Isolated systolic hypertension (ISH) is the predominant form of hypertension in the elderly population and drug treatment is unsatisfactory. We compared the efficacy of an endothelin-receptor antagonist (darusentan), an angiotensin-receptor blocker (irbesartan) and a thiazide diuretic (hydrochlorothiazide, HCTZ) to prevent and regress pulse pressure (PP) elevation and remodeling of large and small arteries, in a rat model of ISH obtained by the chronic administration of warfarin and vitamin K1 (WK).
Warfarin and vitamin K1 treatment for 4 or 8 weeks led to an elevation of PP, associated with increases in aortic calcium deposition and the ratio of collagen to elastin (C/E). Despite these changes in the composition of the aortic wall, the global structure of the aorta was unchanged. In contrast, an outward hypertrophic remodeling was observed in the middle cerebral artery. An early treatment with all drugs (darusentan, irbesartan, HCTZ) prevented PP elevation, changes of aortic media composition and the development of vascular remodeling. However, after 4 weeks of ISH, only darusentan and irbesartan reduced PP when administered from week 4 to 8. Darusentan was the most effective to regress existent aortic calcification, while only irbesartan reversed small artery hypertrophic remodeling.
During the development of ISH, drug treatment appears more beneficial when started early. Indeed, the three agents prevented PP elevation, aortic calcification and C/E increase in the aorta, and hypertrophy in small arteries. In contrast, once the disease is established, endothelin appears crucial in the maintenance of aortic calcification, while angiotensin II sustains small artery hypertrophy.
aFaculty of Pharmacy, bDepartment of Physiology, Faculty of Medicine, Université de Montréal, Montréal and cResearch Center, CHUQ, Hôtel-Dieu Hospital, Québec, Canada.
Sponsorship: The authors acknowledge the financial support of Knoll-BASF AG, Germany, and Bristol-Myers Squibb, Canada. H.H.D. and R.E. received a stipend from the Fonds canadiens pour l'avancement de la recherche and the Groupe de recherche sur le système nerveux autonome, respectively. J.dC. is a JC Edwards career investigator and P.M. is a scholar from the Canadian Institutes of Health Research.
Correspondence and requests for reprints to Pierre Moreau, Associate Professor, Faculty of Pharmacy, Université de Montréal, 2900 Édouard-Montpetit, Room R-313, PO Box 6128, Stn ‘Centre-Ville', Montréal, Québec, H3C 3J7, Canada. Tel: +514 343 6111 ext 3342; fax: +514 343 2102; e-mail: firstname.lastname@example.org
Received 6 March 2002
Revised 22 April 2002
Accepted 23 April 2002
*The first two authors contributed equally to this article