Biomedical subjects

Diarmaid D Houlihan

Publications and source records attributed to Diarmaid D Houlihan.

7 recordsLinked to original sources

PubMed2004

Cannabinoids and the human uterus during pregnancy.

OBJECTIVE: The aim of this study was to investigate the expression of cannabinoid receptors in human uterine smooth muscle during pregnancy and to evaluate the effects of endogenous and exogenous cannabinoids on myometrial contractility in vitro. STUDY DESIGN: Human myometrial biopsy specimens were obtained at elective cesarean delivery and snap frozen or mounted for isometric recording under physiologic conditions. Cumulative doses of the endogenous cannabinoid anandamide or the exogenous cannabinoid Delta(9) (indicates a double bond between carbons 9 and 10) tetrahydrocannabinol were added in the range 1 nmol/L to 100 micromol/L. Selectivity of the cannabinoid receptor agonists was investigated with specific antagonists for the CB(1) and the CB(2) receptors. Reverse transcription-polymerase chain reaction with primers for the CB(1) and CB(2) receptors was performed on messenger RNA that was isolated from human pregnant myometrium. RESULTS: Both anandamide and Delta(9)-tetrahydrocannabinol exerted a direct relaxant effect on human pregnant myometrium in vitro, which was of equal potency for both compounds. This relaxant effect was antagonized by the specific CB(1) receptor antagonist, SR 141716, but not by the specific CB(2) receptor antagonist, SR 144528 (n=6 specimens, P<.01). Both the CB(1) and CB(2) receptors are expressed in human myometrium. CONCLUSIONS: Both endogenous and exogenous cannabinoids exert a potent and direct relaxant effect on human pregnant myometrium, which is mediated through the CB(1) receptor. This highlights a possible role for endogenous cannabinoids during human parturition and pregnancy. These results also support the view that the use of exogenous cannabinoids during pregnancy is not linked independently with preterm labor.

Adult↗

PubMed2004

Effects of polyamines on human umbilical artery tone in vitro.

OBJECTIVE: Polyamines act as endogenous modulators of cell function and excitability. There are no data in relation to their effects on the human fetoplacental circulation. The aim of this study was to investigate the effects of the polyamines, spermine, and spermidine on human umbilical artery resistance in vitro. METHODS: Isometric tension recordings were performed under physiologic conditions on human umbilical arterial rings (n = 12). The in vitro effects of spermine and spermidine (at concentrations ranging between 10(-9) M to 10(-3) M) were measured, and compared with those measured in vehicle control experiments. The maximal inhibition (MMI) at the highest concentration and the pD2 (-log EC50) values for each compound were calculated and compared. RESULTS: Spermine and spermidine exerted a potent relaxant effect on human umbilical arterial tone in comparison to vehicle control experiments. The MMI +/- SEM for spermine was 18.41 +/- 1.437% (n = 6; P <.001) and for spermidine was 38.31 +/- 3.572% (n = 6; P <.001). There was no difference observed between the pD2 +/- SEM values for spermine (5.78 +/- 1.54; n = 6) and spermidine (6.27 +/-0.85; n = 6) (P = .517). CONCLUSION: The polyamines spermine and spermidine exert a potent relaxant effect on human umbilical artery tone suggestive of an endogenous role for these compounds in vasomotor regulation of the fetoplacental circulation.

Adult↗

PubMed2004

Anti-hypertensive therapy and the feto-placental circulation: effects on umbilical artery resistance.

OBJECTIVE: To investigate and compare the direct effects of compounds used in the treatment of hypertensive disease in pregnancy on human umbilical artery resistance in vitro. METHODS: Isometric tension recordings were performed under physiological conditions on human umbilical arterial rings (n=30). The in vitro effects of labetolol, hydralazine, alpha-methyldopa, nifedepine and magnesium sulphate (at concentration ranges from 1 nanomolar to 1 millimolar), and their respective vehicle controls, were measured. Results were expressed as -logEC50 (pD2) and mean maximal inhibition values for each compound. RESULTS: All compounds investigated, except alpha methyldopa, exerted a significant relaxant effect on umbilical arterial tone. Alpha-methyldopa was significantly less potent when compared to all other compounds (mean maximal inhibition value [20.89+/-7.99%] versus all other agents [range 63.15+/-8.70-84.12+/-3.84%] (P<0.01)). The dose response curve of nifedipine yielded a significantly greater PD2 value when compared to that of hydralazine, labetalol, and magnesium sulphate (PD2 value [5.82+/-0.34] versus the above groups [range 3.10+/-0.09-3.52+/-0.14] (P <0.01)). CONCLUSION: These findings demonstrate that agents commonly used for the treatment of hypertensive disease in pregnancy, excluding alpha-methyldopa, have significant direct effects on the feto-placental circulation. These results suggest that alpha-methyldopa administration during pregnancy is less likely to produce significant direct effects on fetal vasculature then other agents used.

Adult↗

PubMed2003

Human chorionic gonadotrophin relaxation of human pregnant myometrium and activation of the BKCa channel.

The uterorelaxant effect of human chorionic gonadotropin (hCG) is regarded as an important mediator in maintenance of uterine quiescence during pregnancy with clinical potential for tocolysis, the mechanisms of which are unknown. The large conductance calcium-activated K(+) channel (BK(Ca)) is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate the involvement of BK(Ca) channel function in the response of human myometrial cells to hCG. Single electrophysiological BK(Ca) channel recordings from freshly dispersed myocytes were obtained in the presence and absence of increasing hCG concentrations. Isometric tension studies, investigating the effects of hCG on isolated myometrial contractions, in the presence and absence of the BK(Ca) channel blocker, iberiotoxin, were performed. The hCG significantly increased the open-state probability of these channels in a concentration-dependent manner [control 0.036 +/- 0.01; 1 IU/ml hCG 0.065 +/- 0.014 (P = 0.262); 10 IU/ml hCG 0.111 +/- 0.009 (P = 0.001); and 100 IU/ml hCG 0.098 +/- 0.004 (P = 0.007)]. In vitro functional studies demonstrated that hCG exerted a significant concentration-dependent relaxant effect on human myometrial tissue. This effect was significantly attenuated by preincubation with iberiotoxin (P < 0.05). These findings outline that activation of BK(Ca) channel activity may explain the potent uterorelaxant effect of hCG.

Calcium Channel Agonists↗

PubMed2002

Polyamine effects on human myometrial contractility.

OBJECTIVE: This study was undertaken to investigate the effects of the polyamine spermine on human uterine contractility. STUDY DESIGN: Under physiologic conditions, an isometric tension recording was performed in isolated myometrial strips from biopsy specimens obtained at elective cesarean delivery (n = 24 specimens) and from premenopausal hysterectomy specimens (n = 6 specimens). The effects of spermine (1 micromol/L-10 mmol/L in cumulative doses) on spontaneous, agonist-induced myometrial contractions were measured, and dose response curves were constructed. The pD(2) (-log EC(50)) values and the maximal inhibition values achieved were compared for spontaneous and agonist-induced contractions. RESULTS: Spermine exerted a potent relaxant effect on all spontaneous and agonist-induced myometrial contractions, with mean maximal inhibition values between 62.8% +/- 4.3% and 91.4% +/- 1.8% and pD(2) values between 2.66 +/- 0.23 and 4.01 +/- 0.20. Its inhibitory effect varied significantly with different contraction types (pD(2), P <.05; mean maximal inhibition, P <.001), and it was least potent on BAY K 8644-elicited contractions (pD(2), P <.05; mean maximal inhibition, P <.01). CONCLUSION: The polyamine spermine exerts a potent relaxant effect on human uterine tissue. This effect appears to be mediated, at least partially, by calcium antagonism. Polyamines may play a role in the maintenance of uterine quiescence during pregnancy.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2002

Beta2- and beta3-adrenoreceptor agonists: human myometrial selectivity and effects on umbilical artery tone.

OBJECTIVE: The purpose of this study was to investigate the functional selectivity of the beta(3)-adrenoreceptor agonist BRL 37344 and the beta(2)-adrenoreceptor agonist ritodrine for their putative receptors in human pregnant myometrium in vitro and to examine the possibility that BRL 37344 may exert an effect on other beta-adrenoreceptor subtypes. This study also aimed comparatively to evaluate the in vitro effects of BRL 37344 and ritodrine on human vascular tissue tone. STUDY DESIGN: The effects of BRL 37344 (1 nmol/L-100 micromol/L) and ritodrine (1 nmol/L-100 micromol/L) on isometric tension recordings that were performed in isolated myometrial strips that were obtained at elective cesarean delivery and in human umbilical artery rings that were obtained at term were measured. Antagonism of the effects of BRL 37344 and ritodrine in human myometrial tissue was investigated with the antagonists butoxamine (1 micromol/L), propranolol (1 micromol/L), and bupranolol (1 micromol/L). The concentrations that produced a 50% maximal effect, the mean maximal inhibition that was achieved, and the percentage of contractility that was observed were compared. RESULTS: Bupranolol (n = 6), but not butoxamine (n = 6) or propranolol (n = 6), antagonized the relaxant effects of BRL 37344 in human pregnant myometrium; all three compounds (n = 6, respectively) antagonized the effects of ritodrine. At concentrations of >1 micromol/L, ritodrine exerted a significantly more potent vasodilatory effect than BRL 37344 on human umbilical artery tone (P <.01). CONCLUSION: The relaxant effects of BRL 37344 appear to be mediated solely through the beta(3)-adrenoreceptor agonist, although ritodrine may exert an effect on beta(1)-, beta(2)-, and beta(3)-adrenoreceptor agonists. This and the reduction in vascular tissue effects observed with BRL 37344 suggest that uterine beta(3)-adrenoreceptor modulation may provide a novel scientific approach to tocolysis with fewer vascular adverse effects.

Adrenergic beta-2 Receptor Agonists↗

PubMed2002

Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine.

The present study set out to establish the chronic mild stress (CMS) animal model of depression in male CD-1 mice, a commonly used mouse strain. Mice were exposed to a series of mild stressors (e.g. soiled bedding, paired housing, cage tilt, white noise) presented in a continuous unpredictable fashion. Intermittently, CMS was discontinued and the mice were presented with both water and a palatable saccharin solution (0.1% w/v) in a two-bottle choice test overnight (15 h). Repeated exposure of these mice to the stressors led to a reduction in preference for the saccharin solution. This change in preference was attributed to an increase in the consumption of water rather than a decrease in the consumption of saccharin solution. Over time and with extensive testing, CMS no longer affected performance in the two-bottle saccharin preference test. Treatment with the tricyclic antidepressant imipramine (20 mg/kg i.p., once daily) had a varied effect on the CMS-induced change in preference for saccharin, dependent on the timing of initiation of imipramine treatment. In the first instance, following 5 weeks of CMS where a reduction in saccharin preference was established, treatment with imipramine for a further 5 weeks maintained the stress-induced deficit in saccharin preference. However, using a different approach, pre-treatment with imipramine once daily for 2 weeks, prior to onset of CMS, and co-treatment thereafter, attenuated CMS-induced changes in saccharin preference. Finally, when imipramine treatment was scheduled to begin with the CMS procedure, imipramine failed to prevent the CMS-induced reductions in saccharin preference. Changes in behaviour observed after exposure to CMS may be linked to a stress-induced deterioration of the sensitivity of the mice to a rewarding stimulus. Treatment with imipramine can reduce these behavioural changes but is only effective when given repeatedly prior to onset of CMS.

Animals↗