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.

难治性高血压是一个严重的医学问题，如果不治疗会导致终末器官损伤、中风和心力衰竭。由于难治性高血压患者的护理标准失败，因此对有效治疗的医疗需求仍然存在大量未满足的需求。通过新型可溶性鸟苷酸环化酶刺激剂对可溶性鸟苷酸环化酶的主动刺激可能提供有效的治疗选择。为了验证这一假设，我们建立了一个新的实验犬模型并研究了可溶性鸟苷酸环化酶刺激剂 BAY 41-2272 的作用。在比格犬中，通过将单侧肾脏包裹与对侧肾脏中的肾动脉闭塞相结合来建立抵抗性高血压表型。最常用的抗高血压药物是口服给药，单独或联合使用，评估了它们对遥测血压的急性影响，并与 BAY 41-2272 进行了比较。选择的疾病刺激导致血压适度和稳定的升高。即使是高剂量的标准护理抗高血压药也只会略微降低血压。相比之下，可溶性鸟苷酸环化酶刺激剂 BAY 41-2272 作为独立疗法的给药导致血压的剂量依赖性降低 (-14.1 ± 1.8 mmHg)。此外，BAY 41-2272 除了标准护理抗高血压药的三重组合（-28.6 ± 13.2 mmHg）外，还可以进一步降低血压。BAY 41-2272 作为难治性高血压的独立治疗非常有效，但除了标准护理治疗外也有效。