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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 3, 2004; DOI: 10.1124/jpet.104.078220

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Received for publication September 27, 2004.
Revised October 29, 2004.
Accepted for publication November 1, 2004.

A new ATP-sensitive potassium channel opener reduces blood pressure and reverses cardiovascular remodeling in experimental hypertension

Hai Wang 1*, Chao-Liang Long 2, Ying-Li Zhang 1

1 Beijing Institute of Pharmacology and Toxicology 2 Beijing Institute of Pharmacology and Toxicology,Thadweik Academy of Medicine

* Address correspondence to: E-mail: wh9588{at}yahoo.com.cn

Abstract

Some potassium channel openers (KCOs) are potent vasodilators that mainly target the ATP-sensitive potassium channels (KATP channels) in vascular smooth muscle cells. Their lack of tissue selectivity limits their clinical use in hypertension therapy. Iptakalim, which belongs to a novel chemical type of KCO, possesses unique pharmacological characteristics. In vitro experiments have shown that iptakalim could limit its vasorelaxing actions to hypertensive small arteries. In this study we investigate the antihypertensive effects of iptakalim on two different experimental hypertensive models: stroke-prone, spontaneously hypertensive rats (SHRsp) and "two kidneys with one-clip" renal hypertensive dogs (2K,1C RHD). In acute hypotensive tests, iptakalim showed stable, long lasting antihypertensive effects in SHRsp and 2K,1C RHD. Meanwhile, it had little effect on heart rate when compared with pinacidil, nifedipine, captopril or bisoprolol. In experimental therapeutic tests, repeated doses in SHRsp for 30 days or in 2K, 1C RHD for 14 days produced consistent antihypertensive effects without causing tolerance. In separate experiments, chronic administration of iptakalim resulted in reversing hypertensive vascular remodeling in SHR and hypertensive cardiac remodeling in SHRsp. These results suggest that iptakalim is a promising antihypertensive drug.


Key words: antihypertensive action, hypertensive cardiac remodeling, hypertensive vascular remodeling, potassium channel opener, renal hypertensive dog, spontaneously hypertensive rat


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