Klaus Dembowsky - Academia.edu (original) (raw)
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Papers by Klaus Dembowsky
Novel Therapeutic Proteins, 2000
Aprotinin (Trasylol@), also known as bovine pancreatic trypsin inhibitor (BPTI), is a small prote... more Aprotinin (Trasylol@), also known as bovine pancreatic trypsin inhibitor (BPTI), is a small protein belonging to the Kunitz-type family of proteins. It is a potent inhibitor of some serine proteases such as trypsin, plasmin, and tissue and plasma kallikrein [ 11. Although being of bovine ...
Journal of the autonomic nervous system, 1981
In chloralose-anesthetized cats activity of the spinal and supraspinal components of the somato-s... more In chloralose-anesthetized cats activity of the spinal and supraspinal components of the somato-sympathetic reflex were evoked in the white ramus at T3 by stimulation of the corresponding intercostal nerve. A blockade of all spinal pathways by means of a reversible cold blockade of the spinal cord at C2-C3 produced the following effects: (1) mean arterial blood pressure fell to 30-50 mm Hg and the tonic background activity in the white ramus was markedly reduced; (2) the amplitude of the spinal reflex was significantly increased and the supraspinal reflex was completely abolished; (3) localized cold block of the dorsolateral funiculus produced the same effect as cold block of the whole spinal cord; (4) neither baroreceptor denervation nor midcollicular decerebration altered these effects; and (5) the alpha-adrenoceptor agonist clonidine reduced the increased amplitude of the spinal reflex during cold blockade; this effect was reversed by the alpha-adrenoceptor antagonist yohimbine. ...
Thrombosis and Haemostasis, 2012
Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern be... more Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.
Neuroscience Letters, 1990
Neurons of the subretrofacial nucleus in the rostral ventrolateral medulla have been studied by i... more Neurons of the subretrofacial nucleus in the rostral ventrolateral medulla have been studied by in vivo intracellular recording in the chloralose-anaesthetized cat. Impalements of sufficient quality to demonstrate inhibition by carotid baroreceptor stimulation (blind sac inflation) were obtained for 9 cells. In 8 of these, a clear hyperpolarization followed approximately 100-200 ms after the baroreceptor stimulus, reaching a maximum of 2-9 mV, 200-500 ms later. These findings confirm by more direct methods the inhibition of subretrofacial neurons by arterial baroreceptors.
Cardiology, 1989
The effects of the two calcium antagonists bepridil and nifedipine on induced ventricular tachyar... more The effects of the two calcium antagonists bepridil and nifedipine on induced ventricular tachyarrhythmias were studied by programmed electrical stimulation in 15 dogs, 4-8 days after myocardial infarction. Recordings from the infarcted and normal anterior wall of the left ventricle were obtained with an epicardial implanted 'composite' electrode. Bepridil (5 mg/kg) or nifedipine (0.025 mg/kg) were administered i.v. on different days and testing was repeated. Sustained ventricular tachycardia was prevented or significantly slowed by bepridil in 11/12 experiments compared with none of 9 experiments with nifedipine. Paradoxically, in 10/15 dogs nifedipine accelerated arrhythmias or even provoked ventricular fibrillation. Bepridil prolonged refractoriness of infarcted myocardium by 15 +/- 4% (mean +/- SD, p less than 0.01), which was greater than the increase it produced in the effective refractory period of normal tissue (9.0 +/- 3.8%) or QTc interval (11 +/- 5.5%). In contrast, nifedipine significantly shortened these parameters. Both drugs did not influence conduction in infarcted and normal zones as indicated by unchanged late potentials, QRS duration and normal-zone electrograms, respectively. The data indicate that the antiarrhythmic action of bepridil was predominantly related to the prolongation of ventricular refractoriness and repolarization (class III effects).
Journal of …, 1992
SUMMARY AND CONCLUSIONS I. The occurrence of potassium-dependent inhibitory postsyn-aptic potenti... more SUMMARY AND CONCLUSIONS I. The occurrence of potassium-dependent inhibitory postsyn-aptic potentials ( K-IPSPs) in relation to burst discharges induced by 4-aminopyridine (4-AP; 30 PM) was studied in CA3, granule and hilar neurons in guinea pig hippocampal ...
MHC-TGFcys 33 ser transgenic mice have elevated levels of active transforming growth factor (TGF)... more MHC-TGFcys 33 ser transgenic mice have elevated levels of active transforming growth factor (TGF)- 1 in the myocardium. Previous studies have shown that these animals develop atrial, but not ventricular, fibrosis. Here we show that atrial fibrosis was accompanied with cardiomyocyte apoptosis. Although similar levels of cardiomyocyte apoptosis were present in the right and left atria of MHC-TGFcys 33 ser hearts, the extent of fibrosis was more pronounced in the right atrium. Thus, additional factors influence the degree of atrial fibrosis in this model. Tritiated thymidine incorporation studies revealed cardiomyocyte cell cycle activity in left atrial cardiomyocytes, but not in right atrial cardiomyocytes. These observations suggested that cardiomyocyte cell cycle activation ameliorated the severity of atrial fibrosis. To directly test this hypothesis, MHC-TGFcys 33 ser mice were crossed with MHC-cycD2 mice (which have constitutive cardiomyocyte cell cycle activity in the right atrium). Mice inheriting both transgenes exhibited right atrial cardiomyocyte cell cycle activity and a concomitant reduction in the severity of right atrial fibrosis, despite the presence of a similar level of cardiomyocyte apoptosis as was observed in mice inheriting the MHC-TGFcys 33 ser transgene alone. These data support the notion that cardiomyocyte cell cycle induction can antagonize fibrosis in the myocardium. (Circ Res. 2006;98:141-148.)
Nature, 2001
Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pa... more Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.
Novel Therapeutic Proteins, 2000
Aprotinin (Trasylol@), also known as bovine pancreatic trypsin inhibitor (BPTI), is a small prote... more Aprotinin (Trasylol@), also known as bovine pancreatic trypsin inhibitor (BPTI), is a small protein belonging to the Kunitz-type family of proteins. It is a potent inhibitor of some serine proteases such as trypsin, plasmin, and tissue and plasma kallikrein [ 11. Although being of bovine ...
Journal of the autonomic nervous system, 1981
In chloralose-anesthetized cats activity of the spinal and supraspinal components of the somato-s... more In chloralose-anesthetized cats activity of the spinal and supraspinal components of the somato-sympathetic reflex were evoked in the white ramus at T3 by stimulation of the corresponding intercostal nerve. A blockade of all spinal pathways by means of a reversible cold blockade of the spinal cord at C2-C3 produced the following effects: (1) mean arterial blood pressure fell to 30-50 mm Hg and the tonic background activity in the white ramus was markedly reduced; (2) the amplitude of the spinal reflex was significantly increased and the supraspinal reflex was completely abolished; (3) localized cold block of the dorsolateral funiculus produced the same effect as cold block of the whole spinal cord; (4) neither baroreceptor denervation nor midcollicular decerebration altered these effects; and (5) the alpha-adrenoceptor agonist clonidine reduced the increased amplitude of the spinal reflex during cold blockade; this effect was reversed by the alpha-adrenoceptor antagonist yohimbine. ...
Thrombosis and Haemostasis, 2012
Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern be... more Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.
Neuroscience Letters, 1990
Neurons of the subretrofacial nucleus in the rostral ventrolateral medulla have been studied by i... more Neurons of the subretrofacial nucleus in the rostral ventrolateral medulla have been studied by in vivo intracellular recording in the chloralose-anaesthetized cat. Impalements of sufficient quality to demonstrate inhibition by carotid baroreceptor stimulation (blind sac inflation) were obtained for 9 cells. In 8 of these, a clear hyperpolarization followed approximately 100-200 ms after the baroreceptor stimulus, reaching a maximum of 2-9 mV, 200-500 ms later. These findings confirm by more direct methods the inhibition of subretrofacial neurons by arterial baroreceptors.
Cardiology, 1989
The effects of the two calcium antagonists bepridil and nifedipine on induced ventricular tachyar... more The effects of the two calcium antagonists bepridil and nifedipine on induced ventricular tachyarrhythmias were studied by programmed electrical stimulation in 15 dogs, 4-8 days after myocardial infarction. Recordings from the infarcted and normal anterior wall of the left ventricle were obtained with an epicardial implanted 'composite' electrode. Bepridil (5 mg/kg) or nifedipine (0.025 mg/kg) were administered i.v. on different days and testing was repeated. Sustained ventricular tachycardia was prevented or significantly slowed by bepridil in 11/12 experiments compared with none of 9 experiments with nifedipine. Paradoxically, in 10/15 dogs nifedipine accelerated arrhythmias or even provoked ventricular fibrillation. Bepridil prolonged refractoriness of infarcted myocardium by 15 +/- 4% (mean +/- SD, p less than 0.01), which was greater than the increase it produced in the effective refractory period of normal tissue (9.0 +/- 3.8%) or QTc interval (11 +/- 5.5%). In contrast, nifedipine significantly shortened these parameters. Both drugs did not influence conduction in infarcted and normal zones as indicated by unchanged late potentials, QRS duration and normal-zone electrograms, respectively. The data indicate that the antiarrhythmic action of bepridil was predominantly related to the prolongation of ventricular refractoriness and repolarization (class III effects).
Journal of …, 1992
SUMMARY AND CONCLUSIONS I. The occurrence of potassium-dependent inhibitory postsyn-aptic potenti... more SUMMARY AND CONCLUSIONS I. The occurrence of potassium-dependent inhibitory postsyn-aptic potentials ( K-IPSPs) in relation to burst discharges induced by 4-aminopyridine (4-AP; 30 PM) was studied in CA3, granule and hilar neurons in guinea pig hippocampal ...
MHC-TGFcys 33 ser transgenic mice have elevated levels of active transforming growth factor (TGF)... more MHC-TGFcys 33 ser transgenic mice have elevated levels of active transforming growth factor (TGF)- 1 in the myocardium. Previous studies have shown that these animals develop atrial, but not ventricular, fibrosis. Here we show that atrial fibrosis was accompanied with cardiomyocyte apoptosis. Although similar levels of cardiomyocyte apoptosis were present in the right and left atria of MHC-TGFcys 33 ser hearts, the extent of fibrosis was more pronounced in the right atrium. Thus, additional factors influence the degree of atrial fibrosis in this model. Tritiated thymidine incorporation studies revealed cardiomyocyte cell cycle activity in left atrial cardiomyocytes, but not in right atrial cardiomyocytes. These observations suggested that cardiomyocyte cell cycle activation ameliorated the severity of atrial fibrosis. To directly test this hypothesis, MHC-TGFcys 33 ser mice were crossed with MHC-cycD2 mice (which have constitutive cardiomyocyte cell cycle activity in the right atrium). Mice inheriting both transgenes exhibited right atrial cardiomyocyte cell cycle activity and a concomitant reduction in the severity of right atrial fibrosis, despite the presence of a similar level of cardiomyocyte apoptosis as was observed in mice inheriting the MHC-TGFcys 33 ser transgene alone. These data support the notion that cardiomyocyte cell cycle induction can antagonize fibrosis in the myocardium. (Circ Res. 2006;98:141-148.)
Nature, 2001
Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pa... more Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.