Michael Kirchengast

Publications of Michael Kirchengast

• Cardioprotective effects of atrasentan, an endothelin-A receptor antagonist, but not of nitric oxide in diabetic mice with myocyte-specific overexpression of endothelial nitric oxide synthase.

  Authors: Gerald Wölkart, Heike Stessel, Zora Saad, Michael Kirchengast, Friedrich Brunner

  British journal of pharmacology. 08/2006; 148(5):671-81.

  1. We investigated the roles of nitric oxide (NO) and endothelin-1 (ET-1) in organ dysfunction in diabetic mice with normal genotype (wild-type, WT) or myocyte-specific overexpression of endothelial1. We investigated the roles of nitric oxide (NO) and endothelin-1 (ET-1) in organ dysfunction in diabetic mice with normal genotype (wild-type, WT) or myocyte-specific overexpression of endothelial NO synthase (eNOS) (transgenic, TG) after chronic oral treatment with the endothelin-A (ETA) receptor antagonist atrasentan. 2. Mice were rendered diabetic by injection of 200 mg kg-1 streptozotocin (STZ). Experimental groups were: untreated WT diabetic (n=9), untreated TG diabetic (n=9), atrasentan-treated WT diabetic (n=9), atrasentan-treated TG diabetic (n=8) and the four corresponding nondiabetic groups (n=5). Atrasentan was administered orally via drinking water at 3 mg kg-1 per day over 28 days. All diabetic mice developed similar hyperglycaemia (27-30 mmol l-1). 3. Atrasentan treatment significantly improved left ventricular systolic and diastolic function in response to exogenous norepinephrine, but there were no differences between genotypes. 4. Atrasentan antagonized the diabetic impairments in endothelium-dependent coronary relaxation and thromboxane-receptor mediated aortic constriction. Further, it improved cardiac and renal oxidant status as evident from reduced tissue malondialdehyde levels. 5. Atrasentan reduced diabetic urine flow, proteinuria and plasma creatinine levels, but creatinine clearance was not significantly altered. 6. These results suggest that in experimental type 1 diabetes, blocking ETA receptors ameliorates myocardial, coronary and renal function and improves tissue oxidant status, whereas raising myocardial NO levels has neither beneficial nor deleterious effects on diabetic cardiomyopathy in this transgenic model.

• Endothelin receptor antagonists: clinical realities and future directions.

  Authors: Michael Kirchengast, Matthias Luz

  Journal of cardiovascular pharmacology. 03/2005; 45(2):182-91.

  Endothelin (ET) is among the strongest endogenous vasoconstrictors known and a potent mitogen. A rich body of experimental evidence suggests that ET contributes to vascular remodeling and end-organEndothelin (ET) is among the strongest endogenous vasoconstrictors known and a potent mitogen. A rich body of experimental evidence suggests that ET contributes to vascular remodeling and end-organ damage in several cardiovascular conditions. Therefore, blockade of ET receptors has been suggested as an attractive target in a number of acute and chronic cardiovascular indications, including pulmonary arterial hypertension (PAH), systemic hypertension, and heart failure. To date, clinical studies have confirmed expectations in PAH and yielded promising initial results in systemic hypertension, which are currently awaiting confirmation in large-scale trials. In contrast, no added benefit could be demonstrated in large clinical trials on top of current standard treatment in both acute and chronic heart failure. Further clinical development in heart failure has therefore been suspended. Other indications that are currently being studied clinically or would possibly merit clinical trials include acute myocardial ischemia and reperfusion, cerebral vasospasm after intracranial bleeding, glaucoma, acute severe pancreatitis, systemic sclerosis, (diabetic) renal failure, restenosis after angioplasty/stent implantation, and late transplant rejection. This article critically reviews the available clinical data on ET receptor antagonism in cardiovascular indications against the background of the underlying preclinical research.

• Effects of chronic endothelin ET(A) receptor blockade on blood pressure and vascular formation of cyclic guanosine-3',5'-monophosphate in spontaneously hypertensive rats.

  Authors: Michael Kirchengast, Klaus Witte, Kerstin Stolpe, Lothar Schilling, Pavel I Nedvetsky, Harald H H W Schmidt, Björn Lemmer

  Arzneimittel-Forschung. 02/2005; 55(9):498-504.

  Endothelin (ET) mediates vasoconstriction in intact arterial blood vessels with functional endothelium via stimulation of ET(A) receptors, while ET(B) receptor stimulation leads to vasodilation viaEndothelin (ET) mediates vasoconstriction in intact arterial blood vessels with functional endothelium via stimulation of ET(A) receptors, while ET(B) receptor stimulation leads to vasodilation via nitric oxide (NO) release and formation of cyclic guanosine-3',5'-monophosphate (cGMP). In spontaneously hypertensive rats (SHR) the cGMP-forming NO-receptor guanylyl cyclase (sGC) is downregulated. It is unclear whether ET contributes to the hypertensive phenotype of SHR, and whether this involves the disturbed cGMP signaling. The selective ETA receptor antagonist darusentan (CAS 171714-84-4), given orally via drinking water (10 mg kg(-1) d(-1)) for 12 weeks, significantly lowered systolic blood pressure of SHR as determined by radiotelemetry. Neither impaired endothelium-dependent relaxation to acetylcholine was restored nor sGC expression and activity affected when compared to control SHR. While these findings show a role for ETA receptors in blood pressure regulation in genetically elevated blood pressure, downregulation of sGC expression and cGMP-mediated vasorelaxant response in SHR were shown to be independent of ETA receptors. The findings suggest distinct mechanisms of gene expression affecting ET and cGMP mediated vasomotor functions.

• Effects of the endothelin a receptor antagonist darusentan on blood pressure and vascular contractility in type 2 diabetic Goto-Kakizaki rats.

  Authors: Klaus Witte, Ina Reitenbach, Kerstin Stolpe, Lothar Schilling, Michael Kirchengast, Björn Lemmer

  Journal of cardiovascular pharmacology. 07/2003; 41(6):890-6.

  The present study evaluated the effects of long-term treatment with the endothelin A (ET(A)) receptor antagonist darusentan (LU135252) on blood pressure (BP) and vascular target-organ damage inThe present study evaluated the effects of long-term treatment with the endothelin A (ET(A)) receptor antagonist darusentan (LU135252) on blood pressure (BP) and vascular target-organ damage in spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. BP was monitored by radiotelemetry in untreated and darusentan-treated GK rats from 10-24 weeks of age. Relaxation of mesenteric artery segments by acetylcholine (ACh) and sodium nitroprusside (SNP) was measured to assess endothelium-dependent and -independent vasorelaxation. Aortic soluble guanylyl cyclase (sGC) activity was studied in vitro after stimulation by the nitric oxide (NO) donor diethylamine-NONOate. Untreated GKs were mildly hypertensive and showed a blunted vascular relaxation by ACh and SNP and a reduction in NO-stimulated sGC activity in comparison with Wistar control rats. Darusentan led to a small but sustained reduction in 24-h BP but did not restore the endothelium-dependent vasorelaxation nor the NO-stimulated cGMP formation in GK rats. The present findings suggest that an activated endothelin pathway may contribute to elevated BP but is not involved in vascular dysfunction in this animal model of type II diabetes.

• Influence of acute selective endothelin-receptor-A blockade on renal hemodynamics in a rat model of chronic allograft rejection.

  Authors: Thomas Knoll, Jens Oltersdorf, Uwe Göttmann, Meike Schaub, Maurice Stephan Michel, Michael Kirchengast, Fokko J van der Woude, Peter Rohmeiss, Claude Braun

  Transplant international : official journal of the European Society for Organ Transplantation. 07/2003; 16(6):425-9.

  We have recently demonstrated up-regulation of renal endothelin (ET) synthesis in a rat model of chronic renal allograft rejection. Treatment with a selective ET-A receptor antagonist improvedWe have recently demonstrated up-regulation of renal endothelin (ET) synthesis in a rat model of chronic renal allograft rejection. Treatment with a selective ET-A receptor antagonist improved survival and reduced functional and morphological kidney damage. However, the underlying mechanisms have not yet been elucidated, as ET exhibits both hemodynamic and inflammatory properties. Therefore, in the present study we investigated acute hemodynamic effects of the selective ET-A receptor antagonist LU 302146 (LU) on chronic renal allograft rejection in rats. Experiments were performed in the Fisher-to-Lewis model of chronic renal allograft rejection. Lewis-to-Lewis isografts served as controls. After 2, 12, and 24 weeks, hemodynamic measurements were performed on anesthetized animals. Measurement of mean arterial pressure (MAP) was performed via a catheter in the femoral artery. Renal blood flow (RBF) was measured by an ultrasonic flow probe placed around the renal transplant artery. Medulla blood flow (MBF) and cortex blood flow (CBF) were determined with laser Doppler probes. Hemodynamic response upon intravenous bolus injection of LU (50 mg/kg) was investigated. The application of LU was followed by a decline in MAP that reached statistical significance only in isografts (ISOs) after 12 weeks and allografts (ALLOs) after 24 weeks. RBF slightly decreased in all groups; however, without reaching statistical significance. MBF showed a small increase in ALLO12 and ALLO24 whereas CBF slightly decreased in all groups. Acute ET-A receptor blockade does not induce important hemodynamic effects in kidneys undergoing chronic rejection. The lack of response to ET-A receptor blockade suggests that the beneficial effect of ET receptor antagonists in this model is likely to be due to improvement of renal morphology.

• Trauma induced by nontraumatic coronary devices and its impact on vascular reactivity and morphology.

  Authors: Jörg M Strotmann, Johann Bauersachs, Daniela Fraccarollo, Michael Kirchengast, Philipp A Schnabel, Jaromir Sykora, Georg Ertl, Wolfram Voelker

  American journal of physiology. Heart and circulatory physiology. 01/2003; 283(6):H2356-62.

  This study evaluated the impact of low-pressure balloon devices on coronary morphology and function. An active coronary perfusion catheter (2.5-mm balloon diameter, inflation with 1 bar for 30 min)This study evaluated the impact of low-pressure balloon devices on coronary morphology and function. An active coronary perfusion catheter (2.5-mm balloon diameter, inflation with 1 bar for 30 min) was placed in the left anterior descending coronary artery of 12 German landrace pigs under general anesthesia. After 3 mo, coronary segments with balloon contact were compared with control segments taken from the right coronary artery as to histology, vascular reactivity, and expression of endothelial nitric oxide synthase. Thirty-three balloon treated segments were analyzed. Twenty of these segments (61%) showed neointima formation. In these segments endothelium-independent relaxation induced by sodium nitroprusside was preserved. However, endothelium-dependent bradykinin-induced relaxation was significantly attenuated compared with both the control segments and the balloon-treated segments without neointima formation. In >60% of the ballooned arterial segments examined, low-pressure balloon devices induced neointima formation accompanied by reduced endothelium-dependent relaxation. Thus interventions with so-called nontraumatic coronary devices can induce relevant vascular injury, with potential adverse clinical consequences.

• Selectivity of different calcium antagonists on T- and L-type calcium currents in guinea-pig ventricular myocytes.

  Authors: Petra De Paoli, Elisabetta Cerbai, Bernd Koidl, Michael Kirchengast, Laura Sartiani, Alessandro Mugelli

  Pharmacological research : the official journal of the Italian Pharmacological Society. 01/2003; 46(6):491-7.

  Both L- and T-type calcium channels are present in the heart. In cardiac myocytes L-type calcium channels are blocked by the classical calcium channel blockers, while T-type calcium channels areBoth L- and T-type calcium channels are present in the heart. In cardiac myocytes L-type calcium channels are blocked by the classical calcium channel blockers, while T-type calcium channels are thought to be insensitive to these drugs and to be selectively blocked by mibefradil. We aimed to compare the T/L calcium channel blocking selectivity of several calcium channel blockers by evaluating their effects on both components evoked in the same cell from a holding potential corresponding to the normal physiological value (-90mV). Currents were recorded in single patch-clamped guinea-pig ventricular myocytes, superfused with a Na(+)- and K(+)-free solution to abolish overlapping currents. Two dihydropyridines (amlodipine and lacidipine), verapamil diltiazem and mibefradil were tested; for each compound concentrations equieffective on L-type Ca(2+) current were used. All calcium channel blockers, at concentrations blocking less than 30% of L-type Ca(2+) current, inhibited a significant amount of T-type Ca(2+) current, varying from 0.8% (diltiazem) to 28% (mibefradil). We calculated for each compound the T/L ratio. As expected, mibefradil showed the highest T selectivity; lacidipine and diltiazem resulted to be L selective. Verapamil and amlodipine were not selective. Thus, the calcium channel blockers can be differentiated on the basis of their T/L selectivity.

• Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs.

  Authors: Cristina Basso, Gaetano Thiene, Mila Della Barbera, Annalisa Angelini, Michael Kirchengast, Sabino Iliceto

  Cardiovascular research. 08/2002; 55(1):113-21.

  OBJECTIVE: Endothelin (ET) receptor antagonists have been reported to reduce both infarct size and no-reflow phenomenon; however, in rat models their effect on the healing process after myocardialOBJECTIVE: Endothelin (ET) receptor antagonists have been reported to reduce both infarct size and no-reflow phenomenon; however, in rat models their effect on the healing process after myocardial infarction (MI) is controversial. The study aimed to evaluate the effect of early administration of the ET(A) receptor antagonist darusentan on scar healing in an ischemia-reperfusion model in dogs. METHODS: Thirty male mongrel dogs surviving 180 min left anterior descending coronary artery balloon occlusion were randomised to: darusentan i.v. bolus-5 mg/kg 5 min before reperfusion-(group I); darusentan i.v. bolus+chronic oral-10 mg/kg/day-(group II); saline (group III). Five age-matched dogs served as controls (group IV). At 6 weeks weight, volume, mass/volume, wall thickness, thinning ratio and expansion index were assessed in the explanted hearts. Infarct size and scar area tissue composition were evaluated by computerized histomorphometry. Cellularity, vessels and TGFbeta in the scar area were scored by immunohistochemistry. RESULTS: 24 dogs (80%; 7 group I, 8 group II, 9 group III) developed an anterior MI, transmural in 15 and subendocardial in 9, mean size 11.5+/-4% of left ventricular area and 37+/-9% of left ventricular endocardial circumference. MIs were homogeneously distributed among the three groups regarding either infarct size or transmural extent. No differences were found in the three MI groups regarding thinning ratio, expansion index and scar area tissue characterization. Percent scar collagen content (37+/-17 vs. 53+/-20 vs. 46+/-14), myofibroblasts (1.2 vs. 1.3 vs. 1.4), macrophages (1.2+/-0.5 vs. 1.3+/-0.5 vs. 1.4+/-0.5), neovessels (2.8+/-0.4 vs. 2.6+/-0.5 vs. 2.9+/-0.3) and TGFbeta score (2 vs. 2.25 vs. 2.11) were not significantly different. CONCLUSIONS: Early administration of the ET(A) receptor antagonist darusentan does not affect the scar healing process at 6 weeks after experimental MI with reperfusion in dogs.

• SELECTIVITY OF DIFFERENT CALCIUM ANTAGONISTS ON T- AND L-TYPE CALCIUM CURRENTS IN GUINEA-PIG VENTRICULAR MYOCYTES

  Authors: PETRA DE PAOLI, ELISABETTA CERBAI, BERND KOIDL, MICHAEL KIRCHENGAST, LAURA SARTIANI, ALESSANDRO MUGELLI

  Pharmacological Research.

  Both L- and T-type calcium channels are present in the heart. In cardiac myocytes L-type calcium channels are blocked by the classical calcium channel blockers, while T-type calcium channels areBoth L- and T-type calcium channels are present in the heart. In cardiac myocytes L-type calcium channels are blocked by the classical calcium channel blockers, while T-type calcium channels are thought to be insensitive to these drugs and to be selectively blocked by mibefradil. We aimed to compare the T/L calcium channel blocking selectivity of several calcium channel blockers by evaluating their effects on both components evoked in the same cell from a holding potential corresponding to the normal physiological value (−90 mV). Currents were recorded in single patch-clamped guinea-pig ventricular myocytes, superfused with a Na+- and K+-free solution to abolish overlapping currents. Two dihydropyridines (amlodipine and lacidipine), verapamil diltiazem and mibefradil were tested; for each compound concentrations equieffective on L-type Ca2+ current were used. All calcium channel blockers, at concentrations blocking less than 30% of L-type Ca2+ current, inhibited a significant amount of T-type Ca2+ current, varying from 0.8% (diltiazem) to 28% (mibefradil). We calculated for each compound the T/L ratio. As expected, mibefradil showed the highest T selectivity; lacidipine and diltiazem resulted to be L selective. Verapamil and amlodipine were not selective. Thus, the calcium channel blockers can be differentiated on the basis of their T/L selectivity.