Hypotensive Effect of a Novel Dihydropyridine with Dual Calcium Channel Blocking and Angiotensin II Antagonistic Properties in a Rat Model

Typically, the Ca 2+ response is characterised by a sharp transient rise in intracellular (Ca 2+ )i, followed by a fall towards a sustained plateau above baseline. 2 Although the sustained increases in (Ca 2+ )i are thought to be mediated through Ca 2+ influx, the early peak response is generally considered to be due to mobilisation of intracellular stores. 3, 6, 8 AT1 receptor-coupled G proteins activate PLC, which, in turn, activates IP3 and DAG, leading to the release of Ca 2+ from the sarcoplasmic reticulum. 6, 9 It has been suggested that increased (Ca 2+ )i activates chloride channels, causing an efflux of chloride and subsequent depolarisation of the cell membrane, leading to opening of voltage-gated Ca 2+ channels. 5, 10, 14 L-type Ca 2+ channel blockers prevent constriction of afferent arterioles and also reduce sustained (Ca 2+ )i increases. 5, 9, 15, 16 Losartan (Dup-753) (Fig. 1) is a nonpeptide angiotensin II receptor (type AT1) antagonist discovered by Duncia et al. in 1990, and its potassium salt (cozaar) has been marketed as an antihypertensive since 1995. 17 To date, many orally available sartans have been developed and are used in the treatment of both hypertension and damage associated with various diseases, such as atherosclerosis and diabetes. The beneficial properties of new nonpeptide ANG II antagonists, such as losartan, have stimulated the design of many different congeners. All the new nonpeptide ANG II antagonists that have been designed/developed All the new nonpeptide ANG II antagonists that have been designed contain a biphenyl fragment bearing an acidic moiety (i.e. a tetrazole, carboxylicor sulphonamidocarboxyl group), linked to a heteroaromatic or acyclic system by a methylene group. Almost all chemical manipulations of the fundamental skeleton of sartans have focused on the substitution of the imidazole ring of losartan with different heteroaromatic groups or acyclic structures. 18