Synthesis and Effects of Novel Dihydropyridines as Dual Calcium Channel Blocker and Angiotensin Antagonist on Isolated Rat Aorta

Document Type : Original Article


1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran


Four novel losartan analogues 5a-d were synthesized by connecting a dihydropyridine nucleus to imidazole ring. The effects of 5a and 5b on angiotensin receptors (AT') and L-type calcium channels were investigated on isolated rat aorta.
Materials and Methods
Aortic rings were pre-contracted with 1 pM Angiotensin II or 80 mM KCl and relaxant effects of losartan, nifedipine, 5a and 5b were evaluated by cumulative addition of these drugs to the bath solution.
The results showed that compounds 5a and 5b have both L-type calcium channel and AT' receptor blocking activity. Their effects on AT' receptors are 1000 and 100,000 times more than losartan respectively. The activity of compound 5b on L-type calcium channel is significantly less than nifedipine but compound 5a has comparable effect with nifedipine.
Finally we concluded that these two new Compounds can be potential candidates to be used as effective antihypertensive agents.


1.Arendshorst WJ, Brannstrom K, Ruan X. Actions of angiotensin II on the renal microvasculature. J Am Soc Nephrol 1999; 10:S149-S61.
2.Inscho EW, Mason MJ, Schroeder AC, Deichmann PC, Stiegler KD, Imig JD. Agonist-induced calcium regulation in freshly isolated renal microvascular smooth muscle cells. J Am Soc Nephrol 1997; 8:569-579.
3.Iversen BM, Arendshorst WJ.ANG II and vasopressin stimulate calcium entry in dispersed smooth muscle cells of preglomerular arterioles. Am J Physiol Renal Physiol 1998; 274:F498-F508.
4.Conger JD, Falk SA, Robinette JB. Angiotensin II-induced changes in smooth muscle calcium in rat renal arterioles. J Am Soc Nephrol 1993; 3:1792-1803.
5.Ruan X, Arendshorst WJ. Calcium entry and mobilization signaling pathways in ANG II-induced renal vasoconstriction in vivo. Am J Physiol 1996; 270:F398-405.
6.Salomonsson M, Sorensen CM, Arendshorst WJ, Steendahl J, Holstein-Rathlou NH. Calcium handling in afferent arterioles. Acta Physiol Scand 2004; 181:421-429.
7.Iversen BM, Arendshorst WJ. ANG II and vasopressin stimulate calcium entry in dispersed smooth muscle cells of preglomerular arterioles. Am J Physiol 1998; 274:F498-508.
8.Iversen BM, Arendshorst WJ. AT1 calcium signaling in renal vascular smooth muscle cells. J Am Soc Nephrol 1999; 10:11:584-589.
9.Loutzenhiser K, Loutzenhiser R. Angiotensin II-induced Ca (2+) influx in renal afferent and efferent arterioles: differing roles of voltage-gated and store-operated Ca (2+) entry. Circ Res 2000; 87:551-557.
10.Navar LG, Inscho EW, Majid SA, Imig JD, Harrison-Bernard LM, Mitchell KD. Paracrine regulation of the renal microcirculation. Physiol Rev 1996; 76:425-536.
11.Carmines PK. Segment-specific effect of chloride channel blockade on rat renal arteriolar contractile responses to angiotensin II. Am J Hypertens 1995; 8:90-94.
12.Jensen BL, Skott O. Blockade of chloride channels by DIDS stimulates renin release and inhibits contraction of afferent arterioles. Am J Physiol 1996; 270:F718-727.
13.Large WA, Wang Q. Characteristics and physiological role of the Ca (2+)-activated Cl- conductance in smooth muscle. Am J Physiol 1996; 271:C435-454.
14.Steendahl J, Holstein-Rathlou NH, Sorensen CM, Salomonsson M. Effects of chloride channel blockers on rat renal vascular responses to angiotensin II and norepinephrine. Am J Physiol Renal Physiol 2004; 286:F323-330.
15.Takenaka T, Kanno Y, Kitamura Y, Hayashi K, Suzuki H, Saruta T. Role of chloride channels in afferent arteriolar constriction. Kidney Int 1996; 50:864-872.
16.Ruan X, Arendshorst WJ. Calcium entry and mobilization signaling pathways in ANG II-induced renal vasoconstriction in vivo. Am J Physiol 1996; 270:F398-F405. 
17.Carmines PK, Navar LG. Disparate effects of Ca channel blockade on afferent and efferent arteriolar responses to ANG II. Am J Physiol 1989; 256: F1015-1020.
18.Takenaka T, Suzuki H, Okada H, Inoue T, Kanno Y, Ozawa Y, et al. Transient receptor potential channels in rat renal microcirculation: actions of angiotensin II. Kidney Int 2002; 62:558-565.
19.Wang JW, Jia J, Li HM, Wang C. Synthesis of Novel Isoxazole-contained Analogues of Losartan. Chin Chem Lett 2000; 11:961-962.
20.Rapposelli S, Cuboni S, Digiacomo M, Lapucci A, Trincavelli ML, Tuccinardi T, et al. Synthesis and AT1 affinity evaluation of benzamidophenyl analogs of known AT1 receptor ligands with similar aromatic skeleton. Arkivoc 2008; 2008:268-286.
21.Shafiee A, Shahbazi-Mojarad J, Jalili MA, Adhami HR, Hadizadeh F. Syntheses of substituted pyrrolo[2,3- d]imidazole-5-carboxylates and substituted pyrrolo[3,2-d]imidazole-5-carboxylates. J Heterocycl Chem 2002; 39:367-373.
22.Guo XZ, Shi L, Wang R, Liu XX, Li BG, Lu XX. Synthesis and biological activities of novel nonpeptide angiotensin II receptor antagonists based on benzimidazole derivatives bearing a heterocyclic ring. Bioorg Med Chem 2008; 16:10301-10310.
23.Drummond RM, Wadsworth RM. In vitro effect of nifedipine on KCl and 5-hydroxytryptamine-induced contractions of the sheep coronary, cerebral and pulmonary arteries. Life Sci 1994; 54:1081-1090.
24.Louch WE, Ferrier GR, Howlett SE. Losartan improves recovery of contraction and inhibits transient inward current in a cellular model of cardiac ischemia and reperfusion. J Pharmacol Exp Ther 2000; 295:697-704.