Biomedical subjects

R E Garfield

Publications and source records attributed to R E Garfield.

At least 37 records · Page 2Linked to original sources

PubMed2000

The effects of pregnancy and smooth muscle contractility on cervical distensibility in the rat.

OBJECTIVE: We sought to compare distensibility of the isolated rat cervix from nonpregnant rats (n = 6), rats at midgestation (n = 5), and rats at term gestation (n = 4). STUDY DESIGN: The cervix was excised, and one cervical channel was cannulated from both ends and positioned in the organ chamber for perfusion-superfusion by a peristaltic pump at an intraluminal pressure of 30 mm Hg for 30 minutes. After the equilibration period, perfusion was stopped, the outlet was closed, and the cervix was inflated with a syringe pump. The volume was increased at a rate of 3.33 microL/s until intraluminal pressure reached approximately 120 mm Hg. The outlet was then opened, and the cervix was perfused at 30 mm Hg of intraluminal pressure for another 30 minutes. The volume-pressure relationships were obtained 3 times without any agent present and in the presence of 60-mmol/L potassium chloride or 10(-4)-mol/L 3-morpholinosydnonimine hydrochloride (also known as SIN-1). RESULTS: The volume-pressure relationship was shifted to the right during progression of pregnancy, demonstrating increased compliance of the cervix. The nonspecific depolarizing agent potassium chloride or the nitric oxide donor 3-morpholinosydnonimine did not affect volume-pressure relationships in cervices from nonpregnant rats, rats at midgestation, or rats at term gestation. CONCLUSION: The volume-pressure relationship in the isolated cannulated rat cervix reflects the resistance of the organ to increased intraluminal pressure. The compliance of the cervix is increased as pregnancy progresses, demonstrating decreased resistance to stretch. Activation or inhibition of cervical smooth muscle does not contribute to the physical properties of the cervix, which controls compliance-resistance.

Animals↗

PubMed2000

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 x 10(-5) mol/L; SQ 22536, 10(-4) mol/L) or guanylate cyclase (LY 83583,3 x 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.

Adenine↗

PubMed2000

Responses of isolated perfused uterine vascular beds of nonpregnant and pregnant rats to endogenous and exogenous nitric oxide.

The responses to endothelial vasodilators and exogenous nitric oxide (NO) were characterized in intact isolated uterine vascular beds of nonpregnant, midpregnant and late-pregnant rats perfused with Kreb's buffer (37 degrees C, 5% CO(2) in air, pH approximately 7.4) containing 2% dextran and indomethacin. Phenylephrine increased perfusion pressure in the vascular beds equally in all three groups. In the presence of phenylephrine, N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly augmented perfusion pressure in the order: nonpregnant<midpregnant<late-pregnant uterine vascular bed. Acetylcholine and bradykinin-induced attenuation of perfusion pressure did not depend on gestational age. The decrease in perfusion pressure induced by acetylcholine was nonsignificantly attenuated by L-NAME in vascular beds from pregnant rats. The attenuation induced by bradykinin reached significant level in the vascular beds from midpregnant rats. The diethylamine (DEA)/NO-induced decrease in perfusion pressure was not influenced by L-NAME in any group. These data demonstrate the augmentation of basal release of NO associated with progression of pregnancy, while the responses to endothelial vasodilators do not depend on gestational age and are not abolished by inhibition of NO synthase, suggesting involvement of nonprostanoid non-NO factor in the control of uterine circulation.

Acetylcholine↗

PubMed2000

Citrulline does not relax isolated rat and rabbit vessels.

The study was prompted by the report of Ruiz E. & Tejerina T., 1998 describing endothelium-independent relaxation by L-citrulline via activation of particulate guanylate cyclase. We compared the effects of L-citrulline and L-arginine in isolated aortic rings of rats and in isolated aortic, carotid and femoral artery rings of rabbits. No significant relaxation to either L-citrulline or L-arginine was found in the concentration range of 10(-12) to 10(-3) M, while 3-morpholinosydnonimine hydrochloride (SIN-1, 10(-6) M) relaxed vascular tissues. This study does not support the conclusion that L-citrulline has direct vasorelaxing action on vascular smooth muscle.

Animals↗

PubMed2000

Adenylate cyclase and 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 degrees C, pH approximately 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. CONCLUSION: 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.

Adenylyl Cyclases↗

PubMed2000

The role of cyclic nucleotides in the spontaneous contractility and responsiveness to nitric oxide of the rat uterus at midgestation and term.

OBJECTIVES: The aim of this investigation was to study the effects of pharmacologic manipulation of cyclic nucleotide levels on the uterine spontaneous contractile activity and responsiveness to nitric oxide in pregnant rats at midgestation and term. STUDY DESIGN: Uterine rings from pregnant rats at midgestation and term were placed in organ chambers for isometric tension recording. Concentration-response curves were obtained for phosphodiesterase and guanylate cyclase inhibitors, membrane-permeable cyclic nucleotide analogs, and forskolin. In addition, the effects of minimal inhibitory concentrations of these agents on the concentration-response relationships for diethylamine nitric oxide (a nitric oxide donor) were studied. RESULTS: Nonselective phosphodiesterase inhibitors induced more inhibition of contractions of uterine rings from pregnant rats at term than at midgestation and zaprinast induced less. Inhibitors of guanylate cyclase and membrane-permeable analogs of cyclic guanosine monophosphate were equally effective in tissues from pregnant rats at midgestation and term. All agents attenuated the inhibitory effect of diethylamine nitric oxide at midgestation; however, dibutyryl cyclic adenosine monophosphate and papaverine increased the inhibitory effect of diethylamine nitric oxide in tissues from pregnant animals at term. CONCLUSIONS: Cyclic nucleotides modulate both spontaneous and nitric oxide-induced changes in uterine contraction during pregnancy. Application of nonselective inhibitors of phosphodiesterase, as well as membrane-permeable analogs of cyclic adenosine monophosphate, may counteract refractoriness to nitric oxide at term.

1-Methyl-3-isobutylxanthine↗

PubMed2000

Effect of stimulatory and inhibitory drugs on uterine electrical activity measured noninvasively from the abdominal surface of pregnant rats.

OBJECTIVE: Our purposes were (1) to identify and analyze parameters of uterine electrical activity that change during active term and preterm labor in response to stimulatory (oxytocin) or inhibitory (terbutaline) agents and (2) to correlate the information obtained from abdominal surface measurement of electrical activity with intrauterine pressure and with the electrical activity measured directly from the uterine surface in vivo. STUDY DESIGN: Electromyographic activity was acquired simultaneously from the uterine wall and the abdominal surface by means of unipolar electrodes. Electromyographic activity was recorded in the 0.3 to 50-Hz range and digitized at 200 samples per second. Intrauterine pressure was measured via an intrauterine catheter. The effect of cumulative doses of oxytocin and terbutaline on power density spectrum, amplitude, number and duration of electromyographic bursts, and intrauterine pressure was recorded in anesthetized rats during spontaneous active term labor (n = 7) and induced preterm labor (n = 6). RESULTS: Bursts of electromyographic activity recorded from the abdominal surface mirrored those from the uterine wall, albeit at a lower amplitude. During active term labor, lower concentrations of oxytocin did not significantly affect power-density-spectrum energy, amplitude, or number of bursts per unit time. The duration of electromyographic bursts increased dose dependently. Myometrial contractions were phasic, with return to the baseline between phases. As the concentration of oxytocin increased, the energy, amplitude, and number of bursts per unit time declined while the intrauterine pressure continued to rise until the contraction became tetanic, without return to the baseline. In rats with induced preterm labor, terbutaline inhibited uterine contractility by decreasing the intrauterine pressure. This was accompanied by a progressive decrease in the power density spectrum, amplitude, number, and duration of the uterine wall and abdominal surface electrical bursts. CONCLUSIONS: First, uterine electromyographic activity measured noninvasively from the abdominal surface reflects changes in uterine electrical activity and intrauterine pressure measured directly and invasively in term and preterm labor, as well as during treatments to stimulate or inhibit labor. Second, this noninvasive method may be useful in monitoring uterine activity in vivo. Third, clinical studies to evaluate this technology in human subjects are warranted.

Abdomen↗

PubMed2000

Modulation of rat uterine contractility by mast cells and their mediators.

OBJECTIVE: This study was designed to test the possibility that mast cells play a role in the regulation of uterine contractility. STUDY DESIGN: Histamine and rat mast cell protease II levels were determined by radioenzymatic assay and standard radial immunodiffusion techniques, respectively, in uterine tissues from Wistar rats with timed pregnancies. Isolated uterine strips from nonsensitized and ovalbumin-sensitized nonpregnant and pregnant Wistar rats were used for isometric tension recording. Contractile responses to compound 48/80, carbachol, ovalbumin, normal rabbit serum, antirat immunoglobulin E, and 5-hydroxytryptamine were obtained. Antagonists methysergide, ketanserin, 5,8,11, 14-eicosatetraynoic acid, diphenhydramine, and sodium meclofenamate were also used. RESULTS: Tissue levels of rat mast cell protease II and histamine were decreased during delivery compared with prepartum and postpartum levels. Carbachol and compound 48/80 stimulated uterine contractility, and responses were highest during late gestation (day 16 to term). Responses to ovalbumin of uterine tissues in rats sensitized to the antigen were highest at midpregnancy and decreased during the last 10 days of gestation. Ovalbumin challenge in vitro increased the frequency and magnitude of contractions in tissues from ovalbumin-sensitized rats. Compound 48/80 and antirat immunoglobulin E stimulated contractility in both control and sensitized rats. None of the antagonists prevented the contractile responses. CONCLUSIONS: Activation of mast cells is an effective mechanism for stimulation of uterine contractility and may play an important role in the control of term and preterm parturition.

Animals↗

PubMed2000

Role of nitric oxide in implantation and menstruation.

Nitric oxide (NO) is a major paracrine mediator of various biological processes, including vascular functions and inflammation. In blood vessels, NO is produced by the low-input constitutive endothelial NO synthase (eNOS) and is a potent vasodilator and platelet aggregation inhibitor. The inducible NOS isoform (iNOS) is capable of producing NO at high concentrations which have pro-inflammatory properties. Immunohistochemical and molecular studies of endometrial NOS expression, as well as animal experiments with NOS inhibitors, indicate that NO plays an important role in endometrial functions such as endometrial receptivity, implantation and menstruation. In rodents, both iNOS and eNOS are highly up-regulated in the implantation sites, and NOS inhibitors show synergistic effects with antiprogestins in inhibiting the establishment of pregnancy. In the human endometrium, eNOS have been localized in the glandular epithelium and in endometrial microvascular endothelium, primarily during the luteal phase. iNOS has been found in the endometrial epithelium during menstruation, in immunocompetent endometrial cells, and in decidualized stromal cells. In primates, NO may be involved in the initiation and maintenance of menstrual bleeding by inducing tissue breakdown and vascular relaxation as well as by inhibiting platelet aggregation. Endometrium-derived NO may also play a role in myometrial relaxation during menstruation. These studies open up new applications for NO-donating and -inhibiting agents in uterine disorders. NO donors may be useful in the treatment of dysmenorrhoea and for promoting fertility. Antiprogestins, progesterone receptor modulators and iNOS inhibitors may find applications in the treatment and prevention of abnormal uterine bleeding.

Animals↗

PubMed2000

Studies of cervical ripening in pregnant rats: effects of various treatments.

The exact mechanisms that regulate cervical softening or ripening during pregnancy are not completely understood. The aim of this study was to estimate the effects of various agents on cervical softening during pregnancy in rats. Cervical resistance was examined after treatment with nitric oxide (NO) donors and inhibitors and different hormonal agents. Cervical resistance was significantly reduced (P< 0.05) in rats treated with the NO donors: sodium nitroprusside, molsidomine and prostaglandin E(2). However, treatments with the NO synthase (NOS) inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME) and L-N(6)-1-iminoethyl-lysine (L-NIL), or the prostaglandin synthesis inhibitor, indomethacin, significantly increased resistance (P<0.05). The antiprogesterone, onapristone, reduced cervical resistance and its effects were only partially blocked by the progesterone agonist, promegestone. Relaxin reduced cervical resistance and NOS inhibitors partially blocked the effect of relaxin. These studies demonstrate that NO regulates cervical ripening. Relaxin also softens the cervix and may act by stimulating NO synthesis. Progesterone seems important in the control of cervical ripening, but its role appears complex. NO and prostaglandin pathways may independently control ripening by acting in parallel or synergistically.

Animals↗

PubMed2000

Distinct regulation of nitric oxide and cyclic guanosine monophosphate production by steroid hormones in the rat uterus.

It has previously been reported that uterine nitric oxide (NO) production is enhanced during rat pregnancy compared to non-pregnant, labouring or postpartum states. The present hypothesis is that these changes in uterine NO production during pregnancy are caused by the interplay of oestrogen and progesterone. It is further postulated that changes in cyclic guanosine monophosphate (cGMP) production closely follow the changes in uterine NO synthesis. To test these hypotheses a variety of hormonal regimens (17beta-oestradiol, progesterone and combinations) were applied to different rat models (prepubertal, non-pregnant intact and ovariectomized as well as pregnant rats). The production of nitric oxide (NO) as well as basal and in-vitro NO-stimulated cGMP tissue content were measured in parallel. NO production was measured by the accumulation of nitrites and nitrates in a 24 h incubation medium as analysed by Greiss reaction. cGMP content was measured by radioimmunoassay. Diethylenetriamine/NO (DETA/NO) was used as NO donor. NO production in the rat uterus was markedly increased by pregnancy compared to other physiological (prepubertal, or cycling dioestrus) and experimentally induced (OVX) states. In contrast, uterine cGMP was significantly decreased in pregnancy. Pregnancy also inhibited the elevation in uterine cGMP after in-vitro NO challenge. Chronic 17beta-oestradiol treatment in prepubertal and/or OVX models increased NO production and also mimicked the effect of pregnancy on cGMP. Administration of progesterone in prepubertal rats induced a parallel decrease in both uterine NO and cGMP. In conclusion, sex steroid hormones distinctly regulate uterine NO and cGMP production depending upon the dose and regimen used, as well as the animal's reproductive state.

Animals↗

PubMed2000

Gap junction communication and connexin 43 gene expression in a rat granulosa cell line: regulation by follicle-stimulating hormone.

Follicle-stimulating hormone is the major regulator of growth and development of antral follicles in the ovary. Granulosa cells (GCs) in these follicles are coupled via gap junctions (GJs) consisting of connexin 43 (Cx 43). Because we and others have found that Cx 43 and GJs, respectively, are more abundant in large antral follicles compared with small antral and preantral follicles, we hypothesized that FSH may control Cx 43 gene expression, GJ formation, and intercellular communication. To directly address these points, we chose a rat GC line (GFSHR-17) expressing the FSH receptor and the Cx 43 gene. The functionality of FSH receptors was shown by the effects of porcine FSH, namely cell rounding, reduced cellular proliferation, and stimulation of progesterone production of GFSHR-17 cells, which are effects that were detectable within hours. Treatment with FSH also statistically significantly increased Cx 43 mRNA levels, as shown after 6 to 9 h in Northern blots. These effects were antedated by altered GJ communication, which was observed within seconds. Using a single-cell/whole-cell patch clamp technique, we showed that FSH rapidly and reversibly enhanced electrical cell coupling of GFSHR-17 cells. Increased GJ communication was associated with statistically significantly decreased phosphorylation of Cx 43, which was observed within 10 min after FSH addition, during immunoprecipitation experiments. Our results demonstrate, to our knowledge for the first time, that the gonadotropin FSH acutely and directly stimulates intercellular communication of GFSHR-17 cells through existing GJs. Moreover, FSH also increases levels of Cx 43 mRNA. These changes are associated with reduced proliferation and enhanced differentiation of GFSHR-17 cells. In vivo factors in addition to FSH may be involved in the regulation of GJ/GJ communication between GCs in the follicle, but our results suggest that improved cell-to-cell coupling, enhanced Cx 43 gene expression, and possibly, formation of new GJs are direct consequences of FSH receptor activation and may antedate and/or initiate the pivotal effects of FSH on GCs.

Animals↗

PubMed1999

The effect of amniotic fluid on the human omental artery in vitro.

OBJECTIVE: The aim of the study was to determine the effect of amniotic fluid on the in vitro contractility of the human omental artery. STUDY DESIGN: Amniotic fluid and a segment of omentum were obtained from each of 5 patients at the time of planned cesarean delivery at normal term gestation for the indication of previous cesarean delivery. The omental artery was cleaned and cut into 3-mm rings, which were placed in 10-mL organ chambers for isometric tension recording. The chambers were filled with Krebs-Henseleit solution bubbled with 5% carbon dioxide in air and maintained at 37 C, pH 7.4. The rings were then equilibrated at 1 g passive tension for 90 minutes. The amniotic fluid was centrifuged for 10 minutes at 3000 rpm to remove all debris. Increasing volumes of supernatant (10-2000 microL) were added to the omental artery rings at baseline tone or after contraction with U46619 (10(-7) mol/L) or potassium chloride (60 mmol/L) to detect contractile and relaxant effects, respectively. Time-solvent control preparations were also run in parallel. RESULTS: Amniotic fluid had no effect on the basal tone of omental artery rings. Amniotic fluid had no effect on the tension in rings previously contracted with either U46619 or potassium chloride. CONCLUSIONS: Amniotic fluid has no direct effect on isolated human omental artery. The catastrophic hemodynamic changes associated with the syndrome of amniotic fluid embolism are not due to a direct effect of circulating amniotic fluid on vascular tone but rather may be due to secondary responses

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Effect of nitric oxide and carbon monoxide on uterine contractility during human and rat pregnancy.

OBJECTIVE: We sought to study the effects of authentic nitric oxide and carbon monoxide on the contractile activity of pregnant human and rat myometrium. STUDY DESIGN: Strips were prepared from uterine biopsy specimens of 10 pregnant, nonlaboring women at term gestation undergoing cesarean delivery. In addition, rings were prepared from the uteri of pregnant rats at midterm (day 14) and at term (day 22) gestation (n = 10-12). The tissues were mounted in organ chambers filled with Krebs-Henseleit solution continuously aerated with 5% carbon dioxide in air (37 degrees C, pH approximately 7.4) for isometric tension recording. The effects of nitric oxide and carbon monoxide gases on spontaneous contractile activity were studied. Responses to hemin (hemoxygenase substrate), which produces endogenous carbon monoxide, were also examined. Responses to nitric oxide and carbon monoxide were also studied in aortic and tail artery rings from pregnant rats after contraction with phenylephrine. RESULTS: Nitric oxide significantly inhibited contractility of human myometrium at term (area under the concentration-response curve, 145.36 +/- 30.02 vs 40.56 +/- 22.81 in controls; P <.05) and rat myometrium at midterm gestation (264.23 +/- 47.86 vs 121.82 +/- 23.50; P <.05) but not at term. No statistically significant inhibition was induced in human or rat myometrium by carbon monoxide, whereas hemin significantly attenuated contractility in human myometrium at term and in rat myometrium at midterm gestation (P <. 05). Nitric oxide, carbon monoxide, and hemin relaxed aortic and tail artery rings. CONCLUSIONS: Authentic nitric oxide inhibits rat uterine contractile activity at midterm gestation but not at term. However, nitric oxide inhibits human myometrium activity at term. Authentic carbon monoxide does not appear to modulate uterine contractility, whereas hemin may have some inhibitory properties.

Adult↗

PubMed1999

The effect of chronic nitric oxide synthase inhibition on blood pressure and heart rate in unrestrained pregnant rats as recorded by radiotelemetry.

OBJECTIVES: The objective of this study was to determine the effect of chronic nitric oxide synthase inhibition on heart rate and intravascular blood pressure in unrestrained pregnant rats as recorded by radiotelemetry. STUDY DESIGN: Heart rate and systolic and diastolic blood pressures were monitored beginning with day 6 of pregnancy and until 1 week post partum with a radiotelemetric device. On day 10 of pregnancy osmotic minipumps were implanted subcutaneously and loaded to continuously deliver N(G)-nitro-L -arginine methyl ester (50 mg/d per rat, n = 6 animals) or vehicle (control group, n = 6 animals). RESULTS: Blood pressure in the animals treated with N(G)-nitro-L -arginine methyl ester significantly increased compared with that in the control group and heart rate significantly decreased immediately after nitric oxide synthase blockade. Blood pressure then trended downward as gestation progressed, until the difference between the control group and the group treated with N(G)-nitro-L -arginine methyl ester became nonsignificant after day 17. Refractoriness to nitric oxide synthase blockade was especially evident in the diastolic pressure. Systolic, diastolic, and mean blood pressures in the rats treated with N(G)-nitro-L -arginine methyl ester were again significantly higher than those in the control group immediately after delivery and remained so despite a lower heart rate until the experiment was ended on postpartum day 6. CONCLUSIONS: Radiotelemetry can be used to monitor heart rate and intra-arterial blood pressure in unstressed, unrestrained animals. Chronic inhibition of nitric oxide does not cause sustained hypertension throughout pregnancy. Nitric oxide does not appear to be the only factor responsible for the vascular changes in pregnancy. The factors responsible for the refractoriness to nitric oxide synthase blockade are specific to pregnancy and disappear immediately after delivery.

Animals↗

PubMed1999

The effect of an endothelin antagonist on blood pressure in a rat model of preeclampsia.

OBJECTIVE: We attempted to determine the role of endothelin in a previously characterized animal model of preeclampsia by studying the effect of a specific endothelin antagonist, BQ123, on blood pressure. STUDY DESIGN: A preeclampsia-like condition was induced by infusing pregnant rats with the nitric oxide synthase inhibitor N(G)-nitro-L -arginine methyl ester. Osmotic minipumps were inserted subcutaneously into timed pregnant Harlan-Sprague-Dawley rats on day 17 of pregnancy (term, 22 days). The pumps were loaded to continuously deliver either vehicle (control group) or N(G)-nitro-L -arginine methyl ester 50 mg/d, either alone or with BQ123 at 0.5 mg/d. In a similar but separate experiment, the dose of BQ123 was increased to 1 mg/d. Blood pressure was measured with the tail-cuff method before pump insertion and then daily until postpartum day 2. RESULTS: Except for a decrease on the day after pump insertion, BQ123 0.5 mg/d had no significant effect on the hypertension induced by N(G)-nitro-L -arginine methyl ester. At the higher dose, however, BQ123 significantly attenuated the increase in blood pressure induced by N(G)-nitro-L -arginine methyl ester during most of the study period. CONCLUSION: The effect of nitric oxide inhibition can be successfully attenuated by the use of an endothelin antagonist, thereby supporting the role of endothelin in the hypertension described with the preeclampsialike condition seen in pregnant rats.

Animals↗

PubMed1999

Roles of potassium channels and nitric oxide in modulation of uterine contractions in rat pregnancy.

OBJECTIVE: We sought to study the involvement of potassium channels in the inhibition by nitric oxide of spontaneous contractions in isolated uterine rings from midterm and term pregnant rats. STUDY DESIGN: Uterine rings from Sprague-Dawley rats at midterm and term gestation were used for isometric tension recording. The inhibition of spontaneous contractile activity by potassium channel openers and nitric oxide was studied in the absence and presence of potassium channel inhibitors. RESULTS: The adenosine triphosphate-dependent potassium channel opener levcromakalim inhibited spontaneous contractions in rings from both midterm and term pregnant rats in a concentration-dependent manner, and the effects were significantly attenuated by pretreatment with selective inhibitor of the adenosine triphosphate-dependent potassium channel inhibitor glibenclamide. The opener of calcium-dependent potassium channel NS 1619 inhibited spontaneous contractions in rings from midterm but significantly less so in rings from term pregnant rats in a concentration-dependent manner, and the effect was significantly attenuated by pretreatment with potassium channel inhibitors tetraethylammonium and tetrabutylammonium but not with glibenclamide. Rings from midterm and term pregnant rats were more sensitive to the inhibitory effect of levcromakalim compared with NS 1619. Nitric oxide donor diethylamine-nitric oxide inhibited spontaneous contractions in rings from midterm but significantly less in rings from term pregnant rats in a concentration-dependent manner, and the effect was attenuated by tetraethylammonium and tetrabutylammonium but not by glibenclamide. CONCLUSIONS: There is gestational age-dependent refractoriness to calcium-dependent potassium but not adenosine triphosphate-dependent potassium channel opener-induced inhibition of spontaneous contractile activity of isolated rat uterine rings. Nitric oxide inhibits uterine contractions by opening of calcium-dependent potassium channels in pregnant rat myometrium. Refractoriness to nitric oxide toward term may result from decreased probability to open or number of calcium-dependent potassium channels.

Adenosine Triphosphate↗

PubMed1999

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 degrees 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.

Animals↗