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1. Chronic kidney disease increases the susceptibility to negative effects of low and high potassium intake

Author

Gritter, M, Wei, KY, Wouda, RD, Musterd-Bhaggoe, UM, Dijkstra, KL, Kers, J, Ramakers, C, Vogt, L, de Borst, MH, Danser, AHJ, Hoorn, EJ, Rotmans, J, Gritter, M, Wei, KY, Wouda, RD, Musterd-Bhaggoe, UM, Dijkstra, KL, Kers, J, Ramakers, C, Vogt, L, de Borst, MH, Danser, AHJ, Hoorn, EJ, and Rotmans, J

Abstract

Background Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is unclear. Here, we hypothesize that CKD increases the susceptibility to the negative effects of low and high K+ diets. Methods We compared the effects of low, normal and high KChloride (KCl) diets and a high KCitrate diet for 4 weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx). Results Compared with rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular K+ depletion and more severe kidney injury, characterized by nephromegaly, infiltration of T cells and macrophages, decreased estimated glomerular filtration rate and increased albuminuria. The high KCl diet caused hyperkalemia, hyperaldosteronism, hyperchloremic metabolic acidosis and severe hypertension in 5/6Nx but not in sham rats. The high KCitrate diet caused hypochloremic metabolic alkalosis but attenuated hypertension despite higher abundance of the phosphorylated sodium chloride cotransporter (pNCC) and similar levels of plasma aldosterone and epithelial sodium channel abundance. All 5/6Nx groups had more collagen deposition than the sham groups and this effect was most pronounced in the high KCitrate group. Plasma aldosterone correlated strongly with kidney collagen deposition. Conclusions CKD increases the susceptibility to negative effects of low and high K+ diets in male rats, although the injury patterns are different. The low K+ diet caused inflammation, nephromegaly and kidney function decline, whereas the high K+ diet caused hypertension, hyperaldosteronism and kidney fibrosis. High KCitrate attenuated the hypertensive but not the pro-fibrotic effect of high KCl, which may be attributable to K+-induced aldosterone secretion. Our data suggest t

Published
2024

2. Hybrid Molecular and Functional Micro-CT Imaging Reveals Increased Myocardial Apoptosis Preceding Cardiac Failure in Progeroid Ercc1 Mice

Author

van Thiel, BS, de Boer, M, Ridwan, Y, de Kleijnen, MGJ, van Vliet, N, van der Linden, J, de Beer, I, van Heijningen, PM, Vermeij, WP, Hoeijmakers, JHJ, Danser, AHJ, Kanaar, R, Duncker, DJ, van der Pluijm, I, Essers, J, van Thiel, BS, de Boer, M, Ridwan, Y, de Kleijnen, MGJ, van Vliet, N, van der Linden, J, de Beer, I, van Heijningen, PM, Vermeij, WP, Hoeijmakers, JHJ, Danser, AHJ, Kanaar, R, Duncker, DJ, van der Pluijm, I, and Essers, J

Abstract

Purpose: In this study, we explored the role of apoptosis as a potential biomarker for cardiac failure using functional micro-CT and fluorescence molecular tomography (FMT) imaging techniques in Ercc1 mutant mice. Ercc1 is involved in multiple DNA repair pathways, and its mutations contribute to accelerated aging phenotypes in both humans and mice, due to the accumulation of DNA lesions that impair vital DNA functions. We previously found that systemic mutations and cardiomyocyte-restricted deletion of Ercc1 in mice results in left ventricular (LV) dysfunction at older age. Procedures and Results: Here we report that combined functional micro-CT and FMT imaging allowed us to detect apoptosis in systemic Ercc1 mutant mice prior to the development of overt LV dysfunction, suggesting its potential as an early indicator and contributing factor of cardiac impairment. The detection of apoptosis in vivo was feasible as early as 12 weeks of age, even when global LV function appeared normal, underscoring the potential of apoptosis as an early predictor of LV dysfunction, which subsequently manifested at 24 weeks. Conclusions: This study highlights the utility of combined functional micro-CT and FMT imaging in assessing cardiac function and detecting apoptosis, providing valuable insights into the potential of apoptosis as an early biomarker for cardiac failure.

Published
2024

3. Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure

Author

Arendse, LB, Danser, AHJ, Poglitsch, M, Touyz, RM, Burnett, JC, Llorens-Cortes, C, Ehlers, MR, Sturrock, E D, and Internal Medicine

Subjects
0301 basic medicine, Combination therapy, Genetic enhancement, Angiotensin III, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Pharmacology, Renin-Angiotensin System, Small Molecule Libraries, 03 medical and health sciences, 0302 clinical medicine, Renin–angiotensin system, medicine, Animals, Humans, Molecular Targeted Therapy, Receptor, Review Articles, Heart Failure, business.industry, medicine.disease, Angiotensin II, 3. Good health, Blockade, 030104 developmental biology, Heart failure, Hypertension, Molecular Medicine, business, Angiotensin II Type 1 Receptor Blockers, 030217 neurology & neurosurgery
Abstract

Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.

Published
2019
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4. Angiogenic markers during preeclampsia: Are they associated with hypertension 1 year postpartum?

Author

Neümañ, Rugina, Figaroa, Aveline, Nieboer, Daan, Saleh, Langeza, Verdonk, Koen, Danser, AHJ, Duvekot, J.J., van den Meiracker, Ton, Roeters van Lennep, Jeanine, Visser, Willy, Neümañ, Rugina, Figaroa, Aveline, Nieboer, Daan, Saleh, Langeza, Verdonk, Koen, Danser, AHJ, Duvekot, J.J., van den Meiracker, Ton, Roeters van Lennep, Jeanine, and Visser, Willy

Abstract

Objectives: Preeclampsia is associated with hypertension in later life, but the underlying pathophysiological mechanisms remain uncertain. We aimed to explore whether the angiogenic markers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) measured in women with preeclampsia could be associated with hypertension 1 year after delivery. Methods: This is a secondary analysis of a prospective cohort study, originally aimed to evaluate the use of sFlt-1/PlGF ratio to predict adverse outcome in women with (suspected) preeclampsia. Office blood pressure (BP) was evaluated at 1 year postpartum in women who had a confirmed diagnosis of preeclampsia within one week of biomarker measurement. Results: Eighty women were included with a median (interquartile range) gestational age (GA) at biomarker measurement of 30 (27–33) weeks. Twenty-three (29%) women had hypertension 1 year postpartum. These women showed higher median SBP during their pregnancy and lower GA at PE diagnosis compared to women without hypertension. Median PlGF levels were lower in women with hypertension 1 year postpartum compared to women without hypertension (23 vs. 48 pg/mL, p = 0.017), while no differences in sFlt-1 or sFlt-1/PlGF ratio were observed. Multivariable analysis adjusted for GA did not show significant association between PlGF (nor sFlt-1, sFlt-1/PlGF ratio) and hypertension 1 year postpartum (OR [95% CI] 0.9 [0.2–4.4], p = 0.97). Conclusion: Our data indicate that sFlt-1, PlGF or their ratio measured during pregnancy are not suitable for the prediction of hypertension 1 year postpartum and hence guiding follow-up of women with previous preeclampsia.

Published
2021

5. Prorenin periconceptionally and in pregnancy:Does it have a physiological role?

Author

Wiegel, Rosalieke, von Versen-Höynck, Frauke, Steegers - Theunissen, Régine, Steegers, Eric, Danser, AHJ, Wiegel, Rosalieke, von Versen-Höynck, Frauke, Steegers - Theunissen, Régine, Steegers, Eric, and Danser, AHJ

Abstract

Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.

Published
2021

6. Human kidney organoids produce functional renin

Author

Shankar, Anusha, Du, Zhaoyu, Tejeda Mora, Hector, van den Bosch, Thierry, Korevaar, Sander, Van den Berg - Garrelds, Ingrid, Bindels, Eric, Lopez-Iglesias, C, Clahsen - van Groningen, Marian, Gribnau, Joost, Baan, Carla, Danser, AHJ, Hoorn, Ewout, Hoogduijn, Martin, Shankar, Anusha, Du, Zhaoyu, Tejeda Mora, Hector, van den Bosch, Thierry, Korevaar, Sander, Van den Berg - Garrelds, Ingrid, Bindels, Eric, Lopez-Iglesias, C, Clahsen - van Groningen, Marian, Gribnau, Joost, Baan, Carla, Danser, AHJ, Hoorn, Ewout, and Hoogduijn, Martin

Abstract

Renin production by the kidney is of vital importance for salt, volume, and blood pressure homeostasis. The lack of human models hampers investigation into the regulation of renin and its relevance for kidney physiology. To develop such a model, we used human induced pluripotent stem cell–derived kidney organoids to study the role of renin and the renin-angiotensin system in the kidney. Extensive characterization of the kidney organoids revealed kidney-specific cell populations consisting of podocytes, proximal and distal tubular cells, stromal cells and endothelial cells. We examined the presence of various components of the renin-angiotensin system such as angiotensin II receptors, angiotensinogen, and angiotensin-converting enzymes 1 and 2. We identified by single-cell sequencing, immunohistochemistry, and functional assays that cyclic AMP stimulation induces a subset of pericytes to increase the synthesis and secretion of enzymatically active renin. Renin production by the organoids was responsive to regulation by parathyroid hormone. Subcutaneously implanted kidney organoids in immunodeficient IL2Ry -/-Rag2 -/- mice were successfully vascularized, maintained tubular and glomerular structures, and retained capacity to produce renin two months after implantation. Thus, our results demonstrate that kidney organoids express renin and provide insights into the endocrine potential of human kidney organoids, which is important for regenerative medicine in the context of the endocrine system.

Published
2021

9. Anti-migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Author

Mulder, IA, Li, M, de Vries, Tessa, Qin, T, Yanagisawa, T, Sugimoto, K, van den Bogaerdt, A, Danser, AHJ, Wermer, MJH, van den Maagdenberg, AM, Maassen van den Brink, Antoinette, Ferrari, MD, Ayata, C, Mulder, IA, Li, M, de Vries, Tessa, Qin, T, Yanagisawa, T, Sugimoto, K, van den Bogaerdt, A, Danser, AHJ, Wermer, MJH, van den Maagdenberg, AM, Maassen van den Brink, Antoinette, Ferrari, MD, and Ayata, C

Published
2020

14. Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system

Author

Labastida Ramirez, Alejandro, Rubio Beltran, Amada, Haanes, Kristian, Chan, Ka yi, Van den Berg - Garrelds, Ingrid, Johnson, KW, Danser, AHJ, Villalon, CM, Maassen van den Brink, Antoinette, Labastida Ramirez, Alejandro, Rubio Beltran, Amada, Haanes, Kristian, Chan, Ka yi, Van den Berg - Garrelds, Ingrid, Johnson, KW, Danser, AHJ, Villalon, CM, and Maassen van den Brink, Antoinette

Published
2020

16. Larger First-Trimester Placental Volumetric Parameters Are Associated With Lower Pressure and More Flow-Mediated Vasodilation of the Fetoplacental Vasculature After Delivery

Author

Hitzerd, Emilie, Reijnders, Igna, Mulders, Annemarie, Koning, Anton, Reiss, Irwin, Danser, AHJ, Steegers - Theunissen, Régine, Simons, SHP (Sinno), Koster, Wendy, Hitzerd, Emilie, Reijnders, Igna, Mulders, Annemarie, Koning, Anton, Reiss, Irwin, Danser, AHJ, Steegers - Theunissen, Régine, Simons, SHP (Sinno), and Koster, Wendy

Published
2020

21. Vasoresponsiveness in patients with heart failure (VASOR):protocol for a prospective observational study

Author

van Vessem, Marieke E., Beeres, Saskia, de Wilde, Rob B.P., de Vries, René, Berendsen, Remco R., de Jonge, Evert, Danser, AHJ, Klautz, Robert J.M., Schalij, Martin J., Palmen, Meindert, van Vessem, Marieke E., Beeres, Saskia, de Wilde, Rob B.P., de Vries, René, Berendsen, Remco R., de Jonge, Evert, Danser, AHJ, Klautz, Robert J.M., Schalij, Martin J., and Palmen, Meindert

Published
2019

24. Placental effects and transfer of sildenafil in healthy and preeclamptic conditions

Author

Hitzerd, Emilie, Broekhuizen, Michelle, Colafella, Katrina, Glisic, Marija, de Vries, René, Koch, Birgit, Raaf, Michiel, Merkus, Daphne, Schoenmakers, Sam, Reiss, Irwin, Danser, AHJ, Simons, SHP (Sinno), Hitzerd, Emilie, Broekhuizen, Michelle, Colafella, Katrina, Glisic, Marija, de Vries, René, Koch, Birgit, Raaf, Michiel, Merkus, Daphne, Schoenmakers, Sam, Reiss, Irwin, Danser, AHJ, and Simons, SHP (Sinno)

Published
2019

25. Effects of Dapagliflozin on Volume Status When Added to Renin-Angiotensin System Inhibitors

Author

Eickhoff, MK, Dekkers, CCJ, Kramers, BJ, Laverman, GD, Frimodt-Moller, M, Jorgensen, NR, Faber, J, Danser, AHJ, Gansevoort, RT, Rossing, P, Persson, F, Heerspink, HJL, Eickhoff, MK, Dekkers, CCJ, Kramers, BJ, Laverman, GD, Frimodt-Moller, M, Jorgensen, NR, Faber, J, Danser, AHJ, Gansevoort, RT, Rossing, P, Persson, F, and Heerspink, HJL

Published
2019

28. Ultrafine particles and ozone perturb norepinephrine clearance rather than centrally generated sympathetic activity in humans

Author

Heusser, K, Tank, J, Holz, O, May, M, Brinkmann, J, Engeli, S, Diedrich, A, Framke, T, Koch, A, Grosshennig, A, Danser, AHJ, Sweep, F, Schindler, C, Schwarz, K, Krug, N, Jordan, J, Hohlfeld, JM, Heusser, K, Tank, J, Holz, O, May, M, Brinkmann, J, Engeli, S, Diedrich, A, Framke, T, Koch, A, Grosshennig, A, Danser, AHJ, Sweep, F, Schindler, C, Schwarz, K, Krug, N, Jordan, J, and Hohlfeld, JM

Published
2019

29. Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery - potential antimigraine efficacy

Author

Labastida Ramirez, Alejandro, Rubio Beltran, Amada, Haanes, Kristian, de Vries, René, Dammers, R., Bogers, Ad, van den Bogaerdt, A, Daugherty, BL, Danser, AHJ, Villalon, Carlos M., Maassen van den Brink, Antoinette, Labastida Ramirez, Alejandro, Rubio Beltran, Amada, Haanes, Kristian, de Vries, René, Dammers, R., Bogers, Ad, van den Bogaerdt, A, Daugherty, BL, Danser, AHJ, Villalon, Carlos M., and Maassen van den Brink, Antoinette

Published
2019

33. Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening

Author

Sorop, Oana, Heinonen, Ilkka, Kranenburg, Matthijs, van de Wouw, Jens, Beer, Vincent, Nguyen, ITN, Octavia, Yanti, Duin, Richard, Stam, Kelly, van Geuns, Robert Jan, Wielopolski, Piotr, Krestin, Gabriel, van den Meiracker, Ton, Verjans, R, van Bilsen, M, Danser, AHJ, Paulus, WJ, Cheng, Caroline, Linke, WA, Joles, JA, Verhaar, MC, Velden, J, Merkus, Daphne, Duncker, Dirk-jan, Sorop, Oana, Heinonen, Ilkka, Kranenburg, Matthijs, van de Wouw, Jens, Beer, Vincent, Nguyen, ITN, Octavia, Yanti, Duin, Richard, Stam, Kelly, van Geuns, Robert Jan, Wielopolski, Piotr, Krestin, Gabriel, van den Meiracker, Ton, Verjans, R, van Bilsen, M, Danser, AHJ, Paulus, WJ, Cheng, Caroline, Linke, WA, Joles, JA, Verhaar, MC, Velden, J, Merkus, Daphne, and Duncker, Dirk-jan

Published
2018

34. Characterization of the trigeminovascular actions of several adenosine A(2A) receptor antagonists in an in vivo rat model of migraine

Author

Haanes, Kristian, Labastida Ramirez, Alejandro, Chan, Ka yi, de Vries, René, Shook, Brian, Jackson, Paul, Zhang, Jimmy, Flores, Christopher M., Danser, AHJ, Villalon, Carlos M., Maassen van den Brink, Antoinette, Haanes, Kristian, Labastida Ramirez, Alejandro, Chan, Ka yi, de Vries, René, Shook, Brian, Jackson, Paul, Zhang, Jimmy, Flores, Christopher M., Danser, AHJ, Villalon, Carlos M., and Maassen van den Brink, Antoinette

Published
2018

36. (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis

Author

Ren, LW, Sun, Yuan, Lu, H, Ye, DE, Han, LJ, Wang, N, Daugherty, A, Li, FR, Wang, MM (Miao-Miao), Su, FT, Tao, WJ, Sun, Jane, Zelcer, N, Mullick, AE, Danser, AHJ, Jiang, YZ, He, YC, Ruan, XZ, Lu, XF, Ren, LW, Sun, Yuan, Lu, H, Ye, DE, Han, LJ, Wang, N, Daugherty, A, Li, FR, Wang, MM (Miao-Miao), Su, FT, Tao, WJ, Sun, Jane, Zelcer, N, Mullick, AE, Danser, AHJ, Jiang, YZ, He, YC, Ruan, XZ, and Lu, XF

Published
2018

37. The effect of bioresorbable vascular scaffold implantation on distal coronary endothelial function in dyslipidemic swine with and without diabetes

Author

Heuvel, Mieke, Sorop, Oana, Ditzhuijzen, Nienke, de Vries, René, Duin, Richard, Peters, Ilona, Loon, Janine, de Maat, Moniek, van Beusekom, H.M.M., Giessen, Wim, Danser, AHJ, Duncker, Dirk-jan, Heuvel, Mieke, Sorop, Oana, Ditzhuijzen, Nienke, de Vries, René, Duin, Richard, Peters, Ilona, Loon, Janine, de Maat, Moniek, van Beusekom, H.M.M., Giessen, Wim, Danser, AHJ, and Duncker, Dirk-jan

Published
2018

42. Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective?

Author

Chai, W (Wenxia), Van den Berg - Garrelds, Ingrid, Arulmani, US (Udayasankar), Schoemaker, RG (Regien), Lamers, Jos, Danser, AHJ, Schoemaker lab, Internal Medicine, and Biochemistry

Subjects
Male, collagen, ANGIOTENSIN-CONVERTING ENZYME, Cardiotonic Agents, SMOOTH-MUSCLE-CELLS, Blood Pressure, cardiomyocyte, In Vitro Techniques, Ventricular Function, Left, II GENERATION, Coronary Circulation, Animals, Vasoconstrictor Agents, FIBROSIS, Rats, Wistar, CARDIAC-HYPERTROPHY, Cells, Cultured, Mineralocorticoid Receptor Antagonists, aldosterone, DNA synthesis, LOW-FLOW ISCHEMIA, HYPERTROPHIC CARDIOMYOPATHY, Angiotensin II, Myocardium, Langendorff heart, KINASE-C-ALPHA, Heart, DNA, Fibroblasts, angiotensin, Rats, Receptors, Mineralocorticoid, spironolactone, Animals, Newborn, MYOCARDIAL-INFARCTION, Papers, ischaemia, MINERALOCORTICOID RECEPTOR, Thymidine
Abstract

1 Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2 Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 11 +/- 4 and 9 +/- 2%, and decreased coronary flow (CF) by maximally 36 +/- 7 and 20 +/- 4%, respectively. Spironolactone did not significantly affect LVP or CF. 3 In hearts that were exposed to a 45-min coronary artery occlusion and 3h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 68 +/- 2 to 45 +/- 3%, similar to the reduction (34 +/- 2%) observed following 'preconditioning' (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (71 +/- 5%). 4 In cardiomyocytes, aldosterone decreased [H-3] thymidine incorporation maximally by 73 +/- 3%, whereas in cardiac fibroblasts it decreased [H-3] proline incorporation by 33 +/- 7%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone. 5 In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure.

Published
2005

43. Selective angiotensin-converting enzyme c-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction

Author

van Esch, JHM Tom, B Dive, V Batenburg, WW Georgiadis, D and Yiotakis, A van Gool, JMG de Bruijn, RJA de Vries, R and Danser, AHJ

Abstract

Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentration-dependently constricted PFAs. RXPA380, at concentrations >1 mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations less than or equal to 0.1 mmol/L. Bradykinin concentration-dependently relaxed PCMAs. RXPA380 (10 mumol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled approximate to 50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t(1/2)) of 42 +/- 3 minutes. Quinaprilat increased the t(1/2) approximate to 4-fold, indicating that 71 +/- 6% of Ang I metabolism was attributable to ACE. RXPA380 ( 10 mumol/L) and RXP407 ( 0.1 mmol/L) increased the t(1/2) approximate to 2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE ( and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I - induced vasoconstriction in vivo but also why ACEi exert blood pressure - independent effects at low (C-domain - blocking) doses.

Published
2005

50. 5/6 Nephrectomy Impairs Acute Kaliuretic Responses and Predisposes to Postprandial Hyperkalemia.

Author

Wei KY, Gritter M, Danser AHJ, Vogt L, de Borst MH, Rotmans JI, Imenez Silva PH, and Hoorn EJ

Abstract

The susceptibility of patients with chronic kidney disease (CKD) to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na + ) and potassium (K + ) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K + loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this to the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K + loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K + concentrations in 5/6Nx rats which were accompanied by corresponding increases in plasma aldosterone. Acute K + loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase (SPAK) and the sodium-chloride cotransporter (NCC) both in sham and 5/6Nx rats. In contrast, the acute K + load decreased the Na + /hydrogen exchanger 3 (NHE3) and increased serum- and glucocorticoid-regulated kinase 1 (SGK1) and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K + load which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia.

Published
2024
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