained estrogen-treated and steroid-untreated ovariectomized rats.

The effect of extended infusions of highly purified porcine relaxin on uterine activity was tested in vivo in conscious unrestrained rats. Relaxin was found to inhibit oxytocin- and prostaglandin F2 alpha-induced uterine contractions in estrogen-treated ovariectomized rats as well as spontaneous contractions in both estrogen-treated and steroid-untreated ovariectomized rats. The inhibition of both induced and spontaneous uterine contractions was more effective in the early phases of relaxin infusion than after prolonged exposure to the hormone. However, this desensitization was not complete, and the inhibition was effective even with extended (up to 72 h in the oxytocin experiments) infusion of relaxin. The results indicate that relaxin may be important in controlling uterine activity in the rat near the end of gestation, and that estrogen priming in ovariectomized rats is not necessary for relaxin to exert its biological effects.