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Martin C Michel

Publications and source records attributed to Martin C Michel.

At least 19 recordsLinked to original sources
PubMed2007

Tools to study beta3-adrenoceptors.

Beta(3)-adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of beta(3)-adrenoceptors has been hampered by a lack of highly specific tools. "Classical" beta(3)-adrenoceptor agonists such as BRL 37,344 [(R*, R*)-(+/-)-4[2-[(3-chlorophenyl)-2-hydroxyethyl) amino] propyl] phenoxyacetic acid] and CGP 12,177 [(+/-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one] are only partial agonists in many settings, have limited selectivity over other beta-adrenoceptor subtypes, and may additionally act on receptors other than beta-adrenoceptors. More efficacious and more selective agonists have been reported and, in some cases, are in clinical development but are not widely available for experimental studies. The widely used antagonist SR 59,230 [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] is not selective for beta(3)-adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of beta(3)-adrenoceptors or for the nonselective labeling of all beta-adrenoceptor subtypes, are also missing. beta(3)- and beta(1)/beta(2) double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of beta(3)-adrenoceptors. While the common availability of more selective agonists and antagonists at the beta(3)-adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of beta(3)-adrenoceptor for the time being.

Adrenergic beta-3 Receptor Agonists↗
PubMed2007

Relationships among symptoms, bother, and treatment satisfaction in overactive bladder patients.

AIMS: We have studied the association between various symptoms, bother, and patient treatment satisfaction in overactive bladder (OAB). METHODS: Episodes of urgency, incontinence, daytime frequency and nocturia and responses to the patient perception of bladder condition scale, the urgency perception scale, and visual analog scales of limitations in daily life and of treatment satisfaction were evaluated in 3,824 OAB patients at baseline and during 9 months treatment with tolterodine ER (4 mg q.d.) in an open-label, observational study. Relationships amongst number of symptoms/ 24 hr and scales were explored. Treatment satisfaction was correlated with improvements in symptoms and scales. RESULTS: At baseline, the number of episodes of the four OAB symptoms correlated only poorly with each other and with the two bother-related scales, while the two scales assessing bother correlated much stronger with each other. Factor analysis identified four components which described "bother," "incontinence," "urgency/frequency," and "nocturia" and in combination explained 81.9% of the total variance. The component "bother" had the strongest individual effect accounting for 42.1% of the total variance. While improvements of symptoms and bother were seen with tolterodine treatment, patient treatment satisfaction correlated strongest with improvements of the two bother-related scales. CONCLUSIONS: We conclude that the counting of episodes of OAB symptoms only insufficiently describes the afflicted patients. Patient bother is the strongest individual component but only poorly explained by episodes of the four symptoms defining OAB. Alterations of bother may better reflect patient-relevant outcomes in OAB treatment than alterations in the number of symptom episodes.

Adult↗
PubMed2006

Signal transduction and regulation: are all alpha1-adrenergic receptor subtypes created equal?

The current manuscript reviews the evidence whether and how subtypes of alpha(1)-adrenergic receptors, i.e. alpha(1A)-, alpha(1B)- and alpha(1D)-adrenergic receptors, differentially couple to signal transduction pathways and exhibit differential susceptibility to regulation. In both regards studies in tissues or cells natively expressing the subtypes are hampered because the relative expression of the subtypes is poorly controlled and the observed effects may be cell-type specific. An alternative approach, i.e. transfection of multiple subtypes into the same host cell line overcomes this limitation, but it often remains unclear whether results in such artificial systems are representative for the physiological situation. The overall evidence suggests that indeed subtype-intrinsic and cell type-specific factors interact to direct alpha(1)-adrenergic receptor signaling and regulation. This may explain why so many apparently controversial findings have been reported from various tissues and cells. One of the few consistent themes is that alpha(1D)-adrenergic receptors signal less effectively upon agonist stimulation than the other subtypes, most likely because they exhibit spontaneous internalization.

Animals↗
PubMed2006

Comparison of three radioligands for the labelling of human beta-adrenoceptor subtypes.

We have compared the ability of three radioligands, [(125)I]-cyanopindolol, [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol, to label the three human beta-adrenoceptor subtypes. Saturation and competition binding experiments were performed using membrane preparations from Chinese hamster ovary cells stably transfected with the three subtypes. While [(3)H]-CGP 12,177 had very similar affinity for beta(1)- and beta(2)-adrenoceptors (about 40 pM), [(125)I]-cyanopindolol and [(3)H]-dihydroalprenolol had 4- to 6-fold higher affinity for beta(2)- as compared to beta(1)-adrenoceptors (10 vs 45 and 187 vs 1,021 pM, respectively). The affinity of [(125)I]-cyanopindolol at beta(3)-adrenoceptors was considerably lower (440 pM) than at the other two subtypes. The beta(3)-adrenoceptor affinity of [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol was so low that it could not be estimated within the tested range of radioligand concentrations (up to 4,000 pM and 30,000 pM for [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol, respectively). We conclude that all three radioligands are ill-suited to label beta(3)-adrenoceptors, particularly in preparations co-expressing multiple subtypes. In the absence of alternatives, [(125)I]-cyanopindolol appears the least unsuitable to label beta(3)-adrenoceptors. There is a need for high-affinity radioligands which are either selective for beta(3)-adrenoceptors or reasonably non-selective among all three beta-adrenoceptor subtypes.

Adrenergic beta-Agonists↗
PubMed2006

Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets.

By virtue of their large number, widespread distribution and important roles in cell physiology and biochemistry, G-protein-coupled receptors (GPCR) play multiple important roles in clinical medicine. Here, we focus on 3 areas that subsume much of the recent work in this aspect of GPCR biology: (1) monogenic diseases of GPCR; (2) genetic variants of GPCR; and (3) clinically useful pharmacological agonists and antagonists of GPCR. Diseases involving mutations of GPCR are rare, occurring in <1/1000 people, but disorders in which antibodies are directed against GPCR are more common. Genetic variants, especially single nucleotide polymorphisms (SNPs), show substantial heterogeneity in frequency among different GPCRs but have not been evaluated for some GPCR. Many therapeutic agonists and antagonists target GPCR and show inter-subject variability in terms of efficacy and toxicity. For most of those agents, it remains an open question whether genetic variation in primary sequence of the GPCR is an important contributor to such inter-subject variability, although this is an active area of investigation.

Alleles↗
PubMed2006

Rho kinase: a target for treating urinary bladder dysfunction?

Urinary incontinence and other urinary storage symptoms are frequent in the general population but available treatments have limited efficacy and tolerability. Rho kinase (ROCK) has a central role in the regulation of smooth muscle contraction, including that of the urinary bladder. Recent experimental evidence indicates that this role could be deregulated and exacerbated in local and systemic pathological conditions that affect the bladder. In vitro studies with prototypical ROCK inhibitors such as Y27632 and in vivo data from animal models indicate that such drugs have potential as future treatments for bladder dysfunction.

Animals↗
PubMed2006

Sphingosine kinase-dependent activation of endothelial nitric oxide synthase by angiotensin II.

OBJECTIVE: In addition to their role in programmed cell death, cell survival, and cell growth, sphingolipid metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate have vasoactive properties. Besides their occurrence in blood, they can also be formed locally in the vascular wall itself in response to external stimuli. This study was performed to investigate whether vasoactive compounds modulate sphingolipid metabolism in the vascular wall and how this might contribute to the vascular responses. METHODS AND RESULTS: In isolated rat carotid arteries, the contractile responses to angiotensin II are enhanced by the sphingosine kinase inhibitor dimethylsphingosine. Endothelium removal or NO synthase inhibition by N(omega)-nitro-L-arginine results in a similar enhancement. Angiotensin II concentration-dependently induces NO production in an endothelial cell line, which can be diminished by dimethylsphingosine. Using immunoblotting and intracellular calcium measurements, we demonstrate that this sphingosine kinase-dependent endothelial NO synthase activation is mediated via both phosphatidylinositol 3-kinase/Akt and calcium-dependent pathways. CONCLUSIONS: Angiotensin II induces a sphingosine kinase-dependent activation of endothelial NO synthase, which partially counteracts the contractile responses in isolated artery preparations. This pathway may be of importance under pathological circumstances with reduced NO bioavailability. Moreover, a disturbed sphingolipid metabolism in the vascular wall may lead to reduced NO bioavailability and endothelial dysfunction.

Angiotensin II↗
PubMed2006

Cyclic AMP-dependent and Epac-mediated activation of R-Ras by G protein-coupled receptors leads to phospholipase D stimulation.

The activation of the Ras-related GTPase R-Ras, which has been implicated in the regulation of various cellular functions, by G protein-coupled receptors (GPCRs) was studied in HEK-293 cells stably expressing the M3 muscarinic acetylcholine receptor (mAChR), which can couple to several types of heterotrimeric G proteins. Activation of the receptor induced a very rapid and transient activation of R-Ras. Studies with inhibitors and activators of various signaling pathways indicated that R-Ras activation by the M3 mAChR is dependent on cyclic AMP formation but is independent of protein kinase A. Similar to the rather promiscuous M3 mAChR, two typical G(s)-coupled receptors also induced R-Ras activation. The receptor actions were mimicked by an Epac-specific cyclic AMP analog and suppressed by depletion of endogenous Epac1 by small interfering RNAs, as well as expression of a cyclic AMP binding-deficient Epac1 mutant, but not by expression of dominant negative Rap GTPases. In vitro studies demonstrated that Epac1 directly interacts with R-Ras and catalyzes GDP/GTP exchange at this GTPase. Finally, it is shown that the cyclic AMP- and Epac-activated R-Ras plays a major role in the M3 mAChR-mediated stimulation of phospholipase D but not phospholipase C. Collectively, our data indicate that GPCRs rapidly activate R-Ras, that R-Ras activation by the GPCRs is apparently directly induced by cyclic AMP-regulated Epac proteins, and that activated R-Ras specifically controls GPCR-mediated phospholipase D stimulation.

Catalysis↗
PubMed2006

Effects of gender, age and hypertension on beta-adrenergic receptor function in rat urinary bladder.

beta-Adrenoceptors mediate urinary bladder relaxation, and gender, age and hypertension have been linked to bladder dysfunction. Therefore, we have studied whether any of these factors affects the ability of beta-adrenoceptor agonists to relax rat bladder detrusor muscle in vitro. For this purpose we have compared male and female Wistar rats, young and old male Wistar rats, and male normotensive and spontaneously hypertensive rats (SHR). Comparisons were done using KCl-precontracted bladder strips (length about 15-20 mm) and the endogenous agonist noradrenaline, the synthetic non-subtype-selective agonist isoprenaline, and the prototypical beta(3)-adrenoceptor agonists BRL 37,344 and CGP 12,177. While all agonists yielded numerically weaker relaxation in female as compared to male rats (for example for noradrenaline E(max) 40+/-4% vs 53+/-6% relaxation, pEC(50) 5.41+/-0.13 vs 5.60+/-0.14), this difference reached statistical significance only for the weak partial agonist CGP 12,177. Responses to all agonists were attenuated in old as compared to young rats, largely due to a reduced maximum effect, although the difference did not reach statistical significance for isoprenaline. The maximum relaxation responses to noradrenaline and isoprenaline were significantly lower in SHR than in normotensive rats, but both strains exhibited similar responses to the partial agonist BRL 37,344. We conclude that factors associated with bladder dysfunction, such as gender, age and hypertension, can be associated with impaired beta-adrenoceptor-mediated bladder relaxation. However, these alterations are not always consistent across various agonists, and the extent of the differences can be small. Therefore, we propose that beta-adrenoceptor dysfunction may contribute to the pathophysiology of such conditions, but is unlikely to be the only or even the major factor in this regard. We speculate that beta-adrenoceptor agonists may be effective in the treatment of bladder dysfunction under all of these conditions.

Adrenergic beta-3 Receptor Agonists↗
PubMed2006

Indomethacin differentiates the renal effects of sphingosine-1-phosphate and sphingosylphosphorylcholine.

The sphingomyelin breakdown products sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) constrict intrarenal microvessels in vitro in a pertussis toxin (PTX) sensitive manner, and S1P also reduces renal blood flow in vivo. Nevertheless, both S1P and SPC have been reported to enhance diuresis and natriuresis. This pattern is similar to that of neuropeptide Y, which also reduces renal blood flow and enhances diuresis and natriuresis. The latter effects are inhibited by the cyclooxygenase inhibitor indomethacin, and various S1P and SPC responses have also been linked to the cyclooxygenase pathway. Therefore, we have investigated whether indomethacin can alter the renal effects of S1P and SPC in anaesthetised rats in vivo. In line with earlier experiments S1P bolus injections dose-dependently reduced renal blood flow (by up to 4.8 +/- 0.5 ml min(-1)), and this was not significantly affected by indomethacin treatment (5 mg kg(-1) i.p.). Infusion of S1P but not of SPC (30 microg kg(-1) min(-1) each) for 60 min reduced renal blood flow by up to 0.8 +/- 0.2 ml min(-1), and this was not markedly altered by indomethacin. Despite the differential renovascular effect, both S1P and SPC enhanced diuresis by up to 215 +/- 65 and 201 +/- 58 microl 15 min(-1) respectively, and natriuresis by up to 25 +/- 9 and 29 +/- 11 micromol 15 min(-1) respectively. While indomethacin abolished the SPC-induced diuresis and natriuresis, it, if anything, slightly enhanced the diuretic and natriuretic effect of S1P. To determine whether tubular SPC effects are receptor-mediated, PTX experiments were performed. SPC-induced enhancements of diuresis and natriuresis were abolished by PTX. We conclude that S1P, SPC and neuropeptide Y exhibit distinct patterns of modulation of renal function and that indomethacin allows such effects to be differentiated.

Animals↗
PubMed2006

In vivo studies on the effects of alpha1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits.

Alpha1-adrenoceptors mediate contraction of iris dilator smooth muscle and hence pupil dilatation. We compared the ability of i.v. bolus injections of alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin to antagonise phenylephrine-induced mydriasis relative to their potency for inhibiting phenylephrine-induced elevations of intraurethral pressure (IUP) in rabbits. Moreover, we compared the ability of these drugs to induce miosis in conscious rabbits in the absence of phenylephrine. All antagonists inhibited the effects of phenylephrine on pupil size and IUP, and the ratio of the respective ED50 values was close to unity in all cases. The doses required to induce statistically significant miosis in the absence of phenylephrine were 30- to 100-fold higher than those inhibiting phenylephrine-induced mydriasis for all antagonists, except for naftopidil. Moreover, the miotic effects of all alpha1-adrenoceptor antagonists were fully reversible within 8 h. We conclude that alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin inhibit phenylephrine-induced mydriasis in the same dose range as they inhibit elevations in IUP. Higher doses of all antagonists are required to induce miosis in the absence of an exogenous agonist, and such miosis is always reversible within hours.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2006

Comparison of the cardiovascular effects of tamsulosin oral controlled absorption system (OCAS) and alfuzosin prolonged release (XL).

OBJECTIVE: The cardiovascular (CV) effects of tamsulosin oral controlled absorption system (OCAS) 0.4 mg were compared with those of alfuzosin prolonged release (XL) 10 mg. METHODS: Two single-dose, crossover studies were performed. In study 1, CV alpha1-adrenoceptor antagonism was assessed by measuring the inhibition of phenylephrine (PE)-induced increases in diastolic blood pressure (DBP) and total peripheral resistance (TPR) before and after dosing with placebo, tamsulosin OCAS, and alfuzosin XL in 18 young subjects. In study 2, orthostatic stress tests (OTs) were performed before and after dosing with tamsulosin OCAS and alfuzosin XL in 40 elderly subjects. Pharmacokinetics were assessed in both studies. RESULTS: In study 1, tamsulosin OCAS induced statistically significantly less inhibition of PE-induced increases in DBP at 2 h after dosing and in TPR at 2 and 4 h after dosing than alfuzosin XL. In study 2, tamsulosin OCAS had a lower incidence of positive OTs than did alfuzosin XL, with the difference between both treatments being statistically significant at 6h after dosing and for all time points after dosing combined. This was in line with smaller changes in vital signs observed for tamsulosin OCAS. The t(max) values for both treatments were comparable. CONCLUSIONS: Tamsulosin OCAS 0.4 mg produces smaller vascular effects than does alfuzosin XL 10 mg.

Administration, Oral↗
PubMed2006

How valid are animal models to evaluate treatments for pulmonary hypertension?

Various animal models of pulmonary hypertension (PH) exist, among which injection of monocrotaline (MCT) and exposure to hypoxia are used most frequently. These animal models have not only been used to characterize the pathophysiology of PH and its sequelae such as right ventricular hypertrophy and failure, but also to test novel therapeutic strategies. This manuscript summarizes the available treatment studies in animal models of PH, and compares the findings to those obtained in patients with PH. The analysis shows that all approaches which have proven successful in patients, most notably prostacyclin and its analogs and endothelin receptor antagonists, are also effective in various animal models. However, the opposite it not always true. Therefore, promising results in animals have to be interpreted carefully until confirmed in clinical studies.

Animals↗
PubMed2006

Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites?

Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the pharmacological activity of their metabolites and discuss how active metabolites may contribute to their efficacy and tolerability in vivo. Except for trospium, and perhaps solifenacin, all of the above drugs form active metabolites, and their presence and activity need to be taken into consideration when elucidating relationships between pharmacokinetics and pharmacodynamics of these drugs. Moreover, the ratios between parent compounds and metabolites may differ depending on genotype of the metabolizing enzymes, concomitant medication, and/or drug formulation. Differential generation of active metabolites of darifenacin or tolterodine are unlikely to influence the overall clinical profile of these drugs in a major way because the active metabolites exhibit a similar pharmacological profile as the parent compound. In contrast, metabolites of oxybutynin and propiverine may behave quantitatively or even qualitatively differently from their parent compounds and this may have an impact on the overall clinical profile of these drugs. We conclude that more comprehensive studies of drug metabolites are required for an improved understanding of their clinical effects.

Benzhydryl Compounds↗
PubMed2006

Sequence of echocardiographic changes during development of right ventricular failure in rat.

BACKGROUND: The temporal relations between the onset of echocardiographic changes and clinical diagnosis of right ventricular (RV) failure are unresolved. We have characterized such relations in a rat monocrotaline (MCT) model of RV failure. METHODS: Eight-week-old male Wistar rats were injected with MCT (60 mg/kg) or vehicle and underwent serial echocardiography. RV free-wall thickness (RVWT), pulmonary artery acceleration time normalized to cycle length (PAAT/CL), RV end-diastolic diameter (RVEDD), and tricuspid annular plane systolic excursion (TAPSE) were measured. RESULTS: Significant differences in echocardiographic parameters between MCT-treated and control rats were found as early as 14 days before RV failure for RVWT, 10 days for PAAT/CL, and 7 days for RVEDD and TAPSE. The time intervals between the onset of changes in RVWT, PAAT/CL, RVEDD, and TAPSE and diagnosis of RV failure were 11.3 +/- 0.8, 10.9 +/- 0.7, 6.5 +/- 0.5, and 5.4 +/- 0.7 days, respectively. The sequence of echocardiographic changes was consistent in all animals during development of RV failure. CONCLUSIONS: Pulmonary hypertension (assessed by PAAT/CL) and RV free-wall thickening (characterized by RVWT) precede RV dilation and RV systolic dysfunction (measured by RVEDD and TAPSE, respectively). Echocardiographic analysis permits accurate determination of the stage of disease development in MCT-induced RV failure.

Animals↗