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

Julia Vogel,Katharina Andrea Schütt,Wilfried Dinh,Jörg Hüser,Thomas Mondritzki,Susanne Homann,Hubert Truebel,Jakob Balitzki,Katharina Boden,Peter Sandner,Mario Boehm,Philip Boehme

doi:10.1038/s41440-021-00748-5

Abstract

Therapy-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.

Highlights

Hypertension (HTN) is the most common risk factor for cardiovascular (CV) events such as stroke or heart failure [1]
We employed a dog model based on severe renal impairment and concomitant sterile inflammation through renal wrapping (RW) combined with renal artery occlusion (RAO)
Three weeks after RW, animals developed a significant rise in mean BP (MBP) of +21.5 ± 8.3 mmHg on average

Summary

Introduction

Hypertension (HTN) is the most common risk factor for cardiovascular (CV) events such as stroke or heart failure [1]. HTN was recently defined as systolic BP over 140 mmHg and diastolic BP over 90 mmHg, and patients with BP above these values should be treated [3] To reach these treatment goals, a combination of different antihypertensive medications has proven to be most beneficial for patients, ~60% are not adequately treated [4]. ESH/ESC guidelines define resistance to treatment if a therapy includes appropriate lifestyle measures, two different classes of antihypertensive drugs and a diuretic, all at adequate doses. If this regimen fails to lower systolic BP (SBP) and diastolic BP (DBP) to

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