Influence of potent and selective beta-adrenoceptor agonist, CL 316243, on the contractile response of non-pregnant human myometrium.

UNLABELLED: The purpose of this study was to evaluate the effect of beta(3)-adrenoreceptor agonist, CL 316243 on human non-pregnant uterine contractility. The activity of myometrium strips was recorded by means of force transducers with digital output. Quantification of the response of myometrium strips was done by calculation of the area under the curve (AUC), as well as the amplitude and frequency of contractions. CL 316243 in a concentration - dependent manner (10(-10)-10(-4) mol/L) decreased the AUC value (logIC(50) -8.088+/-0.29; n=16). Decreased mean frequency of contractions and nearly 30% inhibition of spontaneous contractile activity were also observed. The inhibition of contractions by CL 316243 was not changed by either butoxamine (selective beta(2)-adrenoreceptor antagonist) or propranolol (beta(1)- and beta(2)-adrenoreceptor antagonist), and was partly antagonized by bupranolol (nonselective beta-adrenoreceptor antagonist), each antagonist at 10(-6) mol/L. IN CONCLUSION: CL 316243 causes inhibition of spontaneous contractile activity of human non-pregnant myometrium. Our findings also indicate that CL 316243 attenuates the contractile activity of human non-pregnant myometrium by the beta(3)-adrenoreceptors activation.

Cu(II) complexation potentiates arginine vasopressin action on nonpregnant human myometrium in vitro.

Copper may influence in vivo and in vitro uterine activity. Recent evidence has shown that cupric ions can easily form complexes with oligopeptides like arginine vasopressin (AVP). The high complex stability in vitro suggests a possibility of complex formation in vivo, in the uterus of intrauterine device users. In vitro isometric contractions were recorded in uterine tissues from nonpregnant premenopausal women undergoing hysterectomy and the effect of Cu-AVP complex on isolated human nonpregnant myometrium was investigated. The addition of the Cu(II)-AVP complex to the bath medium led to a concentration-dependent increase of the contractile activity. The activity was somewhat lower for the complex (-log EC(50) of 8.5 +/- 0.2, n = 7) than for AVP, but the difference was not statistically significant (p = 0.11). The maximal responses (E(max)) of the myometrium strips treated with AVP and the Cu (II)-AVP complex did not differ significantly. To assess the effect of presence of Cu (II) in the medium on tissue response to AVP, myometrium strips were preincubated for 20 min in the medium containing 10(-6) mol/L Cu(II) prior to the administration of AVP. The chosen Cu (II) concentration was below the threshold of effect on the spontaneous contractile activity in our experiments. The presence of cupric ions in the bath caused a significant leftward shift in the concentration-response curve to AVP.

Source of calcium for contractile responses of large and small human intramyometrial arteries.

The role of calcium (Ca(2+)) released from intracellular stores and the entry of extracellular Ca(2+) for vasopressin (AVP)-induced responses in large and small, human, intramyometrial arteries was investigated. There was no statistical difference as revealed by pD(2) values (-log EC(50)), in the sensitivity of large and small vessels to AVP. Nimodipine caused an inhibition of contractions induced by low concentrations (10(-10) mol/l) of AVP in both types of vessels but, at higher concentration (>10(-10) mol/l), whereas responses in small arteries were diminished, in large arteries they remained unchanged. In Ca(2+)-free solution, responses of large and small arteries to potassium and to 10(-10) mol/l AVP were abolished. With 10(-6) mol/l AVP, response in small arteries was completely inhibited, whereas in large arteries it was reduced by approximately 50%. Additional experiments were done on large arteries. Thapsigargin (TSG), which causes depletion of internal Ca(2+) stores, caused a significant reduction in responses. Following treatment with TSG, responses to AVP in Ca(2+)-free solution were almost completely inhibited but arteries responded again when incubated in normal physiological salt solution. The results indicate that in contrast to large arteries, small arteries are highly dependent on extracellular Ca(2+). Response of large arteries showed considerable dependence on Ca(2+) stored internally particularly, for maximum activation.

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women.

OBJECTIVE: To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. DESIGN: Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. SETTING: The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. PARTICIPANTS: Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. INTERVENTIONS: The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared. MAIN OUTCOME MEASURES: Receptor binding affinities. In vitro contractile effects and their inhibitions. RESULTS: Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses. CONCLUSIONS: Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

Effects of the vasopressin V1a receptor antagonist, SR 49059, on the response of human uterine arteries to vasopressin and other vasoactive substances.

BACKGROUND: Arginine vasopressin (AVP) activates the uterus via V1a receptors and is apparently an important factor for the myometrial hyperactivity, uterine ischemia and pain of primary dysmenorrhea. The orally active and selective, non-peptide AVP1a receptor antagonist, SR 49059, has been shown to inhibit the myometrial action of AVP, but the specific influence of this substance on the effects of AVP and other vasoactive agents on human uterine arteries is unknown. METHODS: Concentration-responses of AVP on isolated medium-sized human uterine arteries were studied after incubation with only vehicle (DMSO, 0.1%) and with SR 49059 in concentrations of 0.5, 2.5 and 10 nmol/L. Furthermore, the concentration-responses of AVP were investigated without and with SR 49059 (2 and 10 nmol/L) on small and medium-sized arteries. Finally, the influence of 2.5 nmol/L of SR 49059 on concentration-responses of endothelin-1, noradrenaline and prostaglandin F2 alpha was studied. RESULTS: The EC50 for AVP on medium-sized arteries was 0.53 +/- 13 nmol/L. SR 49059 caused a competitive, dose-dependent inhibition of AVP-responses, the highest concentration giving an EC50 of 460 nmol/L. The pA2 value was 9.84. The responses of the small artery preparations to AVP, both without and with the antagonist, were more pronounced than those of the medium-sized ones. The vasoconstrictive effects of endothelin-1, noradrenaline and prostaglandin F2 alpha were less pronounced than those of AVP and unaffected by pre-exposure to SR 49059. CONCLUSIONS: The high potency of AVP on human uterine arteries, particularly those of small size, supports an involvement of the peptide in the regulation of uterine blood flow in both physiological and pathophysiological condition. SR 49059 is a potent and selective AVP V1a receptor antagonist in the smooth muscle of human uterine arteries.

[The effects of heparin on intrauterine arteries of the human non-pregnant uterus: II. The analysis of the route of action]. / Wplyw heparyny na skurcz tetnic nieciezarnej macicy ludzkiej: II. Analiza drogi dzialania.

OBJECTIVE: Our purpose was to elucidate the mechanism of heparin action on smooth muscle of small intramyometrial arteries. MATERIAL AND METHOD: Material was obtained, contractility and calcium concentration were measured as previously described. Calcium influx to the vascular cells was also measured. RESULTS: Heparin did not change basal tension of the arterial strips. The strips precontracted by K(+)-depolarisation were relaxed by heparin at concentration: 200-1000 UI/mL. The maximal relaxation never exceeded 66 +/- 5.1%. Heparin (200 UI/mL) decreased the free calcium concentration in Tyrode solution to 0.8 mM. Such a lowering of the free calcium concentration diminished vascular contractile reactions. Heparin did not disturb the basal calcium influx into vascular cells but significantly decreased that which was stimulated by K+ depolarisation. 120 min treatment with heparin resulted in reducing the arterial response to 3 x 10(-8) M vasopressin recorded in Ca-free conditions. CONCLUSIONS: 1. Our results suggest that heparin, in vitro, effects the vascular smooth muscle contractions by influence on both extracellular free calcium concentration and Ca2+ influx into cytoplasm. 2. Relaxant action of heparine, on the vascular smooth muscle, is activated by additives present in commercial preparation.

[The effects of heparin on intrauterine arteries of the human non-pregnant uterus: I. The action of clinically administered heparin]. / Wplyw heparyny na skurcz tetnic nieciezarnej macicy ludzkiej: I. Dzialanie preparatu leczniczego.

OBJECTIVE: Our purpose was to study the action of commercial unfractionated heparin on small human myometrial arteries, in vitro. MATERIAL AND METHOD: Pieces of myometrial arteries, about 1 mm. in external diameter, were obtained from premenopausal women undergoing hysterectomy. Responses of arteries to K(+)-depolarisation and vassopressin were recorded under isometric condition. Free calcium concentration was determined with ion-selective electrode. RESULTS: Commercial heparin did not change basal tension of myometrial strips. Depolarised K+ strips were relaxed by heparin in concentration-dependent manner. Inhibition of NO synthase or endothelium denudation do not significantly change the reaction to heparin of strips precontracted with K(+)-depolarisation. There was a time-dependent reduction of the arterial response to vasopressin after incubation with heparin. The calcium ion chelation caused by heparin at concentrations up to 220 IU/mL did not account for the relaxation of uterine arteries. CONCLUSION: Our results suggest that clinically observed hypotensive effect of the commercial heparin is caused by its direct action on arterial smooth muscle.

Involvement of K+ATP channels in nitric oxide-induced inhibition of spontaneous contractile activity of the nonpregnant human myometrium.

Nitric oxide (NO), an important endogenous substance, is known to be a strong relaxant of smooth muscle, including myometrium. It has been postulated that the relaxing effect of NO on smooth muscle is achieved by the stimulation of soluble guanylyl cyclase, which leads to an increase in the cyclic guanosine 3',5'-monophosphate (cGMP) levels and hyperpolarization of the cellular membrane. The aim of our study was to investigate the involvement of K+ATP channels in the mechanism of cGMP-independent nitric oxide-induced inhibition of contractile activity of the nonpregnant human myometrium, obtained at hysterectomy. Nitric oxide's influence on contractile activity was recorded in the presence of methylene blue and glybenclamide, blockers of soluble guanylyl cyclase and K+ATP channels, respectively. Nitric oxide, generated by the NO donor DEA/NO, caused a dose-dependent inhibition of the spontaneous contractile activity of human nonpregnant myometrium. Preincubation with methylene blue (5 microM) did not prevent NO-induced relaxation of uterine strips, while 1.5 microM glybenclamide blocked this effect. Our results indicate that nitric oxide relaxes human non-pregnant uterus through K+ATP channels, independent of the cGMP pathway.

Potent inhibition by tamoxifen of spontaneous and agonist-induced contractions of the human myometrium and intramyometrial arteries.

OBJECTIVE: Our purpose was to elucidate the mechanism of direct (nongenomic) action of antiestrogens on spontaneous and agonist-induced contractions of the human myometrium and uterine arteries. STUDY DESIGN: Myometrial strips and pieces of uterine arteries were obtained from nonpregnant premenopausal women undergoing hysterectomy. Spontaneous activity of myometrium and responses of myometrium and artery to K(+)-depolarization and vasopressin were recorded under isometric conditions. Quantification of the responses was done by planimetry. RESULTS: The 50% inhibitory concentration values for tamoxifen, clomiphene, and cyclofenil in the case of myometrial spontaneous activity were 2.8, 43, and 331 nmol/L, respectively. Vasopressin-induced contractions in both the myometrium and arteries were potently inhibited by tamoxifen, and the 50% inhibitory concentration for the myometrium (1.4 nmol/L) was significantly lower (p < 0.05) than that for the arteries (11 nmol/L). Although tamoxifen caused no inhibition of responses induced by high potassium chloride (80 mmol/L), responses induced by low potassium chloride (20 mmol/L) were inhibited by 40% to 50% in both the myometrium and arteries. Glibenclamide reversed the inhibition by tamoxifen of spontaneous myometrial activity. CONCLUSIONS: Tamoxifen is a highly potent inhibitor of the contractile activity of the human nonpregnant myometrium and uterine arteries. It is suggested that tamoxifen could have strong potential in the treatment of dysmenorrhea.

Inhibition of contractile responses of human myometrium and intramyometrial arteries by potassium channel openers.

OBJECTIVES: The effects of cromakalim and pinacidil on the contractile activity of the isolated human myometrium and intramyometrial arteries were studied. MATERIAL AND METHOD: Myometrial strips and pieces of uterine arteries were obtained from women undergoing hysterectomy. Contractions were recorded under isometric conditions. RESULTS: Both compounds (10(-9) M-5 x 10(-6) M) inhibited the spontaneous activity of the myometrium and vasopressin induced contractions of myometrium and intramyometrial arteries. There was no statistically significant difference in the responses of both tissues to cromakalim or pinacidil. Both compounds reduced responses of myometrium and intramyometrial arteries to low concentration of K+ (< 40 mM) but did not decrease contractions induced by 40 mM and 80 mM. CONCLUSION: The combined effect on the uterus and intrauterine vasculature would suggest a potential in the use of cromakalim or pinacidil for the treatment of dysmenorrhea.

Effects of cadmium on myometrial activity of the nonpregnant human. Interactions with calcium and oxytocin.

With respect to recent reports suggesting an involvement of cadmium in preterm labor, the effects of this ion on the activity of myometrial strips from term pregnant women were examined. The interactions of cadmium with calcium and oxytocin on myometrial activity were also studied. Cadmium alone inhibited spontaneous contractile activity already in a concentration of 10(-9) M and in 10(-3) M myometrial contractions were almost completely abolished. Responses to Ca2+ and oxytocin were significantly increased by exposure to cadmium in low concentration (10(-9) M-10(-8) M), whereas higher concentration of Cd2+ had inhibitory action. These results suggest that cadmium not only blocks Ca2+ channels in the human myometrium, but also interferes with intracellular mechanisms involved in excitation-contraction coupling. The increased responses to Ca2+ and oxytocin in the presence of low amounts of Cd2+ support a role of cadmium in mechanisms of preterm labor.

Effect of ovarian steroids and diethylstilbestrol on the contractile responses of the human myometrium and intramyometrial arteries.

Estriol, estradiol, progesterone and diethylstilbestrol in the concentration range of 0.2-40 microM inhibited the spontaneous contractions of the myometrium in a dose-dependent manner but the differences in IC50 values obtained with different hormones were not statistically significant. All these hormones caused a concentration-dependent inhibition of the K(+)-induced contraction. The IC50 values were lowest for diethylstilbestrol and highest for estriol. Vasopressin at concentrations of 1.5 x 10(-6) - 1.8 x 10(-3) U/ml stimulated myometrial contractions. These responses were also inhibited by ovarian steroids and diethylstilbestrol. The IC50 values for estriol and progesterone were significantly higher than for estradiol or diethylstilbestrol. The values for estriol and progesterone did not differ significantly. In the uterine arteries, which lacked spontaneous activity, ovarian steroids and diethylstilbestrol inhibited contractions induced by K+ depolarization. As with myometrium, the lowest effect was observed with estriol and the highest with diethylstilbestrol. A dose-dependent inhibition by all four hormones (0.2-40 microM) of vasopressin-induced contractile responses of the uterine arteries was observed. With the lowest concentration of progesterone, however, the arterial response to vasopressin was enhanced. The increases by progesterone (0.02 and 0.2 microM) of responses induced by vasopressin were statistically significant (P < 0.05). The present data strongly suggest that, in human myometrium and uterine arteries, ovarian steroids and diethylstilbestrol cause a more pronounced inhibition of receptor-mediated than of voltage-dependent Ca2+ channels. The increase by a very low (physiological) concentration of progesterone of vasopressin-induced responses in both myometrium and arteries may be of significance in the pathophysiology of dysmenorrhea.

Influence of cadmium ions on the reactivity of isolated human uterine arteries.

The isometric contractions were recorded for pieces of uterine arteries as well as ascending branches of uterine artery (1-2 mm diameter) obtained from 36 nonpregnant, premenopausal women undergoing hysterectomy. Contractile responses to K(+)-depolarization, noradrenaline, and Ca+2 ions were studied. Cadmium at concentrations 10(-9)-10(-3) M produced no changes of tension in the investigated arteries. Incubation (15 min) with low concentration of cadmium (10(-9)-10(-7) M) evoked an increase of amplitude of K(+)-induced contractions in 50% of investigated vessels. Cadmium at concentrations of 10(-6)-10(-3) M gradually inhibited contractions. The influence of cadmium on contractions evoked by noradrenaline was similar to those on K(+)-induced contractions. In a Ca(2+)-free medium, 10(-5) M cadmium induced tonic contractions and pretreatment with 10(-7) and 10(-5) M cadmium slightly enhanced Ca(2+)-induced contractions. Cadmium concentration of 10(-4) M caused substantial inhibition of Ca(2+)-induced contractions. The results suggest that in the human uterine vessels cadmium is not only a Ca(2+)-channels blocker but also interferes with intracellular mechanisms involved in excitation-contraction coupling.

Diverse actions of cadmium on the smooth muscle myosin phosphorylation system.

The effects of cadmium (Cd) on smooth muscle myosin phosphorylation have been investigated using an in vitro system comprising myosin filaments containing endogenous calmodulin (CM) and myosin light chain kinase (MLCKase). In the absence of calcium (Ca), Cd as well as some other divalent cations caused no activation of phosphorylation. However, when at least one (or possibly two) Ca2+ were bound per CM, the addition of 10 microM to 40 microM Cd2+ resulted in a 2 to 3 fold acceleration of the phosphorylation rate. Higher Cd concentrations caused inhibition of the system independent of Ca2+ concentration through the formation of Cd-ATP complexes. These results explain some previously controversial data on the complex effects of Cd in intact smooth muscles.

Effect of calcium and calmodulin antagonists on contractile responses of the human uterine artery.

1. The dependence on extracellular calcium of contractile responses of intramyometrial arteries (0.5-2 mm diameter), as well as the effects of various types of calcium antagonists on these responses, were studied. Contractions were induced by K-depolarization (K) and noradrenaline (NA). 2. Whereas the K response was completely abolished in a calcium-free medium containing 2 mM LaCl3, the NA response was substantially maintained. 3. Nimodipine strongly inhibited the K response but had a relatively weak effect on the NA response; the IC50 values for the K and NA responses being 2 nM and 6 microM, respectively. Corresponding values for verapamil were about 0.7 and 10 microM. 4. Calmodulin antagonists, particularly trifluoperazine and flunarizine, caused a greater inhibition of the NA than of the K response. 5. These results indicate that besides the extracellular calcium which appears to be the major source of activator calcium, there is an intracellular pool of calcium which can be utilized to activate, albeit to a limited extent, drug-induced contractile responses.

Involvement of prostaglandins in the effect of cupric ions on the human uterus.

The effect of cupric ions on the human uterus and the involvement of prostaglandins (PGs) in mediating this effect was studied by recording of isometric contractions of isolated myometrial strips and pieces of uterine arteries, and by intrauterine pressure recordings in women before the onset of menstruation. In vitro, CuCl2 in concentrations of 10(-4) M and higher caused a significant inhibition of myometrial contractile activity, but no effect on the artery preparations was seen. Furthermore, the contractile response of myometrial strips to PGF2 alpha and PGE2 (10 ng/ml) decreased in the presence of CuCl2 in concentrations of 5 and 50 mumol. In vivo, instillations of 0.3, 1.0 and 2.0 mM of CuCl2 in 0.7 ml of saline solution into the uterine cavity caused a dose-dependent stimulation of uterine activity, but after pretreatment with naproxen, 500 mg orally, the effect of these substances was abolished. After naproxen treatment, but during infusion of PGF2 alpha (5 micrograms/min), the response to the CuCl2 solutions was partially restored. It is suggested that cupric ions, at high concentrations, have an inhibiting effect on myometrial activity. The stimulatory effect of low doses of CuCl2 seen after instillation into the uterine cavity is largely exerted via initiation of synthesis and release of endometrial PGs.

Interaction of vasopressin and prostaglandins in the nonpregnant human uterus.

The interaction of vasopressin (VP) and prostaglandins (PG) on the nonpregnant human uterus was studied in vitro and in vivo. In organ baths arginine (A)- and lysine (L)-VP in concentrations of 0.6 to 100 ng/ml stimulated small human myometrial strips and uterine artery preparations to a similar degree. When these VPs were given in the presence of indomethacin or naproxen in concentrations of 1 microgram/ml and 5 micrograms/ml, respectively, the myometrial and arterial responses were not significantly influenced. PGF2 alpha in concentrations of 0.01-100 ng/ml stimulated the myometrial preparations but caused a slight relaxation of the arteries, with PGE2 the myometrial effects were insignificant and the relaxation of the arteries greater. When AVP was given together with either of the PGs to the bath the result was generally a summation of the individual effects of both types of substances.--In vivo during intrauterine pressure recordings in nonpregnant women 1-2 days before onset of menstruation LVP in single intravenous injection of 1.2 micrograms markedly stimulated uterine contractions. The response remained practically unaltered after pretreatment with 500 micrograms of naproxen given orally. The responses to LVP were also closely similar before, during and after intravenous infusion of PGF2 alpha at a rate of 5 micrograms/min.--It is concluded that the effect of VP on myometrium and uterine arteries is not to any great extent mediated by local synthesis of PG and that PGs do not cause potentiation or inhibition of the VP effects on the nonpregnant uterus.

Vasopressin effects on isolated non-pregnant myometrium and uterine arteries and their inhibition by deamino-ethyl-lysine-vasopressin and deamino-ethyl-oxytocin.

The contractile effects of lysine- (L) and arginine- (A) vasopressin (VP) on isolated non-pregnant myometrium and uterine arteries and the inhibition of these actions by two analogues of posterior pituitary hormones, deamino-ethyl-LVP (dE-LVP) and deamino-ethyl-oxytocin (dE-OXY) were investigated. Both AVP and LVP effectively stimulated the smooth muscle preparations. The threshold dose for both agonists was about 2 ng/ml of bath fluid and a maximal response was obtained with approximately 75 ng/ml. No distinguishable effect was produced by dE-LVP and dE-OXY alone, but when given before the agonists in concentrations of 150 or 300 ng/ml, dose-dependent inhibition of the contractions was seen. The inhibition of the uterine artery responses was always greater than the inhibition of the effects on myometrial activity and dE-LVP appeared to have stronger antagonistic effects than de-OXY on the myometrial responses to the agonists. The inhibition of the myometrial and uterine artery responses to AVP could explain the therapeutic effect of dE-OXY recently found in primary dysmenorrhoea, where increased VP secretion seems to be of aetiological importance.

Relationship between Na+ and Ca++ extracellular levels and prostaglandin F2 alpha action on longitudinal muscle of guinea-pig caecum.

The response of the longitudinal muscle of guinea-pig caecum have been studied in a medium with different concentrations of Na+, K+ and Ca++. Some parameters of the electrical and mechanical activity have been followed simultaneously by the sucrose gap method. Prostaglandin F2 alpha (PGF2 alpha) stimulates the electrical and mechanical activity of the preparations isolated from this smooth muscle. The PGF2 alpha-induced depolarization of the membrane of the smooth-muscle cells, spike potentials and concentrations decrease proportionally to the Na+ reduction in the extracellular medium to 50 mM. K+ excess eliminates the effects of PGF2 alpha. Reduction of Ca++ within the limits of 1.0 to 0.2 mM leads to increase of the PGF2 alpha-induced depolarization and spike potentials, but the contractile response to PGF2 alpha decreases at Ca++ 0.2 mM. In Ca-free solution (containing (EGTA) and on the background of D 600 the spike potentials and the contraction upon treatment with PGF2 alpha are considerably decreased. These results suggest participation of Na+ and Ca++ in the effects of PGF2 alpha and it may be concluded that the extracellular concentration of Na+ and Ca++ modulates the effect of PGF2 alpha.