Hypertension-induced End-organ Damage Research Articles

Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage.

Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated. The hypertensive response to angiotensin II (Ang II, 0.7 mg/kg/day, s.c.) was attenuated by Cmpd17b (50 mg/kg/day, i.p.). Impairments in cardiac and vascular function assessed via echocardiography were improved by Cmpd17b in hypertensive mice. This functional improvement was accompanied by reduced cardiac and aortic fibrosis and vascular calcification. Cmpd17b also attenuated Ang II-induced increased cardiac mitochondrial complex 2 respiration. Proteomic profiling of cardiac and aortic tissues and cells, using label-free nano-liquid chromatography with high-sensitivity mass spectrometry, detected and quantified ∼6000 proteins. We report hypertension-impacted protein clusters associated with dysregulation of inflammatory, mitochondrial, and calcium responses, as well as modified networks associated with cardiovascular remodelling, contractility, and structural/cytoskeletal organization. Cmpd17b attenuated hypertension-induced dysregulation of multiple proteins in mice, and of these, ∼110 proteins were identified as similarly dysregulated in humans suffering from adverse aortic remodelling and cardiac hypertrophy. We have demonstrated, for the first time, that the FPR agonist Cmpd17b powerfully limits hypertension-induced end-organ damage, consistent with proteome networks, supporting development of pro-resolution FPR-based therapeutics for treatment of systemic hypertension complications.

Impact of hypertensive heart disease, risk factors, and age-period-cohort models across 204 nations and regions from 1990 to 2019: a global perspective from the 2019 global burden of disease study.

Hypertensive heart disease (HHD) is a major global public health issue resulting from hypertension-induced end-organ damage. The aim of this study was to examine the global impact, risk factors, and age-period-cohort (APC) model of HHD from 1990 to 2019. Data from the 2019 Global Burden of Disease were used to assess age-adjusted HHD prevalence, disability-adjusted life years (DALYs), mortality rates, and contributions of HHD risk factors with 95% uncertainty intervals (UIs). APC models were used to analyze global age, period, and cohort mortality trends for HHD. In 2019, 18.6 million prevalent HHD cases led to 1.16 million fatalities and 21.51 million DALYs. Age-adjusted rates were 233.8 (95%UI = 170.5-312.9) per 100,000 individuals for prevalence, 15.2 (11.2-16.7) for mortality, and 268.2 (204.6-298.1) for DALYs. Regionally, the Cook Islands (703.1), Jordan (561.6), and Kuwait (514.9) had the highest age-standardized incidence of HHD in 2019. There were significant increases in HHD prevalence in Andean Latin America (16.7%), western sub-Saharan Africa (5.6%), and eastern sub-Saharan Africa (4.6%). Mortality rate varied widely among countries. Risk factors like elevated systolic blood pressure and high body mass index significant influenced DALY rates, especially in females. The APC model revealed an association between mortality rates and age, with a decreasing mortality risk over time and improved survival rates for a later birth cohort. Despite the reduction in prevalence, HHD remains a significant public health issue, particularly in nations with low sociodemographic indices. To alleviate the impact of HHD, prevention efforts should concentrate on the management of hypertension, weight loss, and lifestyle improvement.

Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges.

We have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypertension-induced renal damage. We hypothesized that that effector memory cells that accumulate in the bone marrow respond to repeated salt challenges and can be reactivated and circulate to the kidney. Thus, to determine if mobilization of bone marrow that effector memory cells and secondary lymphoid organs contribute to the hypertensive response to delayed salt challenges, we employed fingolimod (FTY720), an S1PR1 functional antagonist by downregulating S1PR, which inhibits the egress of that effector memory cells used effectively in the treatment of multiple sclerosis and cardiovascular diseases. We exposed wild-type mice to the l-NAME for 2 weeks, followed by a wash-out period, a high salt diet feeding for 4 weeks, a wash-out period, and then a second high salt challenge with or without fingolimod. A striking finding is that that effector memory cell egress was dramatically attenuated from the bone marrow of mice treated with fingolimod with an associated reduction of renal that effector memory cells. Mice receiving fingolimod were protected from hypertension. We found that wild-type mice that received fingolimod during the second high salt challenge had a marked decrease in the renal damage markers. CD3+ T cell infiltration was significantly attenuated in the fingolimod-treated mice. To further examine the redistribution of bone marrow that effector memory cells in response to repeated hypertensive stimuli, we harvested the bone marrow from CD45.2 mice following the repeated high salt protocol with or without fingolimod; that effector memory cells were sorted and adoptively transferred (AT) to CD45.1 naïve recipients. Adoptively transferred that effector memory cells from mice treated with fingolimod failed to home to the bone marrow and traffic to the kidney in response to a high salt diet. We conclude that memory T cell mobilization contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension. Blocking the exodus of reactivated that effector memory cells from the bone marrow protects the kidney from hypertension-induced end-organ damage.

Hypertension and retinal microvascular dysfunction (HyperVasc): protocol of a randomised controlled exercise trial in patients with hypertension

IntroductionHypertension is a global healthcare burden that affects the structure and function of the macrocirculation and microcirculation and induces disease-specific end-organ damage. Vascular biomarkers are essential to timely diagnose this...

Cardiovascular protection by combination of the selective nonsteroidal MR antagonist finerenone and the SGLT2 inhibitor empagliflozin in a preclinical model of hypertension-induced end-organ damage

Abstract Background The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and SGLT2 inhibitors have demonstrated clinical benefits in HFrEF and CKD patients with T2D. Cardiovascular protection with finerenone and the SGLT2 inhibitor empagliflozin in combination in hypertensive cardiorenal disease is unknown. Purpose To test the hypothesis that the combination of finerenone with empagliflozin provides cardiovascular protection in preclinical hypertension-induced end-organ damage. Methods Cardiovascular morbidity and mortality was studied in hypertensive L-NAME (20 mg/L) treated renin-transgenic (mRen2)27 rats. Rats (10–11 weeks old female, n=13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Blood pressure (week 1, 3 and 5), urinary (week 2 and 6) and plasma parameters (week 6 and at the end of the study) were determined during the course of the study, while cardiac histology and left ventricular gene expression analysis were performed after study end. Results Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone co-administration in the combination arm. Treatment with 3 mg/kg finerenone and the low dose combination significantly decreased systolic blood pressure (SBP) after 3 and 5 weeks as well as plasma uric acid after 6 weeks. SBP was significantly more reduced in the combination arm vs. the individual monotherapies after 3 weeks. Plasma NT-proBNP was reduced by empagliflozin, finerenone and the combination with similar efficacy. There was a dose-dependent protection from cardiac vasculopathy, cardiac and vascular fibrosis with both agents while low dose combination therapy was more efficient than the respective monotherapy dosages on these cardiac histology parameters. Placebo-treated rats demonstrated a ca. 50% survival rate over the course of 7 weeks while low dose combination provided the most prominent survival benefit (93%). Conclusion Non-steroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer cardiovascular protection in preclinical hypertensive-induced cardiorenal disease. Combination of these two modes of action at low dosages revealed efficacious reduction in blood pressure, cardiac lesions and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

Effects of Finerenone Combined with Empagliflozin in a Model of Hypertension-Induced End-Organ Damage

Introduction: The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD patients with type 2 diabetes. Clinical data analyzing the potential value of a combination therapy are currently limited. We therefore investigated cardiorenal protection of respective mono- and combination therapy in a preclinical model of hypertension-induced end-organ damage. Methods: Cardiovascular (CV) morbidity and mortality were studied in hypertensive, N(ω)-nitro-L-arginine methyl ester-treated, renin-transgenic (mRen2)27 rats. Rats (10- to 11-week-old females, n = 13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, proteinuria, plasma creatinine and uric acid, blood pressure, and cardiac and renal histology. Results: Placebo-treated rats demonstrated a 50% survival rate over the course of 7 weeks. Drug treatment resulted in variable degrees of survival benefit, most prominently in the low-dose combination group with a survival benefit of 93%. Monotherapies of finerenone or empagliflozin dose-dependently reduced proteinuria, while low-dose combination revealed an early, sustained, and over-additive reduction in proteinuria. Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone coadministration in the combination arm. Low-dose combination but not respective low-dose monotherapies significantly reduced plasma creatinine and plasma uric acid after 6 weeks. Treatment with finerenone and the low-dose combination significantly decreased systolic blood pressure after 5 weeks. There was a dose-dependent protection from cardiac and kidney fibrosis and vasculopathy with both agents, while low-dose combination therapy was more efficient than the respective monotherapy dosages on most cardiorenal histology parameters. Discussion/Conclusions: Nonsteroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer CV protection in preclinical hypertension-induced cardiorenal disease. Combination of these 2 independent modes of action at low dosages revealed efficacious reduction in important functional parameters such as proteinuria and blood pressure, plasma markers including creatinine and uric acid, cardiac and renal lesions as determined by histopathology, and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations.

Could aortic arch calcification help in detection of hypertensive retinopathy?

Hypertension-induced end-organ damage is one of the important determinants of morbidity and mortality in patients with hypertension. All types of hypertension-induced end-organ damages start with vascular damage. Vascular calcification is a marker of vascular damage and aortic arch calcification (AAC) is one of the easily identifiable types of vascular calcification. We hypothesized that AAC predicts retinopathy in hypertensive patients. Consecutive hypertensive patients without diabetes mellitus were included. Chest radiography in the posterior-anterior was used to assess the presence of AAC. All patients underwent ophthalmologic examination for retinopathy. We included 495 hypertensive patients in this study. Of these, 306 (62%) had hypertensive retinopathy. Patients with hypertensive retinopathy had significantly higher prevalence of AAC as compared to the patients without hypertensive retinopathy (88% vs. 22%, P < 0.001). We found a strong and positive correlation between hypertensive retinopathy and AAC grades (r = 639, P < 0.001). Receiver operator characteristics curve analysis yielded a strong predictive ability of AAC for the presence of hypertensive retinopathy [area under curve = 0.814, 95% confidence interval (CI): 0.775-0.853, P < 0.0001]. In multivariate logistic regression analysis, presence of AAC [odds ratio (OR) 13.128; CI: 7.894-21.832] and serum glucose levels (OR 1.020; CI: 1.003-1.037) were strongly and independently associated with hypertensive retinopathy. Presence of AAC on chest radiograph is strongly and independently associated with retinopathy in nondiabetic hypertensive patients. This simple, inexpensive and widely available tool may help in early detection of retinopathy in patients with hypertension.

Abstract P133: Treating Hypertension With An Anti-inflammatory Formyl Peptide Receptor Agonist

Background: Inflammation can play an important role in the progression of hypertension and end organ damage, yet anti-inflammatory drugs remain relatively underexplored as antihypertensive therapeutic options. Formyl peptide receptors (FPR) are integral to the regulation and resolution of inflammation and may be an attractive target for the treatment of hypertension-induced end organ damage, especially given our previous observation that a small molecule FPR prototype molecule reduced cardiac inflammation and fibrosis in a model of myocardial infarction and exhibited vasodilator effects in isolated blood vessels. Objective: The aim of the present study is to determine whether Cmpd17b has antihypertensive and antifibrotic effects in a mouse model of spontaneous hypertension. Methods: Hypertensive BPH/2J (n=14) and normotensive BPN/3J mice (n=12) were treated daily with Cmpd17b (50mg/kg/day, i.p.) or vehicle (8% tween80 and 10% dimethyl sulfoxide in saline, i.p.) for 4 weeks. Mean arterial pressure (MAP) was measured via pre-implanted radiotelemetry probes at baseline and throughout the treatment period. Sirius red staining of left ventricle tissue was used as a marker of cardiac fibrosis. Results: MAP in BPH/2J mice was markedly greater than BPN/3J mice at baseline (126±2 vs 106±1mmHg respectively, P &lt;0.001). Cmpd17b resulted in a 6±1mmHg reduction in MAP from baseline in the BPH/2J mice ( P &lt;0.001), whereas MAP was unchanged from baseline in Cmpd17B treated BPN/3J mice (1±1mmHg, P =0.533) and vehicle treated BPH/2J mice (1±1mmHg, P =0.316). Collagen content in the left ventricle (%LV) was greater in vehicle treated BPH/2J compared with BPN/3J mice ( P &lt;0.05). BPH/2J mice treated with Cmpd17b had lower collagen content compared with vehicle treated BPH/2J (0.7±0.1 vs 1.2±0.2% respectively, P &lt;0.05) whereas collagen content was comparable in BPN/3J treated with Cmpd17b versus vehicle (0.5±0.1 vs 0.5±0.1%). Conclusion: These findings suggest that targeting FPR with the agonist Cmpd17b, has both antihypertensive and antifibrotic effects in hypertensive mice, thus supporting further assessment of FPR based therapeutics for the treatment of hypertension and end organ damage.

Abstract P160: Dual-Specificity Protein Phosphatase 5 Regulates Renal Vessel Myogenic Response via Direct Modulating Extracellular Signal-Related Kinase and Protein Kinase C

Dual-specificity protein phosphatase 5 (DUSP5) is a serine-threonine phosphatase that regulates intracellular signal transduction by dephosphorylating extracellular signal-related kinase (ERK1/2) and protein kinase C (PKC). We previously reported that knockout (KO) of Dusp5 enhanced the myogenic response and autoregulation of cerebral and renal circulation in association with increased levels of phosphorylated ERK1/2 (p-ERK1/2) and phosphorylated protein kinase C (p-PKC) in the vessels. However, the influence of increased levels of p-ERK1/2 and p-PKC on vascular function is unknown. This study investigated whether Dusp5 regulates myogenic reactivity of freshly isolated middle cerebral arteries (MCA, ~140 um), cerebral penetrating arteries (PA, ~15 um), renal arcuate arterioles (AA, ~ 50 um), and interlobular arterioles (IA, ~25 um) of Dusp5 KO and WT rats via inhibition of ERK1/2 and PKC. The myogenic reactivity of both cerebral and renal vasculature was compared at different perfusion pressure. The inner diameters of IA and AA decreased to 87.24 ± 0.76 % and 92.81 ± 2.90 %, respectively, in Dusp5 KO rats (n=4), but only to 99.70 ± 2.76 % and 98.85 ± 2.79 %, respectively, in WT rats (n=4) when perfusion pressure was increased from 60 to 180 mmHg. Similar results were found in MCA and PA. Inhibition of ERK1/2 with FR 180204 (1 uM) or PKC with BIM III (300 nM) diminished myogenic reactivity to a greater extent in cerebral and renal vessels of Dusp5 KO versus WT rats. These results indicate that downregulation of DUSP5 expression increases the myogenic reactivity of both cerebral and renal arteries (both large and small vessels) by increasing p-ERK1/2 and p-PKC levels. Targeting Dusp5 may offer a novel approach for preventing hypertension-induced end-organ damage.

Breeding Characteristics and Dose-dependent Blood Pressure Responses of Transgenic Cyp1a1-Ren2 Rats.

Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic male Cyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet, without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude (I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite being transgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependent hypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d), we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) in the diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ± 19 mm Hg after 3 mo, with no adverse phenotypic features observed. In conclusion, Cyp1a1-Ren2 rats are a useful animal model to investigate hypertension-induced end-organ damage and potential new therapeutic targets to manage hypertension.

Cerebrovascular gene expression in spontaneously hypertensive rats.

Hypertension is a hemodynamic disorder and one of the most important and well-established risk factors for vascular diseases such as stroke. Blood vessels exposed to chronic shear stress develop structural changes and remodeling of the vascular wall through many complex mechanisms. However, the molecular mechanisms involved are not fully understood. Hypertension-susceptible genes may provide a novel insight into potential molecular mechanisms of hypertension and secondary complications associated with hypertension. The aim of this exploratory study was to identify gene expression differences in the middle cerebral arteries between 12-week-old male spontaneously hypertensive rats and their normotensive Wistar-Kyoto rats using an Affymetrix whole-transcriptome expression profiling. Quantitative PCR and western blotting were used to verify genes of interest. 169 genes were differentially expressed in the middle cerebral arteries from hypertensive compared to normotensive rats. The gene expression of 72 genes was decreased and the gene expression of 97 genes was increased. The following genes with a fold difference ≥1.40 were verified by quantitative PCR; Postn, Olr1, Fas, Vldlr, Mmp2, Timp1, Serpine1, Mmp11, Cd34, Ptgs1 and Ptgs2. The gene expression of Postn, Olr1, Fas, Vldlr, Mmp2, Timp1 and Serpine1 and the protein expression of LOX1 (also known as OLR1) were significantly increased in the middle cerebral arteries from spontaneously hypertensive rats compared to Wistar-Kyoto rats. In conclusion, the identified genes in the middle cerebral arteries from spontaneously hypertensive rats could be possible mediators of the vascular changes and secondary complications associated with hypertension. This study supports the selection of key genes to investigate in the future research of hypertension-induced end-organ damage.

Evaluating the significance of hypoglycemia in promoting insulin induced hypertension by using a glucose clamp model

Background: Hypoglycemia unawareness is a detrimental risk factor in diabetic patients leading to serious complications if left untreated. Previous studies from our group determined that recurrent insulin induced hypoglycemia (RIIH) promotes hypertension.Objective: We hypothesize that RIIH not insulin by itself is the source of hypertension and end organ damage in diabetic patients.Methods: Male Sprague-Dawley-rats (200-250g, n=18) were provided with glucose food (125g glucose/kg body weight) and glucose water (0.1g glucose/100g body weight/ml). They were treated with subcutaneous insulin injections (7U/Kg) and blood glucose was monitored intermittently. Daily blood pressure was measured using the tail cuff method. Interstitial samples of ATP and angiotensinII (AngII) were collected by renal microdialysis and analyzed using luciferin-luciferase bioluminescent assay and EIA respectively. Reactive oxygen and nitrogen species in hearts and kidneys were analyzed using Electron Paramagnetic Resonance Spectroscopy (EPR).Results: Renal interstitial ATP levels increased from 90.2± 4.7ng/µl to 99.6± 8.7ng/µl (not significant) and AngII from 0.15± 0.02ng/ml to 0.13± 0.05ng/ml (not significant) from day 0 to 14. There was no significant change in mean arterial pressure (121.3 ± 1.4 mmHg on day 0 to 127.8 ± 1.4mmHg on day 14). Oxidative stress was reduced compared to RIIH model, which was evident from the EPR spectra.Conclusion: We demonstrated that hypertension induced end organ damage in diabetics is due to insulin induced hypoglycemia not insulin alone (by itself).

End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899.

To compare the therapeutic efficacy of SAR407899 with the current standard treatment for hypertension [an angiotensin converting enzyme (ACE)-inhibitor and a calcium channel blocker] and compare the frequency and severity of the hypertension-related end-organ damage. Long-term pharmacological characte-rization of SAR407899 has been performed in two animal models of hypertension, of which one is sensitive to ACE-inhibition (LNAME) and the other is insensitive [deoxycorticosterone acetate (DOCA)]. SAR407899 efficiently lowered high blood pressure and significantly reduced late-stage end organ damage as indicated by improved heart, kidney and endothelial function and reduced heart and kidney fibrosis in both models of chronic hypertension. Long term treatment with SAR407899 has been well tolerated and dose-dependently reduced elevated blood pressure in both models with no signs of tachyphylaxia. Blood pressure lowering effects and protective effects on hypertension related end organ damage of SAR407899 were superior to ramipril and amlodipine in the DOCA rat. Typical end-organ damage was significantly reduced in the SAR407899-treated animals. Chronic administration of SAR407899 significantly reduced albuminuria in both models. The beneficial effect of SAR407899 was associated with a reduction in leukocyte/macrophage tissue infiltration. The overall protective effect of SAR407899 was superior or comparable to that of ACE-inhibition or calcium channel blockade. Chronic application of SAR407899 protects against hypertension and hypertension-induced end organ damage, regardless of the pathophysiological mechanism of hypertension. Rho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications.

Angiotensin-(1-7) prevents angiotensin II-induced fibrosis in cremaster microvessels.

The effect of the heptapeptide hormone Ang-(1-7) on microvascular fibrosis in rats with Ang II-induced hypertension was investigated, since vascular fibrosis/remodeling plays a prominent role in hypertension-induced end-organ damage and Ang-(1-7) inhibits vascular growth and fibrosis. Fibrosis of cremaster microvessels was studied in male Lewis rats infused with Ang II and/or Ang-(1-7). Ang II elevated systolic blood pressure by approximately 40mmHg, while blood pressure was not changed by Ang-(1-7). Ang II increased perivascular fibrosis surrounding 20-50μm arterioles as well as interstitial fibrosis; coadministration of Ang-(1-7) prevented the increases in fibrosis. The fibrotic factor CTGF and phospho-Smad 2/3, which upregulates CTGF, were increased by Ang II; this effect was prevented by coadministration of Ang-(1-7). Although TGF-β phosphorylates Smad 2/3, TGF-β was no different among treatment groups. In contrast, Ang II increased the MAP kinase phospho-ERK1/2, which also phosphorylates Smad; p-ERK was reduced by Ang-(1-7). Ang-(1-7), in the presence or absence of Ang II, upregulated the MAP kinase phosphatase DUSP1. These results suggest that Ang-(1-7) increases DUSP1 to reduce MAP kinase/Smad/CTGF signaling and decrease fibrosis in resistance arterioles, to attenuate end-organ damage associated with chronic hypertension.

New antihypertensive drugs under development.

Hypertension is the most common cardiovascular disease and remains the most prevalent risk factor for cardiovascular diseases and a major cause of death worldwide. Despite the large number of antihypertensive drugs available, in the majority of patients blood pressure still remains not optimally controlled and persists at high risk of cardiovascular complications. The limitations of current therapies have stimulated the research and development of new classes of antihypertensive agents, with different mechanisms of action, that provide a better blood pressure control, greater protection against organ damage, better tolerability and more effective prevention of cardiovascular diseases. However, essential hypertension is a multifactorial and multigenic disorder, which means that various mechanisms contribute to a greater or lesser extent to increase BP. Recent advances in the understanding of the multiple and complex cellular signalling pathways that modulate vascular smooth muscle cell contraction and growth involved in the regulation of vascular tone and in hypertension-induced end-organ damage have provided valuable insight in identifying new therapeutic targets. This article reviews new antihypertensive drugs under development, focusing on their mechanisms of action and possible advantages compared with traditional drugs.

Hypertension in children, not a “small” problem

Hypertension in children, not a “small” problem

Abstract 465: The CB2 Cannabinoid Receptor Mediates the Anti-Proliferative Actions of Angiotensin-(1-7) in Vascular Smooth Muscle Cells

Therapeutic interventions to reduce vascular proliferation are critical for the effective treatment of hypertension-induced end-organ damage, restenosis and atherosclerosis. We showed that angiotensin-(1-7) [Ang-(1-7)] reduces neointimal formation following vascular injury and inhibits vascular growth, through activation of the AT7 receptor mas and production of arachidonic acid derivatives. Endocannaboids (ECs) derived from membrane phospholipids also inhibit vascular proliferation and reduce growth following vascular injury, by stimulation of the CB2 receptor. The impact of CB2 receptor blockade on the anti-proliferative actions of Ang-(1-7) was investigated to assess a potential interaction between the EC and Ang-(1-7)/mas receptor systems. Rat thoracic aortic vascular smooth muscle cells (VSMCs) were treated with platelet-derived growth factor (PDGF) to stimulate growth and incubated with Ang-(1-7), the AT7 receptor antagonist [D-alanine7]-angiotensin-(1-7) [Dala], the CB2 receptor agonist HU308 and/or the CB2 receptor antagonist AM630. PDGF-stimulated VSMC growth was markedly reduced by Ang-(1-7) (74 ± 6% of control, n = 10, p&lt;0.0001) and this effect was blocked by Dala (116 ± 14% of control, n = 4; n.s.). The Ang-(1-7)-mediated reduction in growth was abolished by the CB2 receptor antagonist AM630 (136 ± 16% of control, n = 4; n.s.); AM630 alone had no effect. In contrast, the CB1 receptor antagonist AM281 did not prevent the inhibitory actions of Ang-(1-7) on VSMC growth. CB2 receptor activation by the agonist HU308 also reduced PDGF-stimulated VSMC proliferation to a similar extent as Ang-(1-7) (67 ± 4% of control, n = 5, p&lt;0.001); Dala did not influence the response to HU308 (50 ± 10% of control, n = 5, p&lt;0.005). Ang-(1-7) significantly increased the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) by 48% in VSMC by 24 h (p&lt;0.05, n = 4). We conclude that the growth inhibitory properties of Ang-(1-7) involve a novel pathway culminating in the downstream formation of 2-AG and subsequent activation of the CB2 receptor in VSMC. Thus, Ang-(1-7) and/or CB2 receptor activation may constitute a new and beneficial therapeutic strategy for the prevention of vascular proliferation that is prevalent in cardiovascular disease.

Dimethylarginine Dimethylaminohydrolase1 Is an Organ-Specific Mediator of End Organ Damage in a Murine Model of Hypertension

BackgroundThe endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Moreover, elevated ADMA plasma concentrations are associated with the extent of hypertension. However, data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension.Methodology/Principal FindingsTherefore, we investigated the role of ADMA and DDAH1 in hypertension-induced end organ damage using the uninephrectomized, deoxycorticosterone actetate salt, and angiotensin II-induced hypertension model in human DDAH1 (hDDAH1) overexpressing and wild-type (WT) mice. ADMA plasma concentrations differed significantly between hDDAH1 and WT mice at baseline, but did not significantly change during the induction of hypertension. hDDAH1 overexpression did not protect against hypertension-induced cardiac fibrosis and hypertrophy. In addition, the hypertension-induced impairment of the endothelium-dependent vasorelaxation of aortic segments ex vivo was not significantly attenuated by hDDAH1 overexpression. However, hDDAH1 mice displayed an attenuated hypertensive inflammatory response in renal tissue, resulting in less hypertensive renal injury.Conclusion/SignificanceOur data reveal that hDDAH1 organ-specifically modulates the inflammatory response in this murine model of hypertension. The lack of protection in cardiac and aortic tissues may be due to DDAH1 tissue selectivity and/or the extent of hypertension by the used combined model. However, our study underlines the potency of hDDAH1 overexpression in modulating inflammatory processes as a crucial step in the pathogenesis of hypertension, which needs further experimental and clinical investigation.

Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress.

Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested the hypothesis that the cardiovascular protective effects of NO-insensitive sGC activation would be potentiated under conditions of oxidative stress compared to those of NO-sensitive sGC stimulation. The cardiovascular effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor dose, and a high dose which lowered mean arterial pressure (MAP) by 5–10 mmHg] and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 60-4552 were assessed in (1) Sprague Dawley rats during coronary artery ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats (SHR-SP) on a high salt/fat diet (HSFD). In I/R, neither compound reduced infarct size 24 h after reperfusion. In SHR-SP, HSFD increased MAP, urine output, microalbuminuria, and mortality, caused left ventricular hypertrophy with preserved ejection fraction, and impaired endothelium-dependent vasorelaxation. The low dose of BAY 60-4552, but not that of GSK2181236A, decreased urine output, and improved survival. Conversely, the low dose of GSK2181236A, but not that of BAY 60-4552, attenuated the development of cardiac hypertrophy. The high doses of both compounds similarly attenuated cardiac hypertrophy and improved survival. In addition to these effects, the high dose of BAY 60-4552 reduced urine output and microalbuminuria and attenuated the increase in MAP to a greater extent than did GSK2181236A. Neither compound improved endothelium-dependent vasorelaxation. In SHR-SP isolated aorta, the vasodilatory responses to the NO-dependent compounds carbachol and sodium nitroprusside were attenuated by HSFD. In contrast, the vasodilatory responses to both GSK2181236A and BAY 60-4552 were unaltered by HSFD, indicating that reduced NO-bioavailability and not changes in the oxidative state of sGC is responsible for the vascular dysfunction. In summary, GSK2181236A and BAY 60-4552 provide partial benefit against hypertension-induced end-organ damage. The differential beneficial effects observed between these compounds could reflect tissue-specific changes in the oxidative state of sGC and might help direct the clinical development of these novel classes of therapeutic agents.

Non-peptide AT2-receptor agonists

The renin-angiotensin-system harbours two main receptor subtypes binding angiotensin II which are the AT1-receptor and the AT2-receptor. While the AT1-receptor has been a drug target in cardiovascular disease for many years, the AT2-receptor was only a subject of academic interest. This has changed with the design and synthesis of a first non-peptide, orally active AT2-receptor agonist, compound 21 (C21). First data using C21 revealed tissue protective effects and functional improvement after myocardial infarction and in hypertension-induced end organ damage, notably in a blood-pressure independent way. In all of these models, AT2-receptor mediated anti-inflammation seemed an important underlying mechanism. C21 is awaited to enter a phase I clinical study in 2011.