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Amobi N.I.B.,Kings College London | Guillebaud J.,Elliot Smith Clinic | Smith I.C.H.,Kings College London
Experimental Physiology | Year: 2012

The contractile actions of α,β-methylene ATP (α,β-meATP) and ATP and the effects of K + channel blockers in longitudinal and circular muscles of human vas deferens were investigated with a view to clarifying the functional importance of P2X 1-purinoceptor activation and K + channels in modulating contractility of the tissues. The results provide an experiment-based perspective for resolving differing reports on purinergic activation of the tissues and uncertain roles of large-conductance Ca 2+-activated K + (BK Ca) and voltage-gated delayed rectifier K + (K V) channels. α,β-Methylene ATP (3-100 μm) evoked suramin-sensitive contractions of longitudinal muscle but rarely of circular muscle. ATP (0.1-3 mm) less reliably activated only longitudinal muscle contractions. These were enhanced by ARL 67156 (100 μm), but a different ectonucleotidase inhibitor, POM 1, was ineffective. Both muscle types were unresponsive to ADP-βS (100 μm), a P2Y-purinoceptor agonist. Longitudinal muscle contractions in response to α,β-meATP were enhanced by FPL 64176 (1 μm), an L-type Ca 2+ agonist, TEA (1 mm), a non-specific K + channel blocker, 4-aminopyridine (0.3 mm), a selective blocker of K V channels, and iberiotoxin (0.1 μm), a selective blocker of BK Ca channels. Quiescent circular muscles responded to α,β-meATP reliably in the presence of FPL 64176 or iberiotoxin. Apamin (0.1 μm), a selective blocker of small conductance Ca 2+-activated K + (SK Ca) channels had no effect in both muscle types. Y-27632 (1-10 μm) reduced longitudinal muscle contractions in response to α,β-meATP, suggesting involvement of Rho-kinase-dependent contractile mechanisms. The results indicate that P2X 1-purinoceptor stimulation elicits excitatory effects that: (a) lead to longitudinal muscle contraction and secondary activation of 4-aminopyridine-sensitive (K V) and iberiotoxin-sensitive (BK Ca) K + channels; and (b) are subcontractile in circular muscle due to ancillary activation of BK Ca channels. The novel finding of differential action by P2X 1-purinoceptor agonists in the muscle types has functional implication in terms of the purinergic contribution to overall contractile function of human vas deferens. The modulatory effects of K V and BK Ca channels following P2X 1-purinoceptor activation may be pivotal in providing the crucial physiological mechanism that ensures temporal co-ordination of longitudinal and circular muscle contractility. © 2012 The Authors. Experimental Physiology © 2012 The Physiological Society. Source

Amobi N.,Kings College London | Guillebaud J.,Elliot Smith Clinic | Smith C.H.,Kings College London
BJU International | Year: 2010

Objective: To investigate the effects of the relatively selective T-type Ca2+-antagonists, mibefradil and flunarizine, and the L-type Ca 2+-antagonist, nifedipine, on the contractions of longitudinal and circular muscles of human vas deferens, to elucidate the possible involvement of T-type voltage-gated Ca2+ channels (VOCs) in the contractile function of the tissue. Materials and Methods Human vas deferens specimens from elective vasectomies were cut into strips of longitudinal muscle or transversely into rings of circular muscle. These were set up for tension recording and superfused with Krebs' medium (36° C). Contractions were evoked by noradrenaline or high [K+]o (in the presence of the L-type Ca2+ agonist, FPL 64176) and the effects of Ca2+ antagonists were determined. Results: Noradrenaline (0.1-100 μmol/L) evoked rhythmic and tonic contractions of longitudinal and circular muscles, which were potently inhibited by nifedipine (≤0.1 μmol/L). Mibefradil (1-10 μmol/L) inhibited the contractions but was comparatively more effective in longitudinal than circular muscle. Flunarizine was ineffective except against contractions to low concentrations of noradrenaline. The drugs' potencies as antagonists of L-type VOCs were determined against contractions to high K + (120 mmol/L in the presence of FPL 64176, 1 μmol/L). The contractions in longitudinal and circular muscle had different times to peak and decline but were inhibited comparably by nifedipine (50% inhibitory concentration, IC50, longitudinal and circular muscle, ≈2 nmol/L) or by mibefradil (IC50 longitudinal muscle, 1.1 μmol/L; circular muscle, 2.4 μmol/L) and were less sensitive to flunarizine (up to 30 μmol/L). CONCLUSION These Results indicate that noradrenaline-induced contractions of human vas deferens depend primarily on nifedipine-sensitive L-type VOCs, as opposed to mibefradil/flunarizine-sensitive T-type VOCs. The effects of mibefradil and flunarizine, at concentrations found to be effective against noradrenaline-induced contractions, involve the blockade of L-type VOCs. The modest differential effect of mibefradil in longitudinal and circular muscle is discussed in relation to factors that modulate activation and drug-sensitivity of L-type VOCs. Journal Compilation © 2009 BJU International. Source

MacKenzie I.Z.,Elliot Smith Clinic | Thompson W.,Elliot Smith Clinic | Roseman F.,Elliot Smith Clinic | Turner E.,Elliot Smith Clinic | Guillebaud J.,Elliot Smith Clinic
Maturitas | Year: 2010

Objective: To observe the incidence of menstrual symptoms and relevant surgery after sterilisation. Study design: 1101 women sterilised with Filshie clips between 1983 and 2002 were assessed prospectively comparing menstrual symptomatology documented immediately before surgery and 5-14 years later by questionnaire. Main outcome measures: Prevalence of menstrual dysfunction and subsequent surgery related to pre-operative menstrual symptoms and contraception. Results: After excluding 232 (24%) of the 968 eligible women sent questionnaires whose address had changed, 573 of the remaining 735 women (78%) completed the questionnaire, 223 5-6 years after sterilisation, 175 after 7-9 years and 175 after 10-15 years; the respondents were demographically representative of the total population. Heavy periods increased from 9% before to 35% (P < 0.0001) after sterilisation, painful periods from 2% to 21% (P < 0.0001) and 6% had undergone hysterectomy or endometrial ablation. These findings were not influenced by the pre-sterilisation method of contraception but were inversely related to advancing age (P < 0.0002). The lowest rates of menstrual symptoms were reported 10-15 years after sterilisation. Conclusion: Menstrual symptoms increased following Filshie clip sterilisation irrespective of pre-sterilisation symptoms and contraception. Whatever the causative mechanism, the progestogen-loaded intrauterine system (IUS), with similar efficacy but with improved menstrual symptoms, should be considered before sterilisation. © 2010 Elsevier Ireland Ltd. All rights reserved. Source

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