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Purpose: Onopordon acanthium L. is known for its medicinal properties. Our recent study showed that its seed extract is a novel natura angiotensin-converting-enzyme inhibitor (ACEI). This study was carried out to investigate its possible antihypertensive effects in patients receiving losartan. Methods: This uncontrolled clinical trial was carried out among 20 patients (30-60y) with uncontrolled hypertension despite receiving 50 mg losartan (stage I & II) in two hospitals in Iran. After completing informed consent, patients were treated by 2 capsules [each 1g of Onopordon acanthium seed extract (OSE)] as add-on therapy, two times per day. Results: 18 patients completed the study (50.94 ±8.37y). Mean systolic blood pressure (SBP) at the baseline was 151.9 ± 13.74mmHg and at the end of the study, it was 134.6 ± 18.25 mmHg and mean diastolic blood pressure (DBP) was 97.41 ± 10.36 at the baseline and was 85.71 ± 7.481 after 8 weeks. OSE significantly reduced SBP and DBP at the end of 8 weeks (P=0.003, 95% CI: -19.7, -15.1; P=0.0006, 95% CI: -10.23, -13.15; respectively). No evidence of hepatic or renal toxicity was detected. Conclusion: Based on the results of this study OSE has antihypertensive property with no significant adverse effects. However, because of the low number of samples, this medication may be not safely administered. The results of this study could be the basis for further studies with larger sample size. IRCT registration number: IRCT2013020712391N.

Background: Somatic ACE is a two-domain protein, C and N which are resulted from gene duplication. Presence of two active sites with particular properties, demonstrates functional significance of each domain. Increased levels of circulating N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), could be the result of ACE N-domain selective inhibition. Moreover, ACE C-domain specific inhibitors are able to inactivate bradykinin and inhibit the conversion of angiotensin I to angiotensin II in order to regulate blood pressure as well as reduced side effect profiles. Methods: The present study was designed to determine ACE domain specificity of the novel ACE inhibitor, onopordia which was recently isolated from Onopordon acanthium L. The ACE inhibition activity was determined using Abz-SDK (Dnp)P-OH and Abz-LFK(Dnp)-OH as ACE domain selective substrates. IC50 values of onopordia determined and compared with those of captopril as the standard. Results: IC50 values of onopordia for ACE N and C- domains were 180 µM and 244 µM respectively which demonstrated approximately similar affinity of the mentioned compound to ACE C and N-domains. A pharmacophore model was further generated based on onopordia interactions with the relevant ACE domain active sites. Conclusion: According to onopordia interactions in the ACE C and N-domain active sits, it is a potential to generate more potent and also specific inhibitor based on this new scaffold by doing accurate adjustments. Therefore, this study provides the molecular basis for further designing ACE inhibitors, which are new therapeutics in combating tissue fibrosis diseases.