Hypertension (HTN) is a leading risk factor for cardiovascular events. While combination therapies are beneficial, approximately 60% of patients are inadequately treated, and a growing population exhibits therapy-resistant hypertension (rHTN). rHTN is defined as persistently elevated blood pressure despite treatment with at least three antihypertensive agents from different classes. Current treatments for rHTN, including alpha-blockers, direct renin inhibitors, and mineralocorticoid receptor antagonists, have limitations. The nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cGMP pathway plays a crucial role in regulating vascular tone. sGC stimulators, a novel class of drugs, enhance sGC activity and synergize with endogenous NO. Riociguat, an sGC stimulator, is approved for pulmonary hypertension. Studies suggest that sGC stimulators like BAY 41-2272 reduce blood pressure. This study aimed to create a canine model of rHTN and investigate the efficacy of the sGC stimulator BAY 41-2272 as both a standalone and adjunctive therapy.

The literature extensively documents the prevalence and challenges of treating resistant hypertension. Studies highlight the inadequacy of current treatment strategies and the need for novel therapeutic approaches. The NO-sGC-cGMP pathway's role in vascular tone regulation is well-established, with sGC stimulators emerging as promising candidates. Previous research on sGC stimulators, such as riociguat and BAY 41-2272, demonstrated their blood pressure-lowering effects in various settings. This background informed the design of the current study, focusing on a novel canine model and the evaluation of BAY 41-2272's potential in resistant hypertension.

Six male beagle dogs underwent surgery for telemetry sensor implantation. Hypertension was induced in two stages: left-sided renal wrapping (RW) followed by right-sided renal artery occlusion (RAO). After achieving stable hypertension, acute drug testing was conducted with BAY 41-2272, standard-of-care (SoC) antihypertensives (enalapril, valsartan, atenolol, amlodipine, furosemide), and their combinations. Blood pressure and heart rate were monitored telemetrically for 12 hours post-drug administration. Biomarkers of renal and cardiac function (BNP, PRA, aldosterone, MCP-1, cystatin C, NGAL) were measured at various time points. Echocardiography assessed cardiac function and remodeling. Statistical analysis included one-way ANOVA with Dunnett's test.

The combined RW and RAO procedure successfully induced stable, resistant hypertension in the canine model. Standard-of-care antihypertensive drugs, even at high doses and in combination, only minimally reduced blood pressure. In contrast, BAY 41-2272 demonstrated a dose-dependent decrease in blood pressure (-14.1 ± 1.8 mmHg as standalone therapy). Furthermore, BAY 41-2272 significantly reduced blood pressure when added to a triple combination of standard antihypertensives (-28.6 ± 13.2 mmHg). Biomarker analysis revealed transient elevations in BNP, PRA, and aldosterone, indicating cardiac remodeling and activation of the renin-angiotensin-aldosterone system. Echocardiography confirmed cardiac changes associated with hypertension.

This study successfully established a canine model of resistant hypertension that mirrors clinical challenges. The significant blood pressure reduction achieved with BAY 41-2272, both alone and in combination with standard therapies, strongly supports its potential as a novel treatment for rHTN. The observed biomarker changes further validated the model and revealed the pathophysiological processes involved. The data suggest that sGC stimulation could be a valuable addition to existing rHTN treatment strategies, potentially addressing the substantial unmet medical need.

This study demonstrates the efficacy of the sGC stimulator BAY 41-2272 in lowering blood pressure in a new canine model of resistant hypertension. The drug showed significant effects both as monotherapy and as an adjunct to standard-of-care treatment. These findings suggest that sGC stimulators represent a promising novel therapeutic approach for resistant hypertension. Future research should focus on clinical trials to confirm these preclinical results and explore the long-term effects and safety profile of sGC stimulators in human patients with resistant hypertension.

The study used a relatively small sample size of six dogs, which limits the generalizability of the findings. The model, while robust, might not perfectly recapitulate all aspects of human resistant hypertension. The study focused on acute effects of BAY 41-2272; long-term effects and potential side effects were not fully assessed.