Vascular Pharmacological Characteristics Of The Novel Antihypertensive Drug Iptakalim Hydrochloride

Hypertension is an important risk factor for people's health. Many kinds of antihypertensive drugs are using in clinical treatment, but there is a lack of the optimal drugs having high selectivity, well efficacy and few side-effects. Therefore, it is important to develop novel antihypertensive drugs having stable antihypertensive effects, reversing target organ damage, and improving life quality of patients. ATP-sensitive potassium channel openers (KAjpCOs) represent a novel new class of compounds in the treatment of a range of cardiovascular disorders, particularly hypertension. They have a variety of characteristics such as potent efficacy, high selectivity in cardiovascular system and partially reversing pathological damage. Iptakalim hydrochloride (Ipt), a small molecular aliphatic second amine chemical compound, was synthesized in the Institute of Pharmacology and Toxicology of Academy of Military Medical Sciences. Our previous studies suggest Ipt not only has definite, stable, and lasting antihypertensive effects, but also can reverse the remodeling of cardiovascular system and reverse brain and kidney damage from hypertension.The antihypertensive effect of Ipt is significantly greater in the condition of hypertension. It has few side-effects on heart. The antihypertensive effect can be blocked by glibenclamide, one of the specific blocker of ATP-sensitive potassium channel, and Ipt has similar effect site of pinacidil and PI 075, which belonging to ATP-sensitive potassium channel openers. The out-ward potassium currents in smooth muscle cells derived from pulmonary hypertensive rats and "two-kidney-one-clip" renal hypertensive rats could be increased by Ipt, which could be blocked by glybenclamide. The other investigation suggests that Ipt can reverse pathological elevation of endothelin-1 (ET-1) in plasma from stroke-prone spontaneously hypertensive rats and can prevent to develop pulmonary hypertension induced by injecting ET-1 into pulmonary arteries.These data show that Ipt has some pharmacological characters of agonist of ATP-sensitive K+ channel and Ipt perhaps affects endothelin system. Therefore, it is necessary that the vascular pharmacological characteristics of the novel antihypertensive drug Ipt should be further studied based on these previous studies.1. Selective vasodilating action of iptakalim hydrochloride in arteries of ratsTo compare the differences of pharmacological characteristics of Ipt in big artery and small artery, we investigate the vasodilating action of Ipt at 10-7-10-3mol/L by using isolated rat tail artery helical strips and aortic rings. The present results have demonstrated that Ipt-induced vasorelaxation was observed in rat tail artery strips precontracted with potassium chloride (KC1) in a concentration-dependent manner, and the vasodilating action presents a partially endothelium-dependent character, but no significantly vasodilatingeffect was seen in rat aortic rings. These results suggest the existence of selective vasodilating action of Ipt in small artery. The characteristics of vasodilating action of Ipt in rat tail artery are as following:(1) In rat tail artery, Ipt relax the contractions induced by low concentrations (40mmol/L) more effectively than those induced by high concentrations ( > 50mmol/L) of extracellular KC1. This result parallels the major characteristics of ATP-sensitive potassium channel openers (KAipCOs) that they relax contractions induced by modest increases in extracellular K and fail to relax contractions produced by elevations in extracellular K high enough to stop K efflux through smooth muscle cell membranes.(2) The vasodilating action of Ipt in small artery could be markedly antagonized by glibenclamide (lOumol/L) which only inhibits ATP-sensitive potassium channels, but TEA at Immol/L (which only inhibits calcium-activated potassium channels), barium at lOumol/L (which only inhibits inward rectifier potassium channels) and 4-aminopyridine at Immol/L (which only inhi...