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

The study addresses therapy-resistant hypertension (rHTN), a growing clinical problem where patients fail to achieve target blood pressure despite treatment with multiple antihypertensive agents. rHTN is defined as blood pressure remaining above goal with at least three antihypertensive drugs of different classes (including a diuretic) at adequate doses, or requiring four agents. Its prevalence is estimated at 8–12% of hypertensive patients, with evidence of increasing incidence. Existing pharmacologic add-ons (e.g., alpha blockers, direct renin inhibitors, central sympatholytics, direct vasodilators, mineralocorticoid receptor antagonists like spironolactone) and interventional strategies (e.g., renal denervation) have limitations and often fail to address the unmet need. The nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cGMP pathway is a key regulator of vascular tone. sGC stimulators enhance cGMP production synergistically with endogenous NO and have shown dose-dependent blood pressure reductions in prior studies, with riociguat approved for PAH/CTEPH. Genetic variants in sGC pathway components (e.g., GUCY1A3) have been linked to increased cardiovascular risk and hypertension. The authors aimed to establish an animal model reflecting rHTN and to test whether the sGC stimulator BAY 41-2272 lowers blood pressure as standalone therapy or as an add-on to standard-of-care antihypertensives.

Background literature summarized by the authors indicates: (1) Effective blood pressure lowering reduces cardiovascular morbidity and mortality. Despite combination therapies, a substantial fraction of patients remain uncontrolled, and rHTN prevalence has risen (NHANES data showing increase from 16% to 28% over successive periods). (2) Current pharmacologic options for rHTN (alpha blockers, direct renin inhibitors, central sympatholytics, direct vasodilators, mineralocorticoid receptor antagonists) provide limited benefits, with spironolactone showing the most consistent add-on efficacy. Interventional renal denervation has had limited success. (3) The NO–sGC–cGMP pathway controls vascular smooth muscle tone; NO donors have limitations, whereas sGC stimulators (e.g., riociguat, BAY 41-2272, BAY 41-8543) reduce blood pressure dose-dependently in preclinical and human studies. (4) Genetic links between sGC pathway mutations (GUCY1A3) and cardiovascular disease support targeting sGC in hypertension.

Design: Experimental chronic canine model of resistant hypertension with telemetric hemodynamic monitoring and acute pharmacologic testing. Animals: Six male beagle dogs (10–15 kg). Compound: BAY 41-2272 (3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine), an sGC stimulator. Surgical instrumentation: Under general anesthesia (thiopental/pancuronium, isoflurane maintenance, fentanyl analgesia), a pressure sensor catheter (Model L21, DSI) was implanted in the aorta via left thoracotomy for continuous BP telemetry; ECG leads positioned on the heart. Post-op care included antibiotics (clindamycin), carprofen, fentanyl patch. Disease induction: After recovery, left renal wrapping (RW) with sterilized silk via laparotomy to induce sterile inflammation/renal impairment; post-op antibiotics (enrofloxacin), analgesia (fentanyl patch, metamizole). Eight weeks later, right renal artery occlusion (RAO) via catheter-based placement of an Amplatzer Vascular Plug II through right carotid access, with angiographic guidance. Hemodynamics: Telemetric BP and heart rate recorded weekly over 12 h windows (4 pm–4 am). For drug testing, recordings started 1 h pre-dose through 11 h post-dose; data averaged over 10-min bins. Biomarkers/clinical chemistry: Blood sampled at baseline (healthy), 5 weeks post-RW, 6, 39, and 46 weeks post-RAO (EDTA and lithium heparin). Clinical chemistry (CK, creatinine, uric acid, urea, protein) on ADVIA 2400. Plasma renin activity by RIA (DiaSorin CA1533). Aldosterone measured pre-intervention; 8 weeks post-RW; and 4, 8, 12, 16, 20, 24, 28 weeks post-RAO. Additional ELISAs: cystatin C, NGAL, MCP-1, and BNP. Echocardiography: Transthoracic echo (Vivid i) at healthy, 8 weeks post-RW, and 12 and 26 weeks post-RAO under anesthesia; EF and LV mass (ASE formula) and valvular function assessed with EchoPAC software. Pharmacologic testing: Initiated ~8 weeks post-RAO after stable hypertension (SBP >140 mmHg and DBP >80 mmHg). Acute single-dose, once-per-day testing with 11 h follow-up and 7-day washout between doses; placebo capsules administered before each new drug/regimen to exclude placebo effect. Doses (per kg, p.o.):

• Enalapril (ACEi): 0.3, 1.0, 3.0, 10.0
• Valsartan (AT1 antagonist): 3.0, 10.0, 30.0
• Atenolol (beta-blocker): 1.0, 3.0, 10.0
• Amlodipine (calcium antagonist): 0.3, 1.0, 2.0
• Furosemide (diuretic): 2.0, 4.0
• BAY 41-2272 (sGC stimulator): 0.3, 1.0, 3.0 Triple combinations tested: enalapril (3.0) + furosemide (2.0) + amlodipine (1.0); valsartan (10.0) + furosemide (2.0) + amlodipine (1.0); enalapril (3.0) + furosemide (2.0) + valsartan (10.0). Add-on evaluation: BAY 41-2272 (1.0) added to the triple combination of furosemide (2.0) + valsartan (10.0) + enalapril (3.0). Formulation: 10% ethanol/90% PEG 400, 0.25 ml/kg, filled into gelatin capsules; in combinations, drugs dissolved and administered separately with matched placebos. Statistics: GraphPad Prism 6.07. Data as mean ± SEM or SD. Drug effects analyzed by comparing mean BP averaged 1–12 h post-dose vs. 0–1 h pre-dose baseline. One-way ANOVA with Dunnett’s correction for multiple comparisons. Significance p ≤ 0.05.

• Model establishment: All 6 dogs developed long-term stable hypertension resistant to multiple guideline antihypertensives after left renal wrapping (RW) followed by right renal artery occlusion (RAO).
• Hemodynamics: Baseline mean BP (MBP) 108.1 ± 3.9 mmHg (healthy). Three weeks post-RW, MBP increased by +21.5 ± 8.3 mmHg (pre-RW vs. weeks 4–10, p = 0.0255). After RAO at week 12, BP did not further rise but remained stably elevated with an average increase of +20.4 ± 9.9 mmHg from baseline across weeks 14–58 (p = 0.0070). Heart rate rose from 77.7 ± 4.4 bpm (pre-RW) to 90.8 ± 9.7 bpm at week 14 post-RAO, then stabilized at 72.7 ± 5.4 bpm (weeks 14–58).
• Biomarkers: BNP increased by +23.4 ± 15.3 pg/ml at 6 weeks post-RAO (p = 0.0374) and normalized later. PRA showed a single elevated timepoint 30 weeks post-RAO (+0.33 ± 0.20 ng/ml/h, p = 0.0257). Aldosterone rose after RW (to 117.8 ± 19.1 pmol/l; p = 0.0966) and at 4 weeks after RW (412.0 ± 316.4 pmol/l; p = 0.1978), with a significant elevation only at 24 weeks post-RAO (149.5 ± 47.0 pmol/l; p = 0.0363). MCP-1 trended higher (details not quantified in the excerpt).
• Pharmacologic responses: High doses of standard-of-care antihypertensives produced only slight acute BP reductions in this model. In contrast, BAY 41-2272 as monotherapy produced a dose-dependent BP reduction of −14.1 ± 1.8 mmHg (acute effect). As add-on to a triple SoC combination, BAY 41-2272 further reduced BP by −28.6 ± 13.2 mmHg (acute effect).

The study demonstrates that a canine model combining unilateral renal wrapping with contralateral renal artery occlusion yields stable hypertension that is relatively unresponsive to standard antihypertensive classes, reflecting key features of therapy-resistant hypertension. In this setting, sGC stimulation with BAY 41-2272 produced significant, dose-dependent acute reductions in blood pressure both as standalone therapy and when added to triple-combination standard-of-care regimens. These findings support the central role of the NO–sGC–cGMP pathway in vascular tone regulation and suggest that sGC stimulators can overcome inadequate responses to conventional therapies in resistant hypertension. Biomarker changes consistent with renal injury and transient cardiac remodeling (elevated BNP) were observed, providing physiological context to the model without sustained adverse cardiac remodeling during follow-up. Overall, the results align with prior evidence of BP lowering by sGC stimulators and extend their potential utility to resistant hypertension scenarios.

A novel canine model of resistant hypertension was established via renal wrapping and contralateral renal artery occlusion, producing stable elevations in blood pressure that were minimally responsive to multiple standard antihypertensive drugs. The sGC stimulator BAY 41-2272 significantly lowered blood pressure in a dose-dependent manner as monotherapy and provided additional BP reduction when combined with standard-of-care agents. These data indicate that sGC stimulators may offer an effective pharmacologic option for patients with resistant hypertension. Future research should assess chronic efficacy and safety, optimal dosing strategies, and translational relevance to human rHTN, including evaluation alongside current best-practice combinations.