Abstract Background: Losartan potassium, the first nonpeptide selective blocker of angiotensin II at the ATI receptor, has been shown to exhibit clinical antihypertensive effects. The aim of the present study was to characterize the efficacy and duration of action of losartan by ambulatory blood pressure monitoring. Methods: The study was performed in nonblack hypertensive patients whose baseline untreated clinical diastolic blood pressures were 95 mm Hg or higher and whose average 24-hour ambulatory diastolic blood pressures were 85 mm Hg or higher. Patients were randomized, double-blind, into four treatment groups: placebo (n=32) or losartan, 50 mg once daily (n=29), 100 mg once daily (n=30), or 50 mg twice daily (n=31). Clinical and 24-hour ambulatory blood pressures were measured at baseline (off treatment for at least 4 weeks) and after 4 weeks of treatment. Results: By clinical sphygmomanometer measurements at the end of the 24-hour or 12-hour dosing intervals (trough), all three losartan dosages were significantly more effective than placebo at decreasing systolic and diastolic blood pressures. By average 24-hour ambulatory systolic/ diastolic blood pressure measurements, the decreases produced were 0.0/0.2 mm Hg for placebo and 9.2/6.9, 9.9/6.4, and 13.2/8.5 mm Hg, respectively, for losartan, 50 mg once daily, 100 mg once daily, and 50 mg twice daily. All drug effects were different from placebo (P<.01). The effects of losartan, 50 mg twice daily, were not significantly different from those of losartan, 100 mg once daily, but, as expected, the effects were greater than those of losartan, 50 mg once daily (P<.05). Addition of hydrochlorothiazide, 12.5 mg/d, during an additional 2-week treatment period in patients whose clinical diastolic blood pressure remained at 85 mm Hg or higher while receiving monotherapy produced additional and clinically meaningful blood pressure decrements that were similar in all four treatment groups. There were no clinical adverse events in any group. Conclusion: Ambulatory blood pressure monitoring, which virtually eliminated antihypertensive placebo responses, demonstrated clear 24-hour efficacy for losartan, 50 mg once daily, as well as for higher doses of 100 mg once daily and 50 mg twice daily. This ATI receptor blocker had antihypertensive effects that appeared additive when combined with low-dose diuretic therapy. Losartan was generally well tolerated. (Arch Intern Med. 1995;155:405-411) References 1. Buhler FR, Laragh JH, Baer L, Vaughan ED Jr, Brunner HR. Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renin-dependent hypertensive disease. N Engl J Med . 1972;287:1209-1214.Crossref 2. Weber MA, Neutel JM, Essinger I, Glassman HN, Boger RS, Luther R. Assessment of renin dependency of hypertension with a dipeptide renin inhibitor. Circulation . 1990;81:1768-1774.Crossref 3. Weber MA, Neutel JM, Smith DHG. Circulation and extracirculatory effects of angiotensin-converting enzyme inhibition. Am Heart J . 1992;123:1414-1420.Crossref 4. Case DB, Wallace JM, Keim HJ, Sealey JE, Laragh JH. Usefulness and limitations of saralasin, a weak competitive agonist of angiotensin II, for evaluating the renin and sodium factors in hypertensive patients. Am J Med . 1976;60: 825-836.Crossref 5. Timmermans PB, Chiu AT, Herblin WF, Wong PC, Smith RD. Angiotensin II receptor subtypes. Am J Hypertens . 1992;( (suppl 6) , pt 1):406-410. 6. Weber MA. Clinical experience with the angiotensin II receptor antagonist losartan: a preliminary report. Am J Hypertens . 1992;5:247S-251S. 7. Brunner HR, Christen Y, Munafo A, Lee RJ, Waeber B, Nussberger J. Clinical experience with angiotensin II receptor antagonists. Am J Hypertens . 1992;5: 243S-246S. 8. Neutel JM, Smith DHG, Ram CVS, et al. Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents. Am J Med . 1993;94:181-187.Crossref 9. O'Brein E, O'Malley K, Cox J, Stanton A. Ambulatory blood pressure monitoring in the evaluation of drug efficacy. Am Heart J . 1991;121:999-1006.Crossref 10. Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh JH. How common is white coat hypertension? JAMA . 1988;259:225-228.Crossref 11. White WB. Assessment of patients with office hypertension by 24-hour noninvasive ambulatory blood pressure monitoring. Arch Intern Med . 1986;146: 2196-2199.Crossref 12. Drayer JIM, Weber MA, Nakamura DK. Automated ambulatory blood pressure monitoring: a study in age-matched normotensive and hypertensive men. Am Heart J . 1985;109:1334-1338.Crossref 13. Weber MA, Cheung DG, Graettinger WF, Lipson JL. Characterization of antihypertensive therapy by whole-day blood pressure monitoring. JAMA . 1988; 259:3281-3285.Crossref 14. Conway J, Johnston J, Coats A, Somers V, Sleight P. The use of ambulatory blood pressure monitoring to improve the accuracy and reduce the numbers of subjects in clinical trials of antihypertensive agents. J Hypertens . 1988;6: 111-116. 15. Wong PC, Price WA Jr, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists, XI: pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther . 1990;255:211-217. 16. Munafo A, Christen Y, Nussberger J, et al. Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther . 1992;51:513-521.Crossref 17. Ohlstein EH, Gellai M, Brooks DP, et al. The antihypertensive effect of the angiotensin II receptor antagonist DuP 753 may not be due solely to angiotensin II receptor antagonism. J Pharmacol Exp Ther . 1992;262:595-601. 18. DePasquale MJ, Fossa AA, Holt WF, Mangiapane ML. Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats. Hypertension . 1992;19:668-671.Crossref 19. Wong PC, Bernard R, Timmermans PB. Effect of blocking angiotensin II receptor subtype on rat sympathetic nerve function. Hypertension . 1992;19:663-667.Crossref 20. Jaiswal N, Diz DI, Tallant EA, Khosla MC, Ferrario CM. Characterization of angiotensin receptors mediating prostaglandin synthesis in C6 glioma cells. Am J Physiol . 1991;260:R1000-R1006. 21. Janiak P, Pillon A, Prost JF, Vilaine JP. Role of angiotensin sybtype 2 receptor in neointima formation after vascular injury. Hypertension . 1992;20:737-745.Crossref 22. Bui JD, Kimura B, Phillips Ml. Losartan potassium, a nonpeptide antagonist of angiotensin II, chronically administered p.o. does not readily cross the blood-brain barrier. Eur J Pharmacol . 1992;219:147-151.Crossref 23. Kauffman RF, Beans JS, Zimmerman KM, Brown RF, Steinberg Ml. Losartan, a nonpeptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries. Life Sci . 1991;49: 223-228.Crossref 24. Weinberger MH. Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc Pharmacol . 1985;7:S52-S55.Crossref 25. Nakashima M, Uematsu T, Kosuge K, Kanamaru M. Pilot study of the uricosuric effect of DuP 753, a new angiotensin II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol . 1992;42:333-335.Crossref 26. Tsunoda K, Abe K, Hagino T, et al. Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Am J Hypertens . 1993;6:28-32.
Archives of Internal Medicine – American Medical Association
Published: Feb 27, 1995