6 results on '"Danser, AHJ"'
Search Results
2. Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP.
- Author
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de Vries T, Labruijere S, Rivera-Mancilla E, Garrelds IM, de Vries R, Schutter D, van den Bogaerdt A, Poyner DR, Ladds G, Danser AHJ, and MaassenVanDenBrink A
- Subjects
- Humans, Male, Middle Aged, Female, Signal Transduction drug effects, In Vitro Techniques, Vasodilator Agents pharmacology, Coronary Vessels drug effects, Coronary Vessels metabolism, Coronary Vessels physiology, Calcitonin Gene-Related Peptide metabolism, Calcitonin Gene-Related Peptide pharmacology, Cyclic AMP metabolism, Vasodilation drug effects, GTP-Binding Protein gamma Subunits metabolism, GTP-Binding Protein beta Subunits metabolism
- Abstract
Background and Purpose: Calcitonin gene-related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP-induced relaxation of human isolated coronary arteries (HCA)., Experimental Approach: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration-response curves to human α-CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation., Results: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL-12330A, and PKA inhibitors Rp-8-Br-cAMPs and H89, did not inhibit CGRP-induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM-34 + apamin, iberiotoxin or glibenclamide, or the Gα
q inhibitor YM-254890. Phosphodiesterase inhibitors induced a concentration-dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries., Conclusion: While CGRP signalling is generally assumed to act via cAMP, the CGRP-induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP-induced relaxation than generally believed., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2024
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3. Pharmacology of erenumab in human isolated coronary and meningeal arteries: Additional effect of gepants on top of a maximum effect of erenumab.
- Author
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de Vries T, Rubio-Beltrán E, van den Bogaerdt A, Dammers R, Danser AHJ, Snellman J, Bussiere J, and MaassenVanDenBrink A
- Subjects
- Humans, Male, Middle Aged, Female, Dose-Response Relationship, Drug, Piperidines pharmacology, Antibodies, Monoclonal pharmacology, Calcitonin Gene-Related Peptide metabolism, Vasodilation drug effects, Piperazines pharmacology, Quinazolines pharmacology, Migraine Disorders drug therapy, Migraine Disorders metabolism, In Vitro Techniques, Aged, Adult, Pyridines, Antibodies, Monoclonal, Humanized pharmacology, Coronary Vessels drug effects, Meningeal Arteries drug effects, Calcitonin Gene-Related Peptide Receptor Antagonists pharmacology, Sumatriptan pharmacology
- Abstract
Background and Purpose: Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for migraine treatment. Here, the effect of the monoclonal antibody erenumab on CGRP-induced vasorelaxation was investigated in human isolated blood vessels, as well as the effect of combining erenumab with the small molecule drugs, namely rimegepant, olcegepant, or sumatriptan., Experimental Approach: Concentration-response curves to CGRP, adrenomedullin or pramlintide were constructed in human coronary artery (HCA) and human middle meningeal artery (HMMA) segments, incubated with or without erenumab and/or olcegepant. pA
2 or pKb values were calculated to determine the potency of erenumab in both tissues. To study whether acutely acting antimigraine drugs exerted additional CGRP-blocking effects on top of erenumab, HCA segments were incubated with a maximally effective concentration of erenumab (3 μM), precontracted with KCl and exposed to CGRP, followed by rimegepant, olcegepant, or sumatriptan in increasing concentrations., Key Results: Erenumab shifted the concentration-response curve to CGRP in both vascular tissues. However, in HCA, the Schild plot slope was significantly smaller than unity, whereas this was not the case in HMMA, indicating different CGRP receptor mechanisms in these tissues. In HCA, rimegepant, olcegepant and sumatriptan exerted additional effects on CGRP on top of a maximal effect of erenumab., Conclusions and Implications: Gepants have additional effects on top of erenumab for CGRP-induced relaxation and could be effective in treating migraine attacks in patients already using erenumab as prophylaxis., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2024
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4. Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes.
- Author
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Cruz-López EO, Ren L, Uijl E, Clahsen-van Groningen MC, van Veghel R, Garrelds IM, Domenig O, Poglitsch M, Zlatev I, Rooney T, Kasper A, Nioi P, Foster D, and Danser AHJ
- Subjects
- Animals, Humans, Rats, Albuminuria, Blood Pressure drug effects, Blood Pressure genetics, Liver metabolism, Renin metabolism, Renin-Angiotensin System, Valsartan pharmacology, Angiotensin II drug effects, Angiotensin II genetics, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism, Hypertension drug therapy, Kidney Diseases drug therapy, Kidney Diseases metabolism, Kidney Diseases prevention & control, RNA, Small Interfering metabolism, RNA, Small Interfering pharmacology, RNA, Small Interfering therapeutic use
- Abstract
Background and Purpose: Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown., Experimental Approach: To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT
1 antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry., Key Results: MAP before treatment was 153 ± 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis., Conclusion and Implications: Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
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5. Pentoxifylline as a therapeutic option for pre-eclampsia: a study on its placental effects.
- Author
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Broekhuizen M, de Vries R, Smits MAW, Dik WA, Schoenmakers S, Koch BCP, Merkus D, Reiss IKM, Danser AHJ, Simons SHP, and Hitzerd E
- Subjects
- Adenosine pharmacology, Anti-Inflammatory Agents pharmacology, Cyclic GMP metabolism, Female, Humans, Nitric Oxide Synthase metabolism, Phosphodiesterase Inhibitors pharmacology, Phosphodiesterase Inhibitors therapeutic use, Placenta metabolism, Pregnancy, Purinergic P1 Receptor Antagonists metabolism, Purinergic P1 Receptor Antagonists pharmacology, Purinergic P1 Receptor Antagonists therapeutic use, Vasodilator Agents pharmacology, Pentoxifylline metabolism, Pentoxifylline pharmacology, Pentoxifylline therapeutic use, Pre-Eclampsia drug therapy
- Abstract
Background and Purpose: Recently pentoxifylline, a non-selective phosphodiesterase inhibitor and adenosine receptor antagonist, has attracted much interest for the treatment of the increased vascular resistance and endothelial dysfunction in pre-eclampsia. We therefore investigated the placental transfer, vascular effects and anti-inflammatory actions of pentoxifylline in healthy and pre-eclamptic human placentas., Experimental Approach: The placental transfer and metabolism of pentoxifylline were studied using ex vivo placenta perfusion experiments. In wire myography experiments with chorionic plate arteries, pentoxifyllines vasodilator properties were investigated, focusing on the cGMP and cAMP pathways and adenosine receptors. Its effects on inflammatory factors were also studied in placental explants., Key Results: Pentoxifylline transferred from the maternal to foetal circulation, reaching identical concentrations. The placenta metabolized pentoxifylline into its active metabolite lisofylline (M1), which was released into both circulations. In healthy placentas, pentoxifylline potentiated cAMP- and cGMP-induced vasodilation, as well as causing vasodilation by adenosine A
1 antagonism and via NO synthase and PKG. Pentoxifylline also reduced inflammatory factors secretion. In pre-eclamptic placentas, we observed that its vasodilator capacity was preserved, however not via NO-PKG but likely through adenosine signalling. Pentoxifylline neither potentiated vasodilation through cAMP and cGMP, nor suppressed the release of inflammatory factors from these placentas., Conclusion and Implications: Pentoxifylline is transferred across and metabolized by the placenta. Its beneficial effects on the NO pathway and inflammation are not retained in pre-eclampsia, limiting its application in this disease, although it could be useful for other placenta-related disorders. Future studies might focus on selective A1 receptor antagonists as a new treatment for pre-eclampsia., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2022
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6. Characterization of binding, functional activity, and contractile responses of the selective 5-HT 1F receptor agonist lasmiditan.
- Author
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Rubio-Beltrán E, Labastida-Ramírez A, Haanes KA, van den Bogaerdt A, Bogers AJJC, Zanelli E, Meeus L, Danser AHJ, Gralinski MR, Senese PB, Johnson KW, Kovalchin J, Villalón CM, and MaassenVanDenBrink A
- Subjects
- Animals, Binding, Competitive, CHO Cells, Cell Membrane drug effects, Cell Membrane metabolism, Coronary Vessels metabolism, Coronary Vessels physiopathology, Cricetulus, Dogs, Dose-Response Relationship, Drug, Female, Humans, In Vitro Techniques, Male, Meningeal Arteries metabolism, Meningeal Arteries physiopathology, Protein Binding, Radioligand Assay, Sumatriptan pharmacology, Receptor, Serotonin, 5-HT1F, Benzamides pharmacology, Coronary Vessels drug effects, Meningeal Arteries drug effects, Muscle Contraction drug effects, Piperidines pharmacology, Pyridines pharmacology, Receptors, Serotonin metabolism, Serotonin Receptor Agonists pharmacology, Vasoconstriction drug effects
- Abstract
Background and Purpose: Triptans are 5-HT
1B/1D receptor agonists (that also display 5-HT1F receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT1F receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan., Experimental Approach: Binding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5-HT1A , 5-HT1B , 5-HT1D , 5-ht1E , 5-HT1F , 5-HT2A , 5-HT2B , and 5-HT7 receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration-response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured., Key Results: Lasmiditan showed high selectivity for 5-HT1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT1B receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested., Conclusions and Implications: Lasmiditan is a selective 5-HT1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2019
- Full Text
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