Darusentan, a selective endothelin A receptor antagonist, for the oral treatment of resistant hypertension

Resistant hypertension is defined as failure to lower blood pressure to target when a patient adheres to the maximum tolerated doses of three antihypertensive drugs including a diuretic. Notwithstanding the wide availability of several antihypertensive agents and the continued recommendation of dietary and lifestyle modifications, the prevalence of resistant hypertension remains high and is expected to increase thus underscoring the need for potential new treatment modalities in resistant hypertension. Endothelin-1 is a long-lasting potent vasoconstrictor and plays a key role in cardiovascular haemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The clinical experience and the evidence for therapy with darusentan in resistant systemic hypertension are reviewed. The leading journals that publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. While results from early clinical studies suggested that darusentan might emerge as new treatment option in patients with resistant hypertension, results from recent studies suggests that darusentan appears unlikely to find its way in the armamentarium for treatment of resistant hypertension

OR-53: HMG-CoA reductase inhibitor improves endothelial dysfunction in mineralocorticoid hypertension by inhibition of RhoA

Statins reduce cardiovascular morbidity and mortality. These beneficial effects are not fully explained by their lipid-lowering action. As such, we investigated the impact of a new statin, rosuvastatin, on endothelial function, the key event in early atherogenesis, in an experimental model of normocholesterolemic hypertension. Hypertension was induced in Wistar-Kyoto rats by inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with Glycyrrhizic acid (GA). 11β-HSD2 provides mineralocorticoid receptor specificity for aldosterone by metabolising glucocorticoids to their receptor inactive 11-dehydro derivatives. GA was added to the drinking water (3 g/L) for 21 days. From days 8 to 21 rosuvastatin (20 mg/kg/d) or placebo were added to chow. Endothelium-dependent and -independent relaxation of isolated aortic rings to acetylcholine (ACh, 10-10-10-5 mol/L) and sodium nitroprusside (SNP, 10-10-10-5 mol/L) was measured. In addition, vascular reactivity to endothelin-1 (ET-1; 10-10-10-7 mol/L) was investigated. ETA and ETB receptor mRNA expression was determined by RT-PCR and RhoA activity by a pull-down assay. Systolic blood pressure increased in rats treated with GA (175 vs 153 mmHg in controls; p<0.01). Endothelium-dependent relaxations to acetylcholine were blunted after GA treatment (p≤0.005 vs control), while the responses to SNP remained unchanged. Rosuvastatin normalized NO-mediated endothelium-dependent relaxation in hypertensive animals (p≤0.01 vs placebo), although blood pressure and cholesterol levels were not affected by the statin. Vascular reactivity to ET-1 was increased by GA (p<0.01 vs control), but not affected by rosuvastatin. ETB receptor mRNA decreased in the GA group (p<0.05 vs control) and was upregulated by rosuvastatin (p<0.005; GA+rosuvastatin vs GA), whereas ETA receptor mRNA upregulation in the GA group (p<0.01 vs control) was partially prevented by the statin. In addition, GA increased Rho-GTP binding (p≤0.05 vs control) which was prevented in both groups by rosuvastatin treatment (p≤0.01 control+rosuvastatin vs control and GA+rosuvastatin vs GA). These data for the first time show that HMG-CoA inhibition improves endothelial dysfunction in normocholesterolemic mineralocorticoid hypertension without affecting blood pressure or cholesterol levels by correction of a stimulated endothelin syste

P-341: Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension

Renal safety of selective COX-2 inhibitors (coxibs) is a matter of ongoing discussion. Therefore, in the present study we examined the effects of two different coxibs, celecoxib and rofecoxib, compared to a traditional NSAID, diclofenac, and placebo in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib) or placebo were added to chow from week 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T-lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. COX-2 protein and mRNA were isolated from renal cortex. Untreated hypertensive animals showed preglomerular and glomerular injury including endothelial activation/proliferation, broadened adventitia, collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops and especially high grade of glomerulosclerosis (p<0.05 vs DR-placebo) and CD8 and ED1 positive cells (p<0.01 vs DR-placebo) which was improved by celecoxib but not by diclofenac and rofecoxib. Proteinuria was observed in hypertensive animals (p<0.0001 vs DR-placebo), normalised by celecoxib (p=0.0015 vs DS-placebo) and increased by rofecoxib (p<0.05 vs DS-placebo). COX-2 protein and mRNA levels were comparable in all groups. Renal function and morphology improves after celecoxib but not after rofecoxib or diclofenac. This head-to-head comparison demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertensio

P-274: Activated endothelin system in polyglobulia

The role of the endothelin system, the functional counterpart of NO, in the pathophysiology of polyglobulia remains still elusive. Therefore a novel erythropoietin overexpressing mouse was generated, with hematocrit levels of about 80%. Hence, we analyzed vascular contractions to ET-1 and big endothelin-1 (big ET-1), endothelin-1 (ET-1) promoter activity, ET-1 immunochemistry, endothelin-1 (ET-1)-protein tissue levels, ETA/B-receptor mRNA expression in this novel transgenic model of severe polyglobulia. For analysis of ET-1 promotor activity, EPO transgenic mice were mated with homozygous transgenic mice expressing the lacZ gene under control of the human ET-1 promoter and immunochistochemistry for gal blue was performed in lacZ transgenic animals. Notwithstanding markedly increased eNOS expression, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels indicating enhanced bioavailability of NO, ET-1 tissue levels were also augmented in heart, kidney, liver and aorta (2.2±0.3 vs. 0.5±0.1 pg/mg tissue; P<0.01) of transgenic polyglobulic animals. Accordingly, immunohistochemistry demonstrated enhanced expression of ET-1 protein in the vascular wall of polyglobulic animals as compared to controls (p< 0.05), while increase of ET-1 promoter activity was confined to the perivascular tissue (P<0.05). NOS inhibition with L-NAME unmasked increased vascular reactivity to ET-1 and bigET-1 and aortic ETA/B receptor mRNA gene expression was enhanced (p<0.05 vs. controls). Administration of the NOS inhibitor L-NAME led to acute vasoconstriction of peripheral resistance vessels, hypertension and death of transgenic mice within 2 days, while wildtypes did not show increased mortality. Treatment with the ETA antagonist darusentan doubled survival time of transgenic polyglobulic mice after NO synthase inhibition (p<0.01 vs placebo). In conclusion, in this study we provide first evidence that the tissue endothelin system is activated by polyglobulia. Together with a stimulated NO system it contributes to cardiovascular regulation in pathophysiological conditions associated with increased hematocri

Case report of long-term postural tachycardia syndrome in a patient after messenger RNA coronavirus disease-19 vaccination with mRNA-1273

BACKGROUND Postural tachycardia syndrome (POTS) is characterized by orthostatic intolerance and heart rate increase in an upright position without orthostatic hypotension. It has been described after coronavirus disease-19 (COVID-19) as well as after COVID-19 vaccination. CASE SUMMARY A 54-year-old female patient presented with a 9-months history of severe orthostatic intolerance since COVID-19 vaccination with messenger RNA (mRNA)-1273 (Spikevax, Moderna). Except for diet-controlled coeliac disease, the patient was healthy, had no allergies, and did not take regular medication. Tilt table testing revealed a significant heart rate increase to 168 bpm without orthostatic hypotension accompanied by light-headedness, nausea, and syncope, findings consistent with POTS. Potential underlying causes including anaemia, thyroid dysfunction, adrenal insufficiency, pheochromocytoma, (auto)-immune disease, chronic inflammation as well as neurological causes were ruled out. Echocardiography and cardiac stress magnetic resonance imaging (MRI) did not detect structural or functional heart disease or myocardial ischaemia. Forty-eight-hour-electrocardiogram (ECG) showed no tachycardias other than sinus tachycardia. Finally, genomic analysis did not detect an inherited arrhythmia syndrome. Serologic analysis revealed adequate immune response to mRNA-1273 vaccination without signs of previous severe acute respiratory syndrome-coronavirus-2 infection. While ivabradine was not tolerated and metoprolol extended release only slightly improved symptoms, physical exercise reduced orthostatic intolerance moderately. At a 5-months follow-up, the patient remained dependant on assistance for activities of daily living. DISCUSSION The temporal association of POTS with the COVID-19 vaccination in a previously healthy patient and the lack of evidence of an alternative aetiology suggests COVID-19 vaccination is the potential cause of POTS in this patient. To our knowledge, this is the first case reporting severe, long-term, and treatment-refractory POTS following COVID-19 vaccination with mRNA1273