selectively in responsiveness regulated P-Adrenergic receptor responsiveness is impaired in hypertension. A low-sodium diet both corrects this defect and lowers blood pressure. To determine whether upregulation of P-adrenergic receptor function in hypertension might be related nonspecifically to lowering of blood pressure, vascular P-adrenergic re- sponse was assessed after pharmacologic antihypertensive treatment by use of dorsal hand vein linear differential transformer techniques in patients with hypertension. Subjects were studied after random- ized treatments with placebo and verapamil and after randomized treatments with verapamil and hydro- chlorothiazide. After 2 weeks of treatment, verapamil lowered blood pressure in the subjects with hyper- tension but did not significantly upregulate vascular P-adrenergic response (58% * 8% to 68% & 8%; p > 0.2 versus placebo). Further vascular P-adrenergic responsiveness after treatment with hydrochlo- rothiazide did not significantly differ from that with verapamil (hydrochlorothiazide, 68% 2 9%; verap- amil, 53% & 7%; n = 8, p > 0.3). Thus, reduction of blood pressure with either verapamil or hydro- chlorothiazide did not correct the defect in P-adrenergic responsiveness in hypertension. Vascular P-adrenergic response appears to be regulated selectively in hypertension, not simply by lowering of blood pressure. (CLIN PHARMACOL THER 1993;54:654-60.) Ross D. Feldman, MD, David J. Freeman, PhD, Gordon S. Bierbrier, MD, Susan E. Anthony, BSN, and James E. Brown, MD London) Ontario, Canada Impaired vascular P-adrenergic receptor response has been reported in hypertensive patients'~~ and in older subject^.^-^ This defect could be important in the pathogenesis or maintenance of increased peripheral resistance (especially in the setting of elevated sympa- thetic activity) and therefore could predispose patients to the development of hypertension. We, and others, have shown that in older subjects and in subjects with hypertension, dietary sodium restriction is associated with upregulation of both v a ~ c u l a r ' ~ ~ ~ ~ and lympho- cyte P-adrenergic response6 to levels that do not differ from normotensive young control subjects. Up-regulation of P-adrenergic responsiveness by di- etary salt restriction cannot be explained readily as a recovery from classic agonist-induced desensitization From the Departments of Medicine, Pharmacology, and Toxicol- ogy, University of Western Ontario. Supported by grants from the Medical Research Council of Canada (Ottawa, Ontario) and Searle Canada Inc. (Oakville, Ontario). Dr. Feldman is supported by a Career Investigator Award from the Ontario Heart and Stroke Foundation (Toronto, Ontario). Received for publication March 2, 1993; accepted July 30, 1993. Reprint requests: Ross D. Feldman, MD, Room 6-OF1 1, University Hospital, PO Box 5339, London, Ontario, N6A 5A5 Canada. Copyright O 1993 by Mosby-Year Book, Inc. 0009-9236/93/$1 .OO + 0.10 1311150533 of the P-adrenergic receptor because the low-salt diet that corrects these defects is associated with higher catecholamine concentration^.^,^ Studies in animal models of hypertension have suggested an alternative mechanism, namely, that defective vascular P-adren- ergic responsiveness may be directly related to high blood pressure and that the lowering of blood pressure corrected this d e f e ~ t . ~ . ~ On the basis of these considerations, the present studies were initiated to determine if pharmacologic blood pressure lowering with the calcium channel blocker verapamil and the diuretic hydrochlorothia- zide was associated with up-regulation of defective P- adrenergic response in subjects with hypertension. The data to be presented show that blood pressure lowering with either verapamil or hydrochlorothiazide does not correct the defect in P-adrenergic response in subjects with hypertension. This suggests that the ef- fect of dietary salt restriction in correcting impaired P-adrenergic response is selective and is not directly related to lowering of blood pressure. METHODS To examine the effects of pharmacologic lowering of blood pressure on vascular P-adrenergic respon- siveness, male subjects with mild and borderline hy-