Biomedical subjects

Jörg W Wegener

Publications and source records attributed to Jörg W Wegener.

8 recordsLinked to original sources

PubMed2006

cGMP signals mainly through cAMP kinase in permeabilized murine aorta.

GMP affects vascular tone by multiple mechanisms, including inhibition of the Rho/Rho kinase-mediated Ca(2+) sensitization, a process identified as Ca(2+) desensitization. Ca(2+) desensitization is mediated probably by both cGMP- and cAMP-dependent protein kinases (cGKI and PKA). We investigate to which extent Ca(2+) desensitization is initiated by cGKI and PKA. cGMP/cAMP-induced relaxation was studied at constant [Ca(2+)] in permeabilized aortas from wild-type and cGKI-deficient mice. [Ca(2+)] increased aortic tone in the absence and presence of 50 microM GTPgammaS with EC(50) values of 160 and 30 nM, respectively. In the absence of GTPgammaS, the EC(50) for [Ca(2+)] was shifted rightward from 0.16 microM to 0.43 and 0.82 microM by 1 and 300 microM 8-bromo-cGMP (8-Br-cGMP), and to 8 microM by 10 microM Y-27632. Contractions induced by 300 nM [Ca(2+)] were relaxed by 8-Br-cGMP with an EC(50) of 2.6 microM. Surprisingly, [Ca(2+)]-induced contractions were also relaxed by 8-Br-cGMP in aortas from cGKI(-/-) mice (EC(50) of 19 microM). Western blot analysis of the vasodilator-stimulated phosphoprotein indicated "cross"-activation of PKA by 1 mM 8-Br-cGMP in aortic smooth muscle cells from cGKI(-/-) mice. Indeed, the PKA inhibitor peptide (PKI 5-24) completely abolished the relaxant effect of 8-Br-cGMP in muscles from cGKI(-/-) mice and to 65% in wild-type aortas. The thromboxane analogue U-46619 induced contraction at constant [Ca(2+)], which was only partially relaxed by 8-Br-cGMP but completely relaxed by Y-27632. The effect of 8-Br-cGMP on U-46619-induced contraction was attenuated by PKI 5-24. These results show that cGKI has only a small inhibitory effect on Ca(2+) sensitization in murine aortas.

Animals↗

PubMed2006

Control of intestinal motility by the Ca(v)1.2 L-type calcium channel in mice.

The Ca(v)1.2 L-type Ca2+ channel is the dominant voltage-activated Ca2+ channel in heart and smooth muscle. The functional significance of this channel was studied in intestinal smooth muscle from mice carrying a smooth muscle-specific, conditional inactivation of the Ca(v)1.2 gene (Ca(v)1.2SMACKO mice). Inactivation was complete within 4 wk after tamoxifen treatment and confirmed by RT-PCR, Western blot and functional analysis. Ca(v)1.2SMACKO mice show reduced feces excretion, absence of rhythmic contractions in small and large intestinal muscle and signs of paralytic ileus. Extracellular field stimulation evoked smaller contractions in jejunum muscles from Ca(v)1.2SMACKO than from CTR mice, whereas carbachol-induced contractions of similar magnitude in both muscles. The Ca2+ needed for contraction in jejunum was provided mainly by Ca(v)1.2 channels and by store-operated channels in muscles from CTR and Ca(v)1.2SMACKO mice, respectively. In conclusion, the Ca(v)1.2 channel is essential for electromechanical coupling and important for pharmaco-mechanical coupling in intestinal smooth muscle and cannot be substituted functionally by other Ca2+ entry pathways.

Animals↗

PubMed2005

Mouse models to study L-type calcium channel function.

Calcium influx through voltage gated L-type Ca2+ channels has evolved as one of the most widely used transmembrane signalling mechanisms in eukaryotic organisms. Although pharmacological inhibitors of L-type Ca2+ channels have an important place in medical therapy, the full therapeutic potential of the 4 L-type Ca2+ channel subtypes has not been explored yet. To dissect the physiological relevance of the L-type Ca2+ channel subtype diversity, gene-targeted mouse models carrying deletions of these channels ("knockout mice") have been generated. This review focuses on recent data from studies in mice lacking the Ca(v)1.2 and Ca(v)1.3 pore subunits, which have elucidated some of the roles of L-type Ca2+ channels as mediators of signalling between cell membrane and intracellular processes like blood pressure regulation, smooth muscle contractility, insulin secretion, cardiac development, and learning and memory.

Animals↗

PubMed2004

An essential role of Cav1.2 L-type calcium channel for urinary bladder function.

Mice deficient in the smooth muscle Cav1.2 calcium channel (SMACKO, smooth muscle alpha1c-subunit calcium channel knockout) have a severely reduced micturition and an increased bladder mass. L-type calcium current, protein, and spontaneous contractile activity were absent in the bladder of SMACKO mice. K+ and carbachol (CCh)-induced contractions were reduced to 10-fold in detrusor muscles from SMACKO mice. The dihydropyridine isradipine inhibited K+- and CCh-induced contractions of muscles from CTR but had no effect in muscles from SMACKO mice. CCh-induced contraction was blocked by removing extracellular Ca2+ but was unaffected by the PLC inhibitor U73122 or depletion of intracellular Ca2+ stores by thapsigargin. In muscles from CTR and SMACKO mice, CCh-induced contraction was partially inhibited by the Rho-kinase inhibitor Y27632. These results show that the Cav1.2 Ca2+ channel is essential for normal bladder function. The Rho-kinase and Ca2+-release pathways cannot compensate the lack of the L-type Ca2+ channel.

Amides↗

PubMed2003

Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation.

Blood pressure is regulated by a number of key molecules involving G-protein-coupled receptors, ion channels and monomeric small G-proteins. The relative contribution of these different signaling pathways to blood pressure regulation remains to be determined. Tamoxifen-induced, smooth muscle-specific inactivation of the L-type Cav1.2 Ca2+ channel gene in mice (SMAKO) reduced mean arterial blood pressure (MAP) in awake, freely moving animals from 120 +/- 4.5 to 87 +/- 8 mmHg. Phenylephrine (PE)- and angiotensin 2 (AT2)-induced MAP increases were blunted in SMAKO mice, whereas the Rho-kinase inhibitor Y-27632 reduced MAP to the same extent in control and SMAKO mice. Depolarization-induced contraction was abolished in tibialis arteries of SMAKO mice, and development of myogenic tone in response to intravascular pressure (Bayliss effect) was absent. Hind limb perfusion experiments suggested that 50% of the PE-induced resistance is due to calcium influx through the Cav1.2 channel. These results show that Cav1.2 calcium channels are key players in the hormonal regulation of blood pressure and development of myogenic tone.

Animals↗

PubMed2003

Hypothyroidism does not affect the dihydropyridine sensitivity of precontracted murine uterus.

Thyroid hormones are known to influence various processes of cell differentiation. Recently, it was reported that hypothyroidism reduces the sensitivity to Ca2+-channel antagonists in the rat uterus. We examined the sensitivity to dihydropyridines of the uterus from mice that had reduced thyroid hormone levels. Isradipine relaxed with the same potency precontracted uterine muscle strips from control and hypothyroid mice, independently from a pseudo-pregnant state. These results demonstrate that hypothyroidism does not change dihydropyridine sensitivity (i.e., the pattern of Ca2+-channel expression) in the murine uterus.

Animals↗

PubMed2002

cGMP-dependent protein kinase I mediates the negative inotropic effect of cGMP in the murine myocardium.

To study the role of cGMP-dependent protein kinase I (cGKI) for cardiac contractility, force of contraction (F(c)) was studied in electrically driven heart muscle from wild-type (WT) mice and from conventional and conditional cGKI knockout mice. Both 8-Br-cGMP and 8-pCPT-cGMP reduced Fc in cardiac muscle from juvenile WT but not from juvenile cGKI-null mutants. Similarly, the cGMP analogues reduced F(c) in forskolin-stimulated ventricular muscle from WT mice but not from cGKI-null mutants. In contrast, carbachol reduced F(c) in both groups of animals. 8-Br-cGMP reduced F(c) also in heart muscle from adult WT mice but not from adult cardiomyocyte-specific cGKI-knockout mice. These results demonstrate that cGKI mediates the negative inotropic effect of cGMP in the myocardium of juvenile and adult mice.

Animals↗

PubMed2002

Effects of quinine and quinidine on the transient outward and on the L-type Ca(2+) current in rat ventricular cardiomyocytes.

The effects of the enantiomers quinine and quinidine on the transient outward current (I(to)) and on the L-type Ca(2+) current (I(ca)) were investigated in rat ventricular cardiomyocytes using the patch-clamp technique. At a stimulation frequency of 2 Hz, both quinine and quinidine depressed the magnitude of I(to) and I(Ca); the half-maximal effects on I(to) were achieved at 11 and 15 micromol/l, respectively, and those on I(Ca) at 14 and 10 micromol/l, respectively. At 0.2 Hz, both drugs depressed the magnitude of I(to), but not that of I(Ca). A change in extracellular pH from 7.3 to 8.3 did not significantly influence the effects of the drugs(which are protonated to 98% at pH 7.3) on I(to) or I(Ca). It is concluded that neither the different chemical structure nor the amount of protonation of quinine and quinidine controls their effects on I(to) or I(Ca).

Animals↗