Key result
Olm-NO fails to lower blood pressure in mice compared to olmesartan alone.
Why the study?
The effects of olmesartan with nitric oxide-donor side chains on blood pressure control and AT1 receptor activity were unclear compared to olmesartan alone.
Does olmesartan with NO-donor side chains improve blood pressure control compared to olmesartan in Ang II-infused mice?
Does olmesartan with NO-donor side chains improve blood pressure control compared to olmesartan in Ang II-infused mice?
p-value: p=<0.05
The addition of a nitric oxide donor to olmesartan cancels its blood pressure-lowering effects, suggesting that NO-releasing ARB hybrids may be less effective for hypertension.
While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.
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Yahiro et al. (2015) studied Angiotensin II-induced high blood pressure (n=18). Olmesartan with NO-donor side chains (Olm-NO) vs. Olmesartan (Olm) and Control (Ang II alone) was evaluated on Blood pressure (systolic and diastolic) after 10 days (p=<0.05). The addition of a nitric oxide donor to olmesartan (Olm-NO) failed to lower blood pressure in Angiotensin II-infused mice, whereas olmesartan alone significantly decreased blood pressure.
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