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Martin C Michel

Publications and source records attributed to Martin C Michel.

At least 37 records · Page 2Linked to original sources
PubMed2006

Sphingosine-1-phosphate and sphingosylphosphorylcholine: two of a kind?

Sphingosine-1-phosphate and sphingosylphosphorylcholine are structurally related signalling molecules. Although they share some biological effects, it is debated whether this involves the same receptors. In this issue, Mathieson and Nixon report that these two lipids activate the same transcription factor but do so via distinct signalling pathways. Against this background, we discuss some of the potential pitfalls in studies comparing the effects of the two sphingolipids.

Animals↗
PubMed2006

Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate.

1 We have systematically reviewed the presence, functional responses and regulation of alpha(1)-, alpha(2)- and beta-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes. 2 Alpha(1)-adrenoceptors are only poorly expressed and play a limited functional role in the detrusor. Alpha(1)-adrenoceptors, particularly their alpha(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates. Alpha(1)-adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate. 3 Alpha(2)-adrenoceptors, mainly their alpha(2A)-subtype, are expressed in bladder, urethra and prostate. They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans. Their overall post-junctional function in the lower urinary tract remains largely unclear. 4 Beta-adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate. The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the beta(3)- and beta(2)-subtypes are important in the human bladder and urethra, respectively. Beta(3)-adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder. 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence. Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment.

Adrenergic Agonists↗
PubMed2006

Effects of alpha(1)-adrenoceptor antagonists on male sexual function.

alpha(1)-Adrenoceptor antagonists such as alfuzosin, doxazosin, tamsulosin and terazosin are first-line agents for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH), but are only second-line agents (doxazosin and terazosin only) for the treatment of arterial hypertension. Sexual function is complex and includes multiple domains such as sexual desire (libido), erectile function and ejaculatory function. Erectile and ejaculatory functions are frequently reduced in patients with BPH and can impact on their quality of life. Therefore, the treatment of BPH should aim to maintain or even restore sexual function.alpha(1)-Adrenoceptor antagonists lack major effects on sexual desire in placebo-controlled studies. Reports on erectile function are inconsistent, with both beneficial and adverse effects being reported, but impotence can occur in some patients without clear differences between drugs. Ejaculatory dysfunction during treatment may represent (relative) an ejaculation. It occurs more frequently with tamsulosin than with other drugs of this class, but the differences are not big enough to be consistently detectable in directly comparative studies. We propose that such differences between drugs should be weighed against differences in cardiovascular tolerability when choosing the optimal treatment for each patient.

Adrenergic Antagonists↗
PubMed2005

A rapid and validated HPLC method to quantify sphingosine 1-phosphate in human plasma using solid-phase extraction followed by derivatization with fluorescence detection.

We describe the development and validation of analytical methodology for the determination of sphingosine 1-phosphate (S1P) in plasma. It uses solid-phase extraction (SPE) followed by an automated reversed-phase gradient HPLC column-switching system with a pre-column derivatization with o-phthalaldehyde (OPA) and fluorescence detection. The limit of quantification was determined at 100 ng/ml exogenous sphingosine 1-phosphate with a relative standard deviation for precision and accuracy <15%. The within- and between-day relative standard deviation for precision and accuracy were also less than 15%. This validated method should be suitable to quantify plasma concentration of sphingosine 1-phosphate in relatively large numbers of samples.

Calibration↗
PubMed2005

Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder.

We compared the density and function of M2 and M3 muscarinic acetylcholine receptor subtypes in the urinary bladder of young adult (3 months) and old (23 months) male Wistar rats. Old rats had a reduced density of muscarinic receptors (96+/-10 vs. 156+/-21 fmol/mg protein), but competition experiments with the M3-selective darifenacin did not indicate alterations in the relative roles of M2 and M3 receptors, with the former being more abundant. The amount of immunodetectable alpha-subunits of various G-proteins potentially linked to muscarinic receptor function was unchanged. The potency of carbachol to contract bladder strips was also unaltered; its maximum effects as well as those of a single KCl concentration were unchanged if raw data or those corrected for strip length were analysed, but somewhat reduced when those corrected for strip weight were analysed. Antagonistic effects of atropine, the M2-selective Ro 320-6206 and the M3-selective darifenacin were unchanged. Agonistic effects of the M3-sparing agonist 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-[1,4']bipiperidinyl-1'-carboxylic acid ethyl ester were similarly poor in young and old rats. Additional experiments were concomitantly performed in submandibular glands from the same animals. While total muscarinic receptor density in submandibular glands was not significantly affected by age (56+/-5 vs. 61+/-4 fmol/mg protein), the relative contribution of M3 receptors significantly declined from 68+/-3% to 57+/-2% based upon darifenacin competition curves. We conclude that aged Wistar rats express fewer muscarinic receptors in their urinary bladder, but there is no change in the relative abundance of M2 and M3 receptors; this is accompanied by only minor if any alterations in receptor responsiveness. In contrast, submandibular gland expresses similar receptor numbers in young and old rats, but slightly fewer M3 receptors in old animals.

Aging↗
PubMed2005

Can a GDP-liganded G-protein be active?

The replacement of GDP bound to the alpha-subunit of a G-protein by GTP is generally considered a crucial step in the activation of effectors by a G-protein. New data by Uğur et al. (2005) (p. 720) raise the possibility that for the heterotrimeric G-protein Gs, GDP-liganded Gs is able to activate the effector adenylyl cyclase as potently and effectively as when Gs is in its GTP bound form. We summarize here the evidence that GTP is necessary for effector activation by G-proteins and discuss potential implications and limitations of data to the contrary.

Animals↗
PubMed2005

A role for muscarinic receptors or rho-kinase in hypertension associated rat bladder dysfunction?

PURPOSE: Essential arterial hypertension is a frequent condition. Spontaneously hypertensive rats (SHRs) show bladder dysfunction similar to that seen in patients with overactive bladder. Since muscarinic receptors and rho-kinase have a key role in the regulation of bladder contractility, we determined whether alterations of either one might contribute to hypertension associated bladder dysfunction. MATERIALS AND METHODS: The bladders of SHRs and normotensive Wistar Kyoto rats (WKYs) were compared in in vitro radioligand binding and contractility studies. RESULTS: The mean total number of muscarinic receptors +/- SEM (181 +/- 14 vs 191 +/- 22 fmol/mg protein) and the relative roles of their subtypes were similar in SHRs and WKYs. Contractile responses to the muscarinic agonist carbachol (maximum effect 2.04 +/- 0.24 vs 2.05 +/- 0.14 mN/mm strip length and -log EC50 5.61 +/- 0.07 vs 5.64 +/- 0.04) and to KCl in a receptor independent manner were similar in the 2 strains. The M3 selective antagonist darifenacin inhibited carbachol responses much more potently than the M2 selective antagonist methoctramine but the potency of the 2 drugs was similar in each strain. The rho-kinase inhibitor Y27,632 attenuated carbachol induced contraction in a quantitatively similar manner in SHRs and WKYs. CONCLUSIONS: An altered function of muscarinic receptor subtypes or rho-kinase does not appear to contribute to bladder dysfunction in SHRs.

Animals↗
PubMed2005

Role of muscarinic receptor antagonists in urgency and nocturia.

The overactive bladder (OAB) syndrome is defined as urgency, with or without urgency incontinence, usually accompanied by frequency and nocturia. Muscarinic receptor antagonists are the most established form of treatment for OAB, but until recently their effectiveness was only confirmed for symptoms of incontinence and frequency. In recent studies, selected muscarinic antagonists, including darifenacin, solifenacin, tolterodine and trospium, significantly reduced the number of urgency episodes per day relative to placebo. While some data raise the possibility that certain of these agents may be more effective than others in this regard, this variability in their effect on urgency needs to be confirmed in future studies. Moreover, it remains to be determined whether counting the number of urgency episodes or assessing the subjective intensity of the sensation of urgency more adequately reflects patient needs and therapeutic efficacy. For nocturia, muscarinic receptor antagonists have only inconsistently shown statistically greater effects than placebo. This inconsistency may relate to the multifactorial nature of nocturia, which even in patients with OAB can have many causes, not all of which may respond/be sensitive to muscarinic receptor antagonism.

Age Factors↗
PubMed2004

Comparison of symptom severity and treatment response in patients with incontinent and continent overactive bladder.

PURPOSE: Two thirds of patients with overactive bladder (OAB) are continent, but our knowledge on the treatment of the syndrome is largely based on studies with incontinent patients. Therefore, we have explored baseline symptoms and treatment responses to tolterodine in continent relative to incontinent OAB patients. MATERIALS AND METHODS: Data from an open-label, observational study involving 3824 patients with OAB symptoms were analyzed for baseline symptoms and alterations thereof upon a 9 months treatment with 4 mg q.d. tolterodine ER. RESULTS: Baseline symptoms (number of urgency episodes, total urination frequency, daytime frequency, nocturia, and three scales of OAB severity) were similar in 1147 continent and 2571 incontinent patients, the latter having 4.8+/-3.7 incontinence episodes per 24 h. Tolterodine ER-induced reduction of OAB symptoms was very similar in both groups of patients. CONCLUSIONS: The severity of OAB in continent patients can be similar to that in incontinent ones. Symptom improvement upon treatment with tolterodine ER is very similar in both groups. We propose that continent patients may similarly deserve treatment with a muscarinic receptor antagonist as incontinent ones.

Aged↗
PubMed2004

Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol?

Cyclic AMP is the prototypical second messenger of beta-adrenergic receptors, but recent findings have questioned its role in mediating smooth muscle relaxation upon beta-adrenergic receptor stimulation. We have investigated the signaling mechanisms underlying beta-adrenergic receptor-mediated relaxation of rat urinary bladder. Concentration-response curves for isoproterenol-induced bladder relaxation were generated in the presence or absence of inhibitors, with concomitant experiments using passive tension and KCl-induced precontraction. The adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536; 1 microM), the protein kinase A inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7; 10 microM), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89; 1 microM), and Rp-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMPS; 30 microM), and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 3 microM) produced only minor if any inhibition of relaxation against passive tension or KCl-induced precontraction. Among various potassium channel inhibitors, BaCl2 (10 microM), tetraethylammonium (3 microM), apamin (300 nM), and glibenclamide (10 microM) did not inhibit isoproterenol-induced relaxation. Some inhibition of the isoproterenol effects against KCl-induced tone but not against passive tension was seen with inhibitors of calcium-dependent potassium channels such as charybdotoxin and iberiotoxin (30 nM each). A combination of SQ 22,536 and ODQ significantly inhibited relaxation against passive tension by about half, but not that against KCl-induced tone. Moreover, the combination failed to enhance inhibition by charybdotoxin against KCl-induced tone. We conclude that cAMP and cGMP each play a minor role in beta-adrenergic receptor-mediated relaxation against passive tension, and calcium-dependent potassium channels play a minor role against active tension.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2004

Cardiovascular effects of sphingosine-1-phosphate and other sphingomyelin metabolites.

Upon various stimuli, cells metabolize sphingomyelin from the cellular plasma membrane to form sphingosylphosphorylcholine (SPC) or ceramide. The latter can be further metabolized to sphingosine and then sphingosine-1-phosphate (S1P). Apart from local formation, S1P and SPC are major constituents of blood plasma. All four sphingomyelin metabolites (SMM) can act upon intracellular targets, and at least S1P and probably also SPC can additionally act upon G-protein-coupled receptors. While the molecular identity of the SPC receptors remains unclear, several subtypes of S1P receptors have been cloned and their distribution in cardiovascular tissues is described. In the heart SMM can alter intracellular Ca(2+) release, particularly via the ryanodine receptor, and conductance of various ion channels in the plasma membrane, particularly I(K(Ach)). While the various SMM differ somewhat in their effects, the above alterations of ion homeostasis result in reduced cardiac function in most cases, and ceramide and/or sphingosine may be the mediators of the negative inotropic effects of tumour necrosis factor. In the vasculature, SMM mainly act as acute vasoconstrictors in most vessels, but ceramide can be a vasodilator. SMM-induced vasoconstriction involves mobilization of Ca(2+) from intracellular stores, influx of extracellular Ca(2+) via L-type channels and activation of a rho-kinase. Extended exposure to SMM, particularly S1P, promotes several stages of the angiogenic process like endothelial cell activation, migration, proliferation, tube formation and vascular maturation. We propose that SMM are an important class of endogenous modulators of cardiovascular function.

Animals↗
PubMed2004

Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum.

The SK/IK family of small and intermediate conductance calcium-activated potassium channels contains four members, SK1, SK2, SK3 and IK1, and is important for the regulation of a variety of neuronal and non-neuronal functions. In this study we have analysed the distribution of these channels in human tissues and their cellular localisation in samples of colon and corpus cavernosum. SK1 mRNA was detected almost exclusively in neuronal tissues. SK2 mRNA distribution was restricted but more widespread than SK1, and was detected in adrenal gland, brain, prostate, bladder, liver and heart. SK3 mRNA was detected in almost every tissue examined. It was highly expressed in brain and in smooth muscle-rich tissues including the clitoris and the corpus cavernosum, and expression in the corpus cavernosum was upregulated up to 5-fold in patients undergoing sex-change operations. IK1 mRNA was present in surface-rich, secretory and inflammatory cell-rich tissues, highest in the trachea, prostate, placenta and salivary glands. In detailed immunohistochemical studies of the colon and the corpus cavernosum, SK1-like immunoreactivity was observed in the enteric neurons. SK3-like immunoreactivity was observed strongly in smooth muscle and vascular endothelium. IK1-like immunoreactivity was mainly observed in inflammatory cells and enteric neurons of the colon, but absent in corpus cavernosum. These distinctive patterns of distribution suggest that these channels are likely to have different biological functions and could be specifically targeted for a number of human diseases, such as irritable bowel syndrome, hypertension and erectile dysfunction.

Adult↗
PubMed2004

Extracts from Rhois aromatica and Solidaginis virgaurea inhibit rat and human bladder contraction.

Since extracts from the plants Rhois aromatica and Solidaginis virgaurea are being used in the phytotherapy of bladder dysfunction including the overactive bladder syndrome, and since muscarinic receptors are the main pharmacological target in the treatment of bladder dysfunction, we have investigated whether these extracts can inhibit carbachol-induced, muscarinic receptor-mediated contraction of rat and human bladder. In vitro contraction experiments were performed with rat and human bladder strips. Radioligand binding and inositol phosphate accumulation studies were done with cells transfected with human M(2) or M(3) muscarinic receptors. Both extracts concentration-dependently (final concentrations 0.01-0.1%) inhibited carbachol-induced contraction of rat and human bladder with insurmountable antagonism. Radioligand binding experiments and inositol phosphate accumulation studies with cloned receptors demonstrated direct but non-competitive effects on muscarinic receptors. Reductions of KCl-induced bladder contraction demonstrated that inhibition by the higher extract concentrations also involved receptor-independent effects. We conclude that extracts from Rhois aromatica and Solidaginis virgaurea inhibit muscarinic receptor-mediated contraction of rat and human bladder. While this could contribute to the beneficial effects of these extracts in patients with bladder dysfunction, such therapeutic effects remain to be demonstrated in controlled clinical studies.

Animals↗