sGC stimulation lowers elevated blood pressure in a new canine model of resistant hypertension

AbstractTherapy-resistant hypertension is a serious medical problem, causing end-organ damage, stroke, and heart failure if untreated. Since the standard of care fails in resistant hypertension patients, there is still a substantial unmet medical need for effective therapies. Active stimulation of soluble guanylyl cyclase via novel soluble guanylyl cyclase stimulators might provide an effective treatment option. To test this hypothesis, we established a new experimental dog model and investigated the effects of the soluble guanylyl cyclase-stimulator BAY 41-2272. In beagle dogs, a resistant hypertension phenotype was established by combining unilateral renal wrapping with the occlusion of the renal artery in the contralateral kidney. The most frequently used antihypertensive drugs were administered orally, either alone or in combination, and their acute effect on telemetric measured blood pressure was assessed and compared with that of BAY 41-2272. The chosen disease stimulus led to a moderate and stable increase in blood pressure. Even high doses of standard-of-care antihypertensives only slightly decreased blood pressure. In contrast, the administration of the soluble guanylyl cyclase stimulator BAY 41-2272 as standalone therapy led to a dose-dependent reduction in blood pressure (−14.1 ± 1.8 mmHg). Moreover, BAY 41-2272 could also further decrease blood pressure in addition to a triple combination of standard-of-care antihypertensives (−28.6 ± 13.2 mmHg). BAY 41-2272 was highly efficient as a standalone treatment in resistant hypertension but was also effective in addition to standard-of-care treatment. These data strongly suggest that soluble guanylyl cyclase stimulators might provide an effective pharmacologic therapy for patients with resistant hypertension.

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Improvement of Blood Pressure Control by Adherence Check in Patients With Apparent Treatment-Resistant Hypertension: A Case Series

Clinical Medicine Insights Case Reports ◽

10.1177/1179547620904884 ◽

2020 ◽

Vol 13 ◽

pp. 117954762090488

Author(s):

Keiko Hosohata ◽

Ayaka Inada ◽

Saki Oyama ◽

Takashi Doi ◽

Iku Niinomi ◽

...

Keyword(s):

Blood Pressure ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Case Series ◽

Pressure Control ◽

Supporting Evidence ◽

Treatment Resistant ◽

Uncontrolled Blood Pressure ◽

Important Challenge ◽

Prescribed Medicines

Adherence to medications is an important challenge while treating chronic disease such as resistant hypertension, which is defined as uncontrolled blood pressure (BP) despite treatment with more than 3 antihypertensive drugs to achieve targets. It is possible that poor adherence is the most significant contributor to rates of pseudo-resistance among treated hypertensive patients. In this report, we describe 4 patients with apparent treatment-resistant hypertension, who received intervention to promote adherence by pharmacists who set the prescribed medicines in a weekly medication calendar and conducted a weekly pill count. The results showed that the intervention of pharmacists to medication adherence improved systolic BP in patients with apparent treatment-resistant hypertension; however, further controlled trials are required to strengthen supporting evidence.

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Resistant Hypertension: A Real Entity Requiring Special Treatment?

European Cardiology Review ◽

10.15420/ecr.2016.11.1 ◽

2016 ◽

Vol 11 (1) ◽

pp. 8

Author(s):

Stefano Taddei ◽

Rosa Maria Bruno ◽

◽

Keyword(s):

Blood Pressure ◽

Resistant Hypertension ◽

Renal Denervation ◽

Antihypertensive Drugs ◽

Pressure Control ◽

Clinical Situation ◽

Special Treatment ◽

Separate Clinical Entity ◽

Real Entity ◽

Definition Of

Resistant hypertension (RH) was defined many years ago as a clinical situation in which blood pressure remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses. This operative definition was aimed at identifying a subset of hypertensive patients requiring a more extensive clinical workup in order to achieve an adequate blood pressure control. An oversimplification of this picture led to consider RH as a separate clinical entity requiring special, expensive treatments, such as renal denervation and baroreceptor activating therapy. In this review we will discuss the utility and the shortcomings of the definition of RH and the possible consequences for treatment.

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Non-pharmacological methods in the treatment of resistant hypertension

Folia Medica ◽

10.2478/v10153-011-0081-y ◽

2012 ◽

Vol 54 (2) ◽

pp. 5-12 ◽

Cited By ~ 2

Author(s):

Kostadin N. Kichukov ◽

Hristo V. Dimitrov ◽

Lora K. Nikolova ◽

Ivo S. Petrov ◽

Maria P. Tokmakova

Keyword(s):

Blood Pressure ◽

Resistant Hypertension ◽

Renal Denervation ◽

Antihypertensive Drugs ◽

Adult Population ◽

Clinical Problem ◽

Renal Sympathetic Denervation ◽

Great Promise ◽

Long Term Effects ◽

Blood Pressure Targets

ABSTRACT INTRODUCTION: Arterial hypertension is the most common chronic cardiovascular disease affecting about 25% of the adult population. Meta-analyses have demonstrated a linear relationship between blood pressure and the risk of cardiovascular events. Resistant hypertension defined as failure to reach blood pressure targets despite treatment with three antihypertensive drugs including a diuretic represents a serious clinical problem. It has been estimated that it affects between 8.9% and 12.8% of all treated hypertensive subjects. In resistant hypertension the optimal blood pressure is illusive despite very well tailored therapy. OBJECTIVE: Management of resistant hypertension is exactly the fi eld where blood pressurecontrolling non-pharmacological methods fi t best. The present article aims at throwing light on these methods’ principles of action, on who the target patient groups are and the respective results. Two methods are especially reviewed here: the carotid barorefl ex stimulation and the transcatheter renal sympathetic denervation. Current results from the use of renal denervation suggest stable effi ciency of the method, the results becoming signifi cant 6 months after the procedure is applied and sustained for two years in the follow-up. As much as 90% of the treated patients respond to the procedure. The transcatheter renal denervation is associated with only 2.61% of procedural complications. The barorefl ex carotid stimulation, too, is known to produce a stable effect on blood pressure: the effect become obvious at 12 months in 88% of the treated subjects. The neurologic complications associated with the procedure are reported to occur in 4.4% of cases. CONCLUSION: The present review article clearly demonstrates that non-pharmacological methods for treatment of resistant hypertension show great promise despite some open questions concerning their long term effects and procedural safety.

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Predictors of blood pressure response after renal denervation beyond pretreatment blood pressure

European Heart Journal ◽

10.1093/eurheartj/ehab724.2379 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

R Schmieder ◽

C Delles ◽

L Lauder ◽

C Ott ◽

M Boehm ◽

...

Keyword(s):

Blood Pressure ◽

Resistant Hypertension ◽

Renal Denervation ◽

Antihypertensive Drugs ◽

Blood Pressure Response ◽

Methodological Approach ◽

Large Degree ◽

Initial Value ◽

Study Population ◽

Pre Treatment

Abstract Background The principle of initial value (Wilder's law of initial value) proposes that the “direction of response of body function to any agent depends to a large degree on the initial value of that function”. Indeed, in several trials on renal denervation (RDN), pre-treatment blood pressure (BP) has been consistently and repeatedly found to predict the decrease in BP after RDN. Efforts to discover further statistically significant and clinically meaningful predictors of BP response to RDN failed. Objective By use of a new methodological approach, we aimed to determine predictors of BP response after RDN in patients with resistant hypertension. Methods The study population comprised 266 patients with resistant hypertension (mean age 62 years, 34% females, mean BMI 30.5 kg/m2, 27% had coronary heart disease, 42% had diabetes mellitus and 61% had hypercholesterolaemia) who underwent radiofrequency RDN with the Symplicity catheter at the Universities of Homburg and Erlangen. Clinical data including 24h ambulatory BP (ABP) were obtained prior to, and 3, 6 and 12 months after RDN. The primary parameter of response was defined as change in 24-hour systolic ABP after 6 months from pre-treatment values. As expected, change in 24h systolic ABP correlated with pre-treatment 24h systolic ABP (r2 linear = 0.225, p<0.001), with change in 24h systolic ABP = 73.82 + 0.55 x pre-treatment 24h systolic ABP. To overcome the predominant role of the pre-treatment BP that may mask other factors, we calculated for each individual patient the “expected systolic ABP decrease” by applying this regression equation and the “excessive systolic ABP decrease” by subtracting the measured from expected change in 24h systolic ABP. We divided the study population into 2 groups (above [responders] and below [non-responders] of the median change in excessive 24h systolic ABP. Results Neither pre-treatment 24h systolic or diastolic ABP, nor office systolic or diastolic BP differed between the two groups (all p>0.20). Following RDN, 24h systolic ABP decreased in the responders by −23.3±16 vs non-responders +1.4±11 mmHg at 6 month, and 24h systolic ABP values were also significantly lower in responders at 3 and 12 months (all p<0.001), without difference in number of antihypertensive drugs between the groups. Of all clinical variables at baseline, office heart rate (65.6 vs 68.7±12 bpm, p=0.024) and HbA1c (6.07±0.88 vs. 6.37±1.23%, p=0.035) were lower in responders compared with non-responders. Finally, a multiple regression analysis confirmed that pre-treatment 24h systolic ABP (beta +0.565, p<0001), HbA1c (beta −0.167, p=0.004) and office HR (beta +0.106, p=0.057) were independent predictors of decrease in 24h systolic ABP. Conclusion In patients with resistant hypertension, lower HbA1c and office HR were identified as predictors of BP response in addition to pre-treatment BP. This finding may help to identify hypertensive patients who benefit most from RDN. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Extramural grant provided vy Medtronic INc

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Empagliflozin for Patients With Presumed Resistant Hypertension: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial

American Journal of Hypertension ◽

10.1093/ajh/hpaa073 ◽

2020 ◽

Cited By ~ 3

Author(s):

João Pedro Ferreira ◽

David Fitchett ◽

Anne Pernille Ofstad ◽

Bettina Johanna Kraus ◽

Christoph Wanner ◽

...

Keyword(s):

Blood Pressure ◽

Resistant Hypertension ◽

Repeated Measures ◽

Cox Regression ◽

Antihypertensive Drugs ◽

Target Organ Damage ◽

Organ Damage ◽

Cardiac Events ◽

Post Hoc Analysis ◽

Post Hoc

Abstract BACKGROUND Type 2 diabetes (T2D) and resistant hypertension often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676). METHODS Overall, 7,020 patients received empagliflozin 10, 25 mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs including a diuretic and uncontrolled blood pressure (BP; systolic blood pressure (SBP) ≥140 and/or diastolic blood pressure ≥90 mm Hg) or ≥4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on cardiovascular (CV) death, heart failure (HF) hospitalization, 3-point major adverse cardiac events, all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis. RESULTS 1,579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 vs. placebo was −4.5 (95% confidence interval, −5.9 to −3.1) mm Hg (P < 0.001) in prHT and −3.7 (−4.5, −2.9) mm Hg (P < 0.001) in patients without prHT. SBP was more frequently controlled (<130/80 mm Hg) with empagliflozin than with placebo. Patients with prHT had 1.5- to 2-fold greater risk of HF hospitalization, incident/worsening nephropathy, and CV death compared with those without prHT. Empagliflozin improved all outcomes in patients with and without prHT (interaction P > 0.1 for all outcomes). CONCLUSIONS Empagliflozin induced a clinically relevant reduction in SBP and consistently improved all outcomes regardless of prHT status. Due to these dual effects, empagliflozin should be considered for patients with hypertension and T2D.

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Abstract 13181: Characteristics of Diurnal Change of Pulse Rate in Resistant Hypertension

Circulation ◽

10.1161/circ.130.suppl_2.13181 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Hiroaki Watanabe ◽

Tomoyuki Kabutoya ◽

Satoshi Hoshide ◽

Kazuo Eguchi ◽

Kazuomi Kario

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Autonomic Nervous System ◽

Pulse Rate ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Blood Pressure Monitoring ◽

Hazard Ratio ◽

Diurnal Change ◽

Autonomic Nervous

Introduction: Sympathetic hyperactivity is one of the most important causes of resistant hypertension. Ambulatory blood pressure monitoring (ABPM) allows measurement of blood pressure (BP) and pulse rate (PR) throughout the day, as well as measurement of diurnal variations in BP and PR, which are controlled by the autonomic nervous system. Hypothesis: We hypothesized that abnormal diurnal change of BP and PR are associated with resistant hypertension. Methods: We evaluated 1003 patients with hypertension who were enrolled in the Japan Morning Surge Home Blood Pressure Study and were using ABPM. Resistant hypertension was defined as clinic BP≧140/90 mmHg despite the use of optimal doses of 3 classes of antihypertensive drugs, including a diuretic. BP or PR dipper status was defined as (awake systolic BP (SBP) or PR-sleep SBP or PR)/awake SBP or PR ≧0.1. BP or PR nondipper status was defined as (awake SBP or PR-sleep SBP or PR)/awake SBP or PR <0.1 and ≧0. BP and PR riser status were defined as awake SBP or PR < sleep SBP or PR. Results: The numbers of PR nondippers and PR risers in the resistant hypertensive groups were significantly greater than those in the non-resistant hypertensive groups (x2=9.35, p=0.009), but there were no significant differences in the diurnal variation of BP between the resistant hypertensive and non-resistant hypertensive groups (x2=3.10, p=0.21). In the resistant hypertensive groups, the proportion of PR risers was approximately three-fold greater than that in the non-resistant hypertensive groups after adjustment for age, gender, 24-h BP, PR, and BP variation (Hazard ratio 2.94, 95%Cl 1.25-6.91, p=0.013), but there were no significant differences in the proportion of PR nondippers (Hazard ratio 1.36, 95%Cl 0.82-2.26, p=0.23). Conclusions: A riser pattern of PR was associated with resistant hypertension. ABPM may be useful to identify resistant hypertensive patients who have autonomic nervous system dysfunction.

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Controlling resistant hypertension

Stroke and Vascular Neurology ◽

10.1136/svn-2017-000138 ◽

2018 ◽

Vol 3 (2) ◽

pp. 69-75 ◽

Cited By ~ 7

Author(s):

J David Spence

Keyword(s):

Blood Pressure ◽

Blood Pressure Control ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Renal Hypertension ◽

Pressure Control ◽

Uncontrolled Hypertension ◽

Aldosterone Antagonists ◽

Improve Blood Pressure Control ◽

Blood Pressures

Resistant hypertension (failure to achieve target blood pressures with three or more antihypertensive drugs including a diuretic) is an important and preventable cause of stroke. Hypertension is highly prevalent in China (>60% of persons above age 65), and only ~6% of hypertensives in China are controlled to target levels. Most strokes occur among persons with resistant hypertension; approximately half of strokes could be prevented by blood pressure control. Reasons for uncontrolled hypertension include (1) non-compliance; (2) consumption of substances that aggravated hypertension, such as excess salt, alcohol, licorice, decongestants and oral contraceptives; (3) therapeutic inertia (failure to intensify therapy when target blood pressures are not achieved); and (4) diagnostic inertia (failure to investigate the cause of resistant hypertension). In China, an additional factor is lack of availability of appropriate antihypertensive therapy in many healthcare settings. Sodium restriction in combination with a diet similar to the Cretan Mediterranean or the DASH (Dietary Approaches to Stop Hypertension) diet can lower blood pressure in proportion to the severity of hypertension. Physiologically individualised therapy for hypertension based on phenotyping by plasma renin activity and aldosterone can markedly improve blood pressure control. Renal hypertension (high renin/high aldosterone) is best treated with angiotensin receptor antagonists; primary aldosteronism (low renin/high aldosterone) is best treated with aldosterone antagonists (spironolactone or eplerenone); and hypertension due to overactivity of the renal epithelial sodium channel (low renin/low aldosterone; Liddle phenotype) is best treated with amiloride. The latter is far more common than most physicians suppose.

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Acute blood pressure effects of YC-1-induced activation of soluble guanylyl cyclase in normotensive and hypertensive rats

British Journal of Pharmacology ◽

10.1038/sj.bjp.0703320 ◽

2000 ◽

Vol 130 (2) ◽

pp. 205-208 ◽

Cited By ~ 42

Author(s):

Lars Rothermund ◽

Andreas Friebe ◽

Martin Paul ◽

Doris Koesling ◽

Reinhold Kreutz

Keyword(s):

Blood Pressure ◽

Guanylyl Cyclase ◽

Soluble Guanylyl Cyclase ◽

Pressure Effects ◽

Hypertensive Rats ◽

Blood Pressure Effects

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RESISTANT HYPERTENSION IN TYPE 2 DIABETES: PREVALENCE AND PATIENT CHARACTERISTICS

Medicine and Pharmacy Reports ◽

10.15386/cjmed-441 ◽

2015 ◽

Vol 88 (3) ◽

pp. 327-332

Author(s):

Dana Mihaela Ciobanu ◽

Hélène Kilfiger ◽

Bogdan Apan ◽

Gabriela Roman ◽

Ioan Andrei Veresiu

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Resistant Hypertension ◽

Enzyme Inhibitors ◽

Antihypertensive Drugs ◽

Angiotensin Converting Enzyme Inhibitors ◽

Angiotensin Ii Receptors ◽

Converting Enzyme Inhibitors ◽

Β Blockers

Background and aims. Resistant hypertension is defined as failure to achieve blood pressure lower than 140/90 mmHg when using three antihypertensive agents or controlled blood pressure with four or more drugs. We aimed at assessing the prevalence of resistant hypertension and to describe a type 2 diabetes population with resistant hypertension.Methods. The retrospective observational study included (n=73) type 2 diabetes subjects with resistant hypertension selected from (n=728) subjects admitted to the Centre of Diabetes, Cluj, Romania. Results. The subjects (70% women) had a mean age of 65.0±8.9 yrs. and diabetes duration 11(6-19) yrs. Prevalence of resistant hypertension was 10%. Chronic diabetes complications and cardiovascular disease were present in 77% and 56% of subjects respectively. On admission, antihypertensive drugs used were: angiotensin-converting enzyme inhibitors or angiotensin II receptors blockers 93%, β-blockers 88%, diuretics 78%, calcium channels blockers 59%, adrenergic α-antagonists 11%. Systolic and diastolic blood pressure were lower in the last compared to first admission day. Diuretics and calcium channels blockers were the most frequently newly added antihypertensive agents.Conclusion. Although the prevalence of resistant hypertension in type 2 diabetes did not differ from the general population, we observed that these patients had increased frequency of chronic diabetic complications. Angiotensin-converting enzyme inhibitors or angiotensin II receptors and β-blockers were the most used antihypertensive drugs, while the most frequently newly prescribed drugs were diuretics and calcium channel blockers.

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Resistant hypertension: a review

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20213252 ◽

2021 ◽

Vol 8 (9) ◽

pp. 1433

Author(s):

Anant Parasher ◽

Rajat Jhamb

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Resistant Hypertension ◽

Alcohol Intake ◽

Antihypertensive Drugs ◽

Patient Adherence ◽

Dietary Sodium ◽

Lifestyle Modifications ◽

Refractory Hypertension ◽

Uncontrolled Blood Pressure

Resistant hypertension is currently defined as uncontrolled blood pressure despite the use of optimal doses of three antihypertensive medications, of which one is a diuretic. Several factors have been identified as contributors to resistant hypertension such as poor patient adherence, physician inertia, inadequate doses or inappropriate combinations of antihypertensive drugs, excess alcohol intake, certain drugs and volume overload. Uncontrolled blood pressure is a considerable cardiovascular and neurological risk factor that can lead to possible end-organ consequences of untreated hypertension, including heart failure, stroke, ischemic heart disease and renal failure. A comprehensive history and physical examination are essential for pointing towards to an underlying diagnosis. A PubMed search was conducted for review articles and papers from 1955 to 2019 containing the keywords ‘resistant hypertension’, ‘secondary hypertension’, ‘refractory hypertension’, ‘heart failure’ and ‘stroke’, and the literature was compiled. Non-pharmacological measures chiefly include lifestyle modifications such as smoking cessation, reduction in alcohol intake, dietary sodium restriction, healthy eating plans, increased physical activity and weight loss. Among recommended drugs, spironolactone and beta blockers are the preferred fourth- and fifth-line drugs respectively, in patients unresponsive to ACE Inhibitors, calcium channel blockers as well as diuretics. Although most patients are well controlled on extended drug regimes, some develop refractory hypertension which does not even respond to the five-drug regimen. Interventional therapies such as renal denervation and carotid sinus stimulation have been developed for patients with refractory hypertension, but still require further research and follow up to ascertain their full potency and efficacy.

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