Biomedical subjects

Stephan L M Peters

Publications and source records attributed to Stephan L M Peters.

12 recordsLinked to original sources

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↗

PubMed2005

Impaired flow-induced dilation in mesenteric resistance arteries from receptor protein tyrosine phosphatase-mu-deficient mice.

The transmembrane receptor-like protein tyrosine phosphatase-mu (RPTPmu) is thought to play an important role in cell-cell adhesion-mediated processes. We recently showed that RPTPmu is predominantly expressed in the endothelium of arteries and not in veins. Its involvement in the regulation of endothelial adherens junctions and its specific arterial expression suggest that RPTPmu plays a role in controlling arterial endothelial cell function and vascular tone. To test this hypothesis, we analyzed myogenic responsiveness, flow-induced dilation, and functional integrity of mesenteric resistance arteries from RPTPmu-deficient (RPTPmu(-/-)) mice and from wild-type littermates. Here, we show that cannulated mesenteric arteries from RPTPmu(-/-) mice display significantly decreased flow-induced dilation. In contrast, mechanical properties, myogenic responsiveness, responsiveness to the vasoconstrictors phenylephrine or U-46619, and responsiveness to the endothelium-dependent vasodilators methacholine or bradykinin were similar in both groups. Our results imply that RPTPmu is involved in the mechanotransduction or accessory signaling pathways that control shear stress responses in mesenteric resistance arteries.

Animals↗

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

Vasopressin-induced vasoconstriction is dependent on MAPKerk1/2 phosphorylation.

To investigate the involvement of the mitogen-activated protein kinase (MAPK) family of extracellular signal-regulated kinase (ERK) 1 and 2 (MAPKerk1/2) in the vasopressin-mediated vasoconstriction in the rat aorta. Vasopressin-induced vasoconstriction was measured in isolated rat thoracic aortae in the presence or absence of MAPKerk1/2 kinase (MKKmek1/2) inhibitors. Thereafter the MAPKerk1/2 phosphorylation in the rat aorta was quantified using Western blot analysis. Vasopressin (1-300 nm) induced a concentration-dependent vasoconstriction, which could be inhibited concentration dependently by the selective MKKmek1/2 inhibitors, PD 98059 (10 and 100 microm) and U 0126 (10 and 100 microm). Western blot analysis revealed a 2.7 +/- 0.6-fold increase in the MAPKerk1/2 phosphorylation induced by vasopressin (300 nm). This phosphorylation could be dose dependently prevented by both PD 98059 (100 microm) and U 0126 (10 and 100 microm). These results indicate that vasoconstriction induced by vasopressin is partly regulated by the MAPKerk1/2 pathway.

Animals↗

PubMed2004

Antioxidant activity of nebivolol in the rat aorta.

The beta-blocker nebivolol is a racemic mixture of D- and L- enantiomers that displays negative inotropic as well as direct vasorelaxant activity. In addition, it has been proposed that nebivolol exerts endothelium-protective effects caused by its antioxidant properties. In the present study we investigated the effect of D-, L-, and d/l-nebivolol on reactive oxygen species (ROS)-induced endothelial damage and compared it with carvedilol and metoprolol. Isolated rat aortic rings were exposed to ROS by electrolysis of the organ bath medium. Before and after electrolysis, endothelial function was measured by preconstricting the vessels with phenylephrine followed by the addition of methacholine. Carvedilol and nebivolol protected against ROS-induced endothelial damage, whereas metoprolol did not. The protective effect of nebivolol proved not to be stereoselective. Furthermore, we attempted to determine whether nebivolol acts a scavenger itself or whether another mechanism is involved. By means of HPLC measurements it was shown that nebivolol concentrations were decreased after exposure to electrolysis-induced ROS, thus indicating that nebivolol is degraded by its reaction with ROS. Functional experiments, in the rat aorta, demonstrated that exposure of nebivolol to ROS also affects its vasodilator activity. In conclusion, the present study demonstrates that nebivolol alleviates ROS-induced impairment of endothelium-dependent vasorelaxation. This protective effect is very likely the result of a direct ROS-scavenging action by the nebivolol molecule itself.

Adrenergic beta-Antagonists↗

PubMed2004

Involvement of reactive oxygen species in angiotensin II-induced vasoconstriction.

In recent years it has been shown that angiotensin II (Ang II) stimulates formation of reactive oxygen species (ROS), presumably by activation of NAD(P)H oxidase. This ROS formation has been primarily associated with cellular growth regulation by Ang II. The objective of the present study was to investigate whether these ROS contribute to Ang II-induced vasoconstriction. Experiments were performed in isolated rat thoracic aorta. Concentration response curves were constructed for Ang II in the absence and presence of the NAD(P)H oxidase inhibitor DPI, and ROS scavengers catalase and EUK-8. Inhibition of NAD(P)H oxidase as well as scavenging of ROS, decreased the contractile response to Ang II. Administration of NADPH, a substrate for NAD(P)H oxidase, produced vasoconstriction that proved to be sensitive for DPI, catalase, and EUK-8. Exposure of the vessels to exogenous ROS, induced by electrolysis of the organ bath medium, also resulted in a contractile response that was decreased by ROS scavenging. The results suggest that ROS play a role in Ang II-induced vasoconstriction via the activation of NAD(P)H oxidase.

Angiotensin II↗

PubMed2003

The influence of endogenously generated reactive oxygen species on the inotropic and chronotropic effects of adrenoceptor and ET-receptor stimulation.

Reactive oxygen species (ROS) play a role in cardiovascular diseases such as heart failure and hypertension. Furthermore, increasing evidence has accumulated suggesting that ROS can also be formed subsequent to the stimulation of various receptors, thus functioning as second messengers. The objective of the present study was to elucidate the role of intracellular-generated ROS in the inotropic and chronotropic effects of the alpha1- and beta-adrenoceptor and the ET-receptor stimulation in isolated rat atria. In addition, we investigated whether the MAPKerk pathway is involved in the ROS-provoked rise of contractile force. For this purpose hydrogen peroxide was applied, which is known to serve several endogenous functions as a second messenger. Moreover, hydrogen peroxide readily crosses cell membranes, which thus allows to mimic the intracellular formation. Preincubation of atria with EUK 8 (400 microM), a cell permeable superoxide dismutase- and catalase-mimetic, reduced the positive inotropic effect upon alpha1-adrenoceptor and ET-receptor stimulation. The responsiveness to beta-adrenoceptor stimulation remained unaffected by this pretreatment. The chronotropic effects were not altered by preincubation with EUK 8. In contrast to the MAPK(p38) inhibitor SB203580 (2 and 10 microM), the two MKKmek inhibitors PD98059 (30 and 100 microM) and U0126 (10 microM) significantly attenuated the positive inotropic response to hydrogen peroxide in isolated rat left atria. In addition, inhibition of the Na+/H+ exchange (NHE) by cariporide (1 microM) counteracted ROS-provoked increase of contractile force. From the present study we conclude that the inotropic responses to alpha1-adrenoceptor and ET-receptor stimulation are, at least partially, caused by intracellular-formed ROS, that subsequently may activate the MAPKerk pathway and the NHE.

Animals↗

PubMed2003

Effects of hypochlorite and hydrogen peroxide on cardiac autonomic receptors and vascular endothelial function.

1. Reactive oxygen species (ROS) are known to be involved in the progression of various cardiovascular diseases. One source of ROS is activated neutrophils, which can release superoxide anion radicals and hydrogen peroxide by membrane-bound NAD(P)H oxidases. These ROS not only destroy bacteria, but may also affect mammalian tissue. In addition, hydrogen peroxide serves as a substrate for myeloperoxidase, an enzyme that is released by activated neutrophils during inflammatory processes, as seen, for instance, in reperfusion injury and atherosclerosis. Myeloperoxidase catalyses the oxidation of chloride by hydrogen peroxide, yielding hypochlorite, an extremely potent oxidant. 2. The purpose of the present study was to evaluate the effects of hypochlorite on a variety of receptor-dependent processes in rat isolated left atria and rat thoracic aorta and to compare these results with the phenomena observed after incubation with hydrogen peroxide. 3. In the presence of hypochlorite (300 micro mol/L), the positive inotropic response of alpha1-adrenoceptor stimulation by methoxamine (300 micro mol/L) was converted into a negative inotropic response. In contrast, the positive inotropic effects of the beta1/beta2-adrenoceptor agonist isoprenaline (3 micro mol/L) and endothelin (ET)-1 (100 nmol/L) remained largely unaffected. 4. The inversion of alpha1-adrenoceptor-mediated inotropy was not obtained in the presence of hydrogen peroxide (500 micro mol/L). Hydrogen peroxide did not affect the positive inotropic response of isoprenaline, but it completely abolished the inotropic effect of ET-1. 5. The effect of cardiac M2-receptor stimulation was studied in the presence of hypochlorite and hydrogen peroxide. The negative inotropic response to acetylcholine (ACh) was significantly enhanced after hypochlorite incubation compared with control. 6. In the rat thoracic aorta, endothelial function, evaluated by means of ACh-induced vasodilation, was completely abolished in the presence of hypochlorite (100 micro mol/L), but remained unaffected by treatment with the same concentration of hydrogen peroxide. 7. From these data, we conclude that hypochlorite exerts more toxic properties than its precursor hydrogen peroxide, leading to substantial physiological alterations in cardiac and vascular tissue.

Acetylcholine↗

PubMed2003

Involvement of the beta3 adrenoceptor in nebivolol-induced vasorelaxation in the rat aorta.

Nebivolol is a highly selective beta(1) adrenoceptor blocker with additional vasodilating properties. Although it has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) and cGMP dependent, the receptor that mediates these actions remains controversial, and serotonergic as well as beta-adrenergic pathways may be involved. Therefore, functional experiments investigating the receptor involved in nebivolol-induced vasorelaxation were performed in the rat aorta. Isolated aortic rings were exposed to cumulative concentrations of nebivolol. Nebivolol concentrations of 3 micromol/L and higher caused vasorelaxation, which was inhibited by the presence of the NO synthase inhibitor l-NNA (100 micromol/L), or by mechanical removal of the endothelium. Exposure of the vessel rings to the selective 5-HT(1A) antagonist NAN-190 (1 micromol/L) or the 5-HT(1/2) antagonist methysergide (1 micromol/L) did not influence nebivolol-induced vasorelaxation. Similarly, the incubation with the beta(2)-adrenoceptor antagonist butoxamine (50 micromol/L) did not prevent vasorelaxation. The selective beta(3)-adrenoceptor antagonist S-(-)-cyanopindolol (1 micromol/L), however, significantly counteracted the nebivolol-induced vasorelaxation. Furthermore, exposure of the aortic rings to cumulative concentrations of the beta(3) selective adrenoceptor agonist BRL37344 caused, like nebivolol, NO-dependent vasorelaxation that was antagonized by S-(-)-cyanopindolol. The results suggest that nebivolol-induced NO-dependent vasorelaxation is, at least in part, caused by a beta(3)-adrenoceptor agonistic effect.

Animals↗

PubMed2002

A mitogen-activated protein kinase is involved in the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1.

The activation of mitogen-activated protein kinase (MAPK) pathways in the heart, for instance by alpha(1)-adrenoceptor agonists and endothelin-1, has primarily been associated with cellular growth regulation. Here we have investigated a possible role of MAPK pathways in the inotropic and chronotropic effects of adrenoceptor agonists and endothelin-1 in isolated rat left and right atria. Inotropic and chronotropic responses of the isolated atria to methoxamine, isoprenaline and endothelin-1 were measured in the absence and presence of inhibitors of MAPK pathways. The MAPK kinase (MKK(mek)) inhibitors PD98059 (100 microM) and U0126 (10 microM) significantly inhibited the inotropic responses to the alpha(1)-adrenoceptor agonist methoxamine (300 microM) and endothelin-1 (50 nM), but not the chronotropic responses to these agonists. U0126 but not PD98059 inhibited the inotropic response to 3 microM isoprenaline. None of the aforementioned inotropic and chronotropic effects were inhibited by the MAPKP(p38) inhibitor SB203580 (2 microM). We conclude that activation of the PD98059/U0126-sensitive MAPK pathway is essential for the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1.

Adrenergic Agonists↗