Response to Combination Therapy for Treatment or Prevention of Atherosclerosis
We thank Koh and Quon1 for their interest in our article2 and thoughtful feedback. They have discussed the interesting scientific rational for recommending the combination of peroxisome proliferator-activated receptor (PPAR)-α or PPAR-γ and angiotensin II type I receptor blockers (ARBs) to prevent atherosclerosis and coronary heart disease. We agree with Koh and Quon,1 particularly that the combination of candesartan with pioglitazone may be a promising therapeutic strategy for coronary heart disease in hypertensive patients with type 2 diabetes.
Previously, we have found that candesartan, independent of blood pressure, prevents stroke in the stroke-prone spontaneously hypertensive rat by ameliorating reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase–mediated oxidative stress.3 Furthermore, we have shown recently that pioglitazone also directly prevents stroke in the stroke-prone spontaneously hypertensive rat via the similar mechanisms to candesartan.4 Thus, the reduction of NADPH oxidase-mediated oxidative stress is the common key mechanism for their beneficial effects. The combination therapy of candesartan with pioglitazone seems to be also useful for the prevention of stroke.
Regarding the potential mechanisms explaining the additional beneficial effect of combined candesartan and pioglitazone, Koh and Quon1 proposed that several interacting mechanisms between these drugs may participate in the additional beneficial effects, including the activation of PPAR-γ by ARBs. However, ARBs with PPAR-γ activity are limited, and most of the clinically available ARBs, including candesartan, have no significant intrinsic PPAR-γ activity. Furthermore, the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial,5 which compared telmisartan, the ARB with most potent PPAR-γ activity among all ARBs, with ramipril in high-risk patients, provides no findings supporting the importance of PPAR-γ activation by telmisartan in a clinical setting, because no difference is noted between telmisartan and ramipril in cardiovascular outcomes and the new onset of diabetes. Therefore, the potential clinical implication of PPAR-γ activation by ARBs should be cautiously discussed. In our article,2 we have shown that the combination of candesartan and pioglitazone exerts additive suppression of NADPH oxidase activity in cardiac and vascular tissues of stroke-prone spontaneously hypertensive rats. Importantly, this additive inhibition of NADPH oxidase by the combination is attributed to the additive downregulation of NADPH oxidase subunits p22phox and Nox1.2 Therefore, our data support the notion that the beneficial effects of combined candesartan and pioglitazone may be mainly mediated by the additive suppression of NADPH oxidase activity through additive downregulation of NADPH oxidase subunits rather than the interacting mechanisms between these drugs. Additional study is needed to elucidate more detailed mechanisms for the beneficial effects of the combination therapy. Previous findings by us2 and by Koh and Quon1 highlight the combination of candesartan with pioglitazone as a promising therapeutic strategy for cardiovascular diseases and stroke in metabolic syndrome.
Sources of Funding
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Koh KK, Quon MJ. Combination therapy for treatment or prevention of atherosclerosis. Hypertension. 2008; 52: e18.
Nakamura T, Yamamoto E, Kataoka K, Yamashita T, Tokutomi Y, Dong YF, Matsuba S, Ogawa H, Kim-Mitsuyama S. Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan. Hypertension. 2008; 51: 296–301.
Kim-Mitsuyama S, Yamamoto E, Tanaka T, Zhan Y, Izumi Y, Izumiya Y, Ioroi T, Wanibuchi H, Iwao H. Critical role of angiotensin II in excess salt-induced brain oxidative stress of stroke-prone spontaneously hypertensive rats. Stroke. 2005; 36: 1083–1088.
Nakamura T, Yamamoto E, Kataoka K, Yamashita T, Tokutomi Y, Dong YF, Matsuba S, Ogawa H, Kim-Mitsuyama S. Pioglitazone exerts protective effects against stroke in stroke-prone spontaneously hypertensive rats, independently of blood pressure. Stroke. 2007; 38: 3016–3022.