Inhibition Of Uterine Contractions Research Articles

Outcomes of nursing monitoring for pregnant women under tocolytic therapies: a comparative study

Background Preterm birth (PTB) is the most common cause of neonatal morbidity and mortality worldwide. Tocolytic drugs had not been shown to improve fetal outcome, but were used to postpone delivery for 48 h to allow for maximal effect of parenteral steroids administered to the mother. The aim of the current study was to evaluate the outcomes of nursing monitoring for the pregnant mother under tocolytic therapy. Design An observational, comparative design was used to achieve the aim of the study. Setting The study was conducted at El Manial University Hosbital and El Galaa Maternity Teaching Hospital. Sample A convenience sample collected throughout one year of 30 preterm pregnant mothers under tocolytic therapy in each hospital. Tools Four tools were used: tool (1) Structured interviewing questionnaire, (2) Tocolytic monitoring, (3) Partograph, and (4) Apgar score. Result The study findings showed that 53.4% of mothers in group A as compared with 63.3% in group B received Epilate as a tocolytic agent. It shows that there were no statistically significant differences among both groups related to mean frequency of uterine contractions and mean duration of U.C, P=(0.329 and 0.189, respectively). It also shows that the side effects of tocolytic drugs in the first 24 h were dizziness, headache, tachycardia, and hypotension in group A (3.3%, 10%, 3.3%, and 6.7, respectively) as compared with (0%, 6.7%, 0%, and 10%, respectively). While only one 3.3% mother in group A had a fetus with bradycardia as a side effect of tocolytic drugs. In all, 93% and 96.7% of mothers in both groups had inhibition of uterine contractions and prolonged their pregnancy for 24 h. Conclusion Based on the results of this study, it could be concluded that tocolytic agents that were administered for 48 h reduced the uterine contractions and increased the period of pregnancy for preterm pregnant mother and improved neonatal outcomes by giving corticosteroids, but they had minimal side effects that occurred for mother and fetus in both groups. Recommendation (1) Close monitoring for all preterm pregnant women who are under tocolytic agents, (2) the newborn for women under tocolytic agents should be under close monitoring, and (3) provide education in the same strain to all nurses working in the maternity hospital with regard to care of women under tocolytic agents.

Ethanolic Extracts of Adlay Testa and Hull and Their Active Biomolecules Exert Relaxing Effect on Uterine Muscle Contraction through Blocking Extracellular Calcium Influx in Ex Vivo and In Vivo Studies

Dysmenorrhea is one of the most prevalent disorders in gynecology. Historically, adlay (Coix lachryma-jobi L. var. Ma-yuen Stapf.) has been explored for its anti-tumor, pain relief, anti-inflammatory, and analgesic effects. The aim of this study was to evaluate the effects of adlay seeds on the inhibition of uterine contraction and thus dysmenorrhea relief, in vitro and in vivo. HPLC-MS and GC were used to elucidate the ethyl acetate fraction of adlay testa ethanolic extract (ATE-EA) and ethyl acetate fraction of adlay hull ethanolic extract (AHE-EA). Elucidation yielded flavonoids, phytosterols, and fatty acids. Uterine leiomyomas and normal adjacent myometrial tissue were evaluated by oxytocin- and PG-induced uterine contractility. ATE-EA and AHE-EA suppressed uterine contraction induced by prostaglandin F2 alpha (PGF2α), oxytocin, carbachol, and high-KCl solution ex vivo. In addition, the external calcium (Ca2+) influx induced contraction, and increased Ca2+ concentration was inhibited by ATE-EA and AHE-EA on the uterine smooth muscle of rats. Furthermore, ATE-EA and AHE-EA effectively attenuated the contraction of normal human myometrium tissues more than adjacent uterine leiomyoma in response to PGF2α. 3,5,6,7,8,3′,4′-Heptamethoxyflavone and chrysoeriol produced a remarkable inhibition with values of IC50 = 24.91 and 25.59 µM, respectively. The experimental results showed that treatment with ATE-EA at 30 mg/day effectively decreased the writhing frequency both on the oxytocin-induced writhing test and acetic acid writhing test of the ICR mouse.

Uterosacral Nerve Stimulation via Cuff Electrode: A Preliminary Animal Study for Potential Application to Treatment of Preterm Labor.

Preterm labor occurs in about 12% of all pregnancies, accounting for at least 75% of neonatal deaths. The neonatal outcomes depend on mainly the gestational age at delivery. The lower the gestational age, the higher the risk of morbidity and mortality. The management of preterm labor involves early detection of high-risk women, prevention and treatment. In this study, the feasibility and stability of implantable cuff electrodes detection and inhibition of uterine contractions for preterm labor treatment were investigated by in-vivo mouse test. In order to check functionality of implanted electrodes, acute in-vivo test at mouse uterosacral ligament was performed by using cuff electrode which stimulate and record nerve activity. As results, the electrical stimulation via a stimulating cuff electrode at mouse uterosacral ligament was properly applied and nerve fiber's signal was recorded via the recording electrode. In addition, the implanted cuff electrodes could obtain stable recording signal to the periodic electrical stimulation for 7 weeks.

Nifedipine Versus Magnesium Sulfate for Treatment of Preterm Labor: Comparison of Efficacy and Adverse Effects in a Randomized Controlled Trial

Objectives: The study aimed to compare the efficacy and side effects of intravenous magnesium sulfate (MgSO4) and oral nifedipine for inhibition of preterm labor. Methods: This randomized controlled trial was performed on 220 women with preterm labor between 32 and 34 weeks of gestation who were randomly assigned to receive either MgSO4 or nifedipine. The primary outcome was inhibition of preterm labor, defined as prevention of delivery for 48 hours with inhibition of uterine contraction, and the secondary outcome was maternal side effects. Results: From 220 patients, 110 received nifedipine and 110 received MgSO4. There were no differences in suppression of labor pain in 24 hours and 48 hours between the two groups. Also, there were not statistically significant differences in one-minute and five-minute Apgar scores, neonatal respiratory distress syndrome, and NICU admission between the two groups. Maternal hypotension was higher in the nifedipine group, but the difference was not significant (P = 0.08). Dyspnea (P = 0.01) and minor maternal side effects (P ≤ 0.001) were significantly higher in the MgSO4 group than the nifedipine group. Serious maternal adverse effects and severe hypotension were not seen in any of the groups. Conclusions: Nifedipine is as effective as MgSO4 in arresting labor and delaying delivery for 48 hours. However, nifedipine is associated with significantly fewer maternal adverse effects.

Role of uterine contraction in regeneration of the murine postpartum endometrium.

The endometrium undergoes continuous repair and regeneration without scarring throughout the reproductive life of women. However, the mechanisms responsible for this complete restoration remain mostly unexplored. We hypothesized that the ischemic state and local hypoxia present after parturition may create a special microenvironment for endometrial healing, and that this ischemia might be caused by reduction in organ volume via postpartum uterine contraction. Here, we developed a mouse model using a combination of cesarean section and the administration of a beta 2 adrenergic receptor agonist (ritodrine hydrochloride) in postpartum mice that had been ovariectomized to exclude the effect of ovarian hormones. Our results revealed that transient hypoxia indeed occurred in postpartum uteri. Furthermore, we found that the number of M2 macrophages, which play a central role in wound healing, peaked on Postpartum Day 3 and gradually decreased thereafter in hypoxic injury sites. Almost concurrently, significant upregulation of vascular endothelial growth factor and transforming growth factor beta (TGFbeta) was observed. In particular, the antifibrotic factor TGFbeta3 was released during the endometrial healing process. These changes were significantly suppressed by inhibition of uterine contraction. Taken together, these results suggest that uterine contraction is essential, not only for hemostasis, but also for endometrial regeneration, leading to a process that involves the activation of macrophages, increased endometrial cell proliferation, and upregulation of nonfibrotic growth factors. This study paves the way to a novel approach for investigating the process of scarless wound healing.

Effect of lipopolysaccharide on the production of prostaglandin E2 and inhibition of uterine contractions by nitric oxide in pregnant inducible nitric oxide synthase knockout mice

The aim of the present study was to evaluate the effect of lipopolysaccharide (LPS) on the production of prostaglandin E2 (PGE2) and inhibition by nitric oxide (NO) of spontaneous contractions of uterine rings from pregnant inducible isoform of nitric oxide synthase knockout (iNOS KO) mice. iNOS KO and wild-type mice were sacrificed 6 h after intraperitoneal (i.p.) administration of LPS on day 14 of gestation. Uterine rings were equilibrated in Krebs-Henseleit solution for isometric tension recording. In part of the uterine rings, placental tissues were left attached. The bathing solution was analyzed for PGE2 by radioimmunoassay. Changes in spontaneous contractions in response to cumulative concentrations of L-arginine, diethylamine/nitric oxide (DEA/NO), and 8-bromo-cyclic guanosine monophosphate (8-br-cGMP) were determined. Treatment with LPS increased PGE2 production by uterine rings from wild-type and iNOS-KO mice. DEA/NO and 8-br-cGMP inhibited spontaneous contractions in uterine rings in the absence or presence of placenta, in both LPS-treated and LPS-untreated animals. LPS treatment attenuated maximal inhibition induced by the agents, both in the absence and presence of placental tissues in iNOS KO and wild-type mice. LPS induces PG production in mice myometrium that is not dependent on the integrity of iNOS, while LPS could induce pathophysiological iNOS obstruct uterine quiescence by physiological iNOS. Infection affects uterine contractile activity through PG production, as well as through placental and genetic factors. NO may be a double-edged sword in pregnant mice myometrium.

Potential Role for Oxidative Stress in 2,2′-Dichlorobiphenyl–Induced Inhibition of Uterine Contractions but not Myometrial Gap Junctions

Previously, we reported that 2,2'-dichlorobiphenyl (2,2'-DCB)-induced decreases of amplitude and synchronization of uterine contractions are dependent on MAPK-induced phosphorylation of Connexin43 (Cx43) and inhibition of myometrial gap junctions. Recent studies show that oxidative stress inhibits uterine contractions and myometrial gap junctions also. The present study examines the hypothesis that 2,2'-DCB-induced modification of uterine contraction is dependent on oxidative stress-mediated inhibition of myometrial gap junctions via activation of mitogen-activated protein kinase (MAPK) and phosphorylation of Cx43. In uterine strips treated with alpha-tocopherol (100 microM), deferoxamine mesylate (Def, 50 microM), or superoxide dismutase (SOD, 1000 U) after a 1-h exposure to 100 microM 2,2'-DCB, modification of uterine contractions reversed 1 h after initiating antioxidant treatment. Treatment of uterine strips with 100 microM 2,2'-DCB for 1 h lowered total SOD activity and also induced a surge of superoxide generation after 5 min of exposure. However, myometrial cells exposed in culture to 100 microM 2,2'-DCB did not produce reactive oxygen species as determined by the lack of superoxide anion generation measured by the cytochrome c reduction assay, reactive species by the formazan assay, hydrogen peroxide by the 2',7'-dichlorofluorescein assay, and lipid peroxidation by the thiobarbituric acid-reactive substance assay. Furthermore, cotreatment with SOD or Def was unable to prevent 2,2'-DCB-induced phosphorylation of Cx43, activation of MAPK, and inhibition of myometrial gap junctions. Although antioxidants reversed 2,2'-DCB-induced inhibition of uterine contraction force and synchronization, the myometrial cell culture experiments failed to support oxidative stress as a mechanistic link between 2,2'-DCB-induced inhibition of myometrial gap junctions and modification of uterine contraction.

420 Effect of lipopolysaccharide on inhibition of uterine contractions by nitric oxide in INOS knockout mice

420 Effect of lipopolysaccharide on inhibition of uterine contractions by nitric oxide in INOS knockout mice

Role of nucleotide cyclases in the inhibition of pregnant rat uterine contractions by the openers of potassium channels

Objective: Our objective was to study the involvement of adenylate and guanylate cylases in spontaneous uterine contractions and inhibition induced by the opening of potassium channels. Study Design: Uterine rings from rats at mid and term gestation and from rats at term gestation in labor were suspended in organ chambers for isometric tension recording. Concentration-response relationships to an opener of adenosine triphosphate–dependent potassium channels, levcromakalim, or to an opener of calcium-dependent potassium channels, NS 1619, were studied in the absence and presence of inhibitors of adenylate cyclase (MDL 12330 A, 2 × 10 –5 mol/L; SQ 22536, 10 –4 mol/L) or guanylate cyclase (LY 83583,3 × 10 –6 mol/L). Results: MDL 12330 A and SQ 22536 accentuated contractions in rings from rats at mid gestation but not at term gestation or at term gestation in labor. LY 83583 inhibited contractions in the rings from all 3 groups. Levcromakalim was equally effective in inhibiting contractions of rings from all 3 groups. MDL 12330 A, but not SQ 22536, decreased sensitivity and maximal inhibition induced by levcromakalim (term gestation greater than mid gestation greater than term gestation in labor). LY 83583 decreased the sensitivity to and maximal inhibition induced by levcromakalim in rings from pregnant rats at mid gestation. NS 1619 attenuated contraction of rings from rats at mid gestation and, to a lesser extent, at term gestation but accentuated contractions in rings from animals at term gestation in labor. MDL 12330 A, but not SQ 22536 or LY 83583, attenuated the changes induced by NS 1619 in rings from all 3 groups. Conclusions: (1) The influence of nucleotide cyclases on basal uterine contractility depends on gestational age. (2) The inhibition of uterine contractions that results from the opening of calcium-dependent potassium channels depends on adenylate cyclase, whereas that of adenosine triphosphate–dependent potassium channels depends on both adenylate and guanylate cyclases. 3. Activation of adenosine triphosphate–dependent potassium channels is more efficient than activation of calcium-dependent potassium channels. 4. The inhibition induced by calcium-dependent potassium channel openers, but not adenosine triphosphate–dependent potassium channel openers, decreases as pregnancy progresses, and at delivery the activation of spontaneous contractile activity is evident. (Am J Obstet Gynecol 2000;182:913-8.)

Adenylate cyclase an potassium channels are involved in forskolin- and 1,9-dideoxyforskolin-induced inhibition of pregnant rat uterus contractility

Objective:We sought to study the contribution of potassium channels in the effect of forskolin and 1,9-dideoxyforskolin on uterine contractility in the pregnant rat. Study Design:Rings taken from the middle portions of uterine horns from rats at 16 days of gestation were positioned in organ chambers containing physiologic salt solution bubbled with 5% carbon dioxide in air (37°C, pH −7.4) for isometric tension recording under 2 g passive tension. The effects of cumulative concentrations of forskolin and 1,9-dideoxyforskolin in the absence or presence of an adenylate cyclase inhibitor (MDL-12,330A, 10−5 mol/L), a nonselective potassium channel blocker (tetrabutylammonium, 10−4 mol/L), or an adenosine triphosphate-dependent potassium channel blocker (glibenclamide 10−5 mol/L) were studied. Results:Both forskolin and, to a lesser extent, 1,9-dideoxyforskolin inhibit uterine contractions. Tetrabutylammonium, glibenclamide, and MDL-12,330A attenuated the effects of forskolin, whereas glibenclamide was less effective against 1,9-dideoxyforskolin. Conclusions:Activation of adenylate cyclases, as well as adenosine triphosphate-dependent potassium channels and, to a greater extent, calcium-dependent potassium channels, is involved in the inhibitory effect of forskolin in uterine rings from rats at 16 days of gestation. Inhibition of uterine contractions by 1,9-dideoxyforskolin is less than that by forskolin and involves activation of adenylate cyclase and calcium-dependent potassium channels. Whether activation of guanylate cyclase is involved in the effect of the agents on calcium-dependent potassium channels needs further investigation. 1,9-Dideoxyforskolin is not an inactive isomer of forskolin in rat uterine rings.

Effect of placental tissue on inhibition of uterine contraction by nitric oxide donors

Objective: Our purpose was to test the hypothesis that placental tissue modulates the effect of nitric oxide on spontaneous uterine contractility in pregnant rats. Study Design: Rings (approximately 4 mm) of uterus taken from rats on day 14 (midpregnancy, n = 6), day 18 (late pregnancy, n = 4), and day 22 (term, n = 4) of gestation were placed in organ chambers filled with Krebs-bicarbonate buffer bubbled with 5% carbon dioxide in air (37°C, pH approximately 7.4) for isometric tension recording. In some rings a piece of placenta was left attached to the uterine wall. In the other rings the fetuses, placentas, and membranes were removed completely. Change of spontaneous contractions of the rings (percentage change of basal integral activity for 10 minutes) in response to cumulative concentrations of the nitric oxide donors diethylamine–nitric oxide and nitroglycerin (10 –6 mol/L to 10 –4 mol/L) were compared between rings with and without placenta. Results: Diethylamine–nitric oxide and nitroglycerin inhibited spontaneous uterine contractions in rings from midpregnancy, in both the absence and the presence of placenta. In rings from midpregnancy, the maximal inhibition of contractions by diethylamine–nitric oxide but not by nitroglycerin was significantly ( P < .05) higher in the presence (26.7% ± 3.5% of basal activity) than in the absence (39.6% ± 3.3%) of placenta. Inhibition of contraction by nitric oxide donors in rings from late and term pregnancy was less than in midpregnancy, and the presence of placental tissue did not influence the responses. Conclusions: The presence of placental tissue enhances inhibition of uterine contractility by agents that spontaneously release nitric oxide, such as diethylamine–nitric oxide, but not by nitroglycerin, which requires metabolic transformation for nitric oxide to be released. Refractoriness to nitric oxide near or at term does not depend on the presence or absence of placental tissue. (Am J Obstet Gynecol 1999;181:415-8.)

Both soluble guanylate cyclase and particulate guanylate cyclase regulate myometrial contractility

OBJECTIVE: Our purpose was to compare the effects of agents stimulating particulate and soluble guanylate cyclase with spontaneous rat uterine contractions at midgestation and term. STUDY DESIGN: Uterine rings from midgestation (day 13) and term nonlaboring (day 22) rats were positioned in organ chambers for isometric force recording. Rings were treated with increasing concentrations of atrial natriuretic peptide, permeable analogs of cyclic guanosine monophosphate, and diethylamine/nitric oxide. RESULTS: Atrial natriuretic peptide was more effective in inhibition of uterine contractions than diethylamine/nitric oxide. The 50% inhibitory concentrations were –7.4 ± 0.12 and –7.38 ± 0.11 for atrial natriuretic peptide and –5.68 ± 0.09 and –4.23 ± 0.12 for diethylamine/nitric oxide at midgestation and term, respectively. Pretreatment of uterine rings with atrial natriuretic peptide significantly attenuated inhibition of spontaneous contractions by diethylamine/nitric oxide at midgestation. CONCLUSIONS: Uterine spontaneous contractions are influenced by both soluble and particulate guanylate cyclase; the former, but not latter, is gestational age dependent. (Am J Obstet Gynecol 1998;179:111-6.)

Role of nucleotide cyclases in the inhibition of uterine contractions by K-channel openers in pregnant rats

Role of nucleotide cyclases in the inhibition of uterine contractions by K-channel openers in pregnant rats

Increased expression of nitric oxide synthase in the myometrium of the pregnant rat uterus.

Nitric oxide (NO) relaxes uterine smooth muscle and is produced by the pregnant uterus. Our previous studies revealed an increase in rat uterine NO synthase (NOS) activity in pregnancy and a decline at term. In the present study, we have examined the distribution of NOS isoform expression to determine whether their regulation is consistent with a role in the inhibition of uterine contractions before term. At day 17-18 of pregnancy, NOS immunohistochemistry revealed expression of two isoforms: endothelial constitutive form of NOS (ecNOS) in vascular endothelium and inducible form of NOS (iNOS) in myometrial and vascular smooth muscle and in decidual epithelium. Immunoblotting revealed that expression of iNOS declined nearly fivefold, whereas ecNOS declined twofold in laboring rats at term. We conclude that iNOS is expressed in myometrium of pregnant rat uterus but not the virgin rat and that iNOS expression declines at term when labor is present. The pattern of changes in myometrial iNOS expression with advancing gestation suggests that NO could act in an autocrine and/or paracrine manner to inhibit uterine contractions before term.

Magnesium sulfate inhibits oxytocin-induced calcium mobilization in human puerperal myometrial cells: Possible involvement of intracellular free magnesium concentration

Our purpose was to elucidate the mechanisms of the tocolytic action of Mg2+ on the human myometrium. The effects of extracellular Mg2+ on oxytocin-induced increases in the intracellular free Ca2+ concentration in human puerperal myometrial cells were examined by means of indo-1-AM. The changes in the intracellular free Mg2+ concentration under various conditions were also measured with Mg(2+)-fura-2-AM. The increase in intracellular free Ca2+ concentration induced by oxytocin was reduced to 26% of that in the normal solution 20 minutes after replacement of the normal solution with an extracellular Mg2+ solution, 10 mmol/L. When extracellular Ca2+ was removed, the increase in intracellular free Ca2+ concentration was not suppressed even 20 minutes after the replacement. A solution of extracellular Mg2+ concentration, 10 mmol/L, raised the intracellular free Mg2+ concentration gradually, by approximately 150% in 20 minutes, concomitant with the suppression of the response to oxytocin in the intracellular free Ca2+ concentration. High intracellular free Mg2+ concentration, caused by high extracellular Mg2+, is essential for suppression of oxytocin-induced Ca2+ influx across the cell membrane; this presumably results in inhibition of uterine contractions.

Influence of ovarian steroids on myometrial sensitivity and tolerance to relaxin in the rat in vivo: lack of cross-tolerance between relaxin, salbutamol and cromakalim.

The influence of oestradiol benzoate and progesterone on uterine sensitivity and development of tolerance to relaxin was investigated in bilaterally ovariectomized non-pregnant rats in vivo. Bolus doses of relaxin (2-20 micrograms/kg i.v.) produced rapid and reversible inhibition of uterine contractions in a dose-dependent manner. Treatment with oestradiol benzoate or oestradiol benzoate plus progesterone significantly increased uterine sensitivity to relaxin over 48 h by 2.4- to 8.5-fold. Tolerance to relaxin developed during continuous infusion of the hormone at 20 micrograms/kg per h for 40 h. A 7.8- to 17.4-fold reduction in sensitivity to relaxin was observed in relaxin-infused rats, whereas no change in sensitivity was observed in saline-infused rats. Infusion of relaxin at 50 micrograms/kg per h for 40 h produced a 131.8-fold reduction in uterine sensitivity to relaxin. The uterus remained tolerant to relaxin for up to 24 h after cessation of infusion. Treatment with oestradiol benzoate and/or progesterone did not influence the extent of tolerance development, but a more rapid recovery of uterine sensitivity to relaxin was observed in rats treated with oestradiol benzoate plus progesterone. Cross-tolerance with other uterine relaxant drugs was measured to investigate possible common mechanisms of action and sites of tolerance between relaxin and a beta-adrenoceptor agonist (salbutamol) and potassium channel openers (cromakalim and minoxidil sulphate). No cross-tolerance was observed between relaxin and salbutamol, or relaxin and cromakalim or minoxidil sulphate. Cross-tolerance between cromakalim and minoxidil sulphate was seen.

Oxytocin Receptor Blockade: A New Principle in the Treatment of Preterm Labor?

The concentration of myometrial and decidual oxytocin receptors increases dramatically in normal women in late pregnancy, causing enhanced uterine sensitivity to physiologic levels of oxytocin. Similar increase in myometrial oxytocin receptors has been found in women in preterm labor, indicating a role for oxytocin also in idiopathic preterm labor. A newly synthesized oxytocin analogue, 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin, has been found to be a competitive inhibitor of oxytocin. The present study was conducted to test its efficacy in suppressing uterine contractions during preterm labor in women. Twelve patients with established, uncomplicated preterm labor between 27 and 33 weeks of gestational age were given intravenous infusions of the analogue for 1.5 to 13 hours during continuous external cardiotocographic monitoring. In nine patients inhibition of uterine contractions was achieved and further progression in cervical scores was arrested. In three patients, all at 27 weeks of gestational age, no significant tocolytic effect was observed during a 1.5-hour infusion of the analogue and the patients were then given ritodrine intravenously. No side effects were observed in any of the patients. These preliminary findings support the concept that an increased concentration of uterine oxytocin receptors is an important etiologic factor in uncomplicated preterm labor and therefore oxytocin receptor blockade may be a therapeutic alternative for this condition.

Calcium and calmodulin antagonism for inhibition of uterine contractions.

In search for a new tocolytic agent we investigated felodipine, a calmodulin-antagonizing drug. Felodipine reduced the spontaneous activity of 22 uterine strips taken from the uterus in the course of a cesarean section to 52 +/- 12% (mean +/- SEM) after 10 min, to 20 +/- 7% after 20 min and to 12 +/- 4% after 60 min (P less than 0.001).

Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects.

1 The kinetics of diltiazem were investigated in ovariectomized (ovx) non-pregnant and intact late pregnant anaesthetized rats following a bolus i.v. injection (2 mg kg-1) and during a 180 min i.v. infusion (50 micrograms kg-1 min-1 and 100 micrograms kg-1 min-1). Uterine contractions, mean blood pressure and heart rate were measured in the non-pregnant rats. 2 Measurement of serum diltiazem concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: volume of distribution area (V(area)) - 256 +/- 46 ml; rate constants k12 - 0.46 +/- 0.10 min-1; k21 - 0.09 +/- 0.01 min-1; kel - 0.13 +/- 0.03 min-1; elimination clearance - 3.2 +/- 0.3 ml min-1; distribution t1/2 (t1/2) - 1.4 +/- 0.3 min; elimination t1/2 (t1/2 beta) - 61.2 +/- 13.0 min. In pregnant rats, a biexponential decay was also observed with similar parameters to those in non-pregnant animals except for markedly increased V(area) - 1004 +/- 184 ml; kel - 0.54 +/- 0.16 min-1 and elimination clearance - 14.8 +/- 2.3 ml min-1. 3 Measurement of serum diltiazem concentrations during infusion yielded the following parameters in non-pregnant ovx rats: V(ss)--79 +/- 10 ml; rate constants k12 - 1.02 +/- 0.21 min-1; k21 - 0.03 +/- 0.01 min-1; kel - 0.39 +/- 0.06 min-1; elimination clearance - 7.8 +/- 1.2 ml min-1. In pregnant rats a marked increase was observed in kel - 1.25 +/- 0.38 min-1 and elimination clearance - 36.4 +/- 13.8 ml min-1. 4 An immediate reduction in uterine contractions, mean blood pressure and heart rate was observed after bolus i.v. injection of diltiazem with a return towards control values as serum diltiazem concentrations declined. There were significant correlations between the inhibition of the 3 parameters and the log serum concentrations of diltiazem. Serum concentration-response curves indicated IC50 values of 0.5 microgram ml-1 for inhibition of uterine contractions, 0.7 microgram ml-1 for reduction in blood pressure and 1.2 micrograms ml-1 for reduction in heart rate. There were maintained reductions in the integral of uterine contractions, mean blood pressure and heart rate during infusion. 5 The metabolite desacetyldiltiazem was rarely detected after i.v. bolus injection and was not found in 5/13 rats infused with diltiazem, yet significant inhibition of uterine contractions was observed in all rats. Diltiazem was 3.2 fold more potent than desacetyldiltiazem as an inhibitor of contractions of the rat isolated uterus. 6 These findings indicate that the inhibition of uterine contractions is due to a direct action of diltiazem, and not the metabolite desacetyldiltiazem, and suggest only a slight selectivity for uterine inhibition compared to cardiovascular effects.

Fetal movements in isoxsuprine-treated patients

Fetal activity expresses fetal condition in utero. Daily monitoring of fetal movements provides a good criterion for estimating fetal well-being. I The number of fetal movements per day is inAuenced by gestational age a nd other factors . I It has been suggested that drugs, such as barbiturates and diaze pam, reduce fetal movements. ~ Isoxsuprine hydrochloride (Duvadilan) is a ,a-adrenergic drug generally used in prevention of premature labor by inhibition of uterine contraction. It is known that uterine contractions are associated with fetal movements.