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Objective: To determine whether obesity-induced hypertension was associated with alterations in vascular contractility and/or cardiac function., Design: Male Sprague-Dawley rats were fed either a low fat (LF; 11% kcal as fat) or a moderately high fat (MHF; 32% kcal as fat) diet for 11 weeks., Measurements: Body weight; mean arterial pressure; angiotensin peptides; mesenteric contractile response to phenylephrine (PE), potassium chloride (KCl), serotonin, angiotensin II (AngII), calcium chloride; baseline and isoproterenol-induced cardiac contractility; baseline and isoproterenol-induced coronary artery blood flow., Results: Rats fed the MHF diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups. OP rats exhibited elevations in mean arterial pressure (MAP) and elevations in systemic concentrations of angiotensin peptides. Mesenteric arteries from OP rats exhibited a greater contractile response to PE, KCl and serotonin (5-HT). Heightened responses to PE persisted in arteries from OP rats even after normalization of the response to KCl. In contrast, the response of permeabilized mesenteric arteries to a maximal concentration of calcium was similar in rats from each group. Isolated perfused hearts exhibited similar baseline and isoproterenol-induced contractility in rats from each group. However, isoproterenol was unable to increase coronary artery blood flow in hearts from OP rats., Conclusion: Enhanced vascular reactivity may contribute to obesity-induced hypertension, while reductions in coronary artery relaxation would impair the ability of the heart to respond to increased myocardial demand.

Study Objectives: To evaluate whether variability in S-metoprolol kinetics and lymphocyte beta 2-receptor-mediated cyclic adenosine monophosphate (cAMP) accumulation is related to the variability in antihypertensive response to metoprolol of black men., Design: Prospective, unblinded study., Setting: University-based preventive medicine clinic., Patients: Twelve hypertensive black men., Measurements and Main Results: Ambulatory blood pressure was measured over 24 hours before and after metoprolol administration. Ex vivo responsiveness of lymphocyte beta 2-receptors to isoproterenol was established for each subject before initiating metoprolol therapy. Plasma samples were collected over 12 hours at the conclusion of the study, from which metoprolol enantiomer concentrations were determined by chiral high-performance liquid chromatography, and kinetic values were calculated. The 24-hour ambulatory blood pressure responses to metoprolol were highly variable, with systolic blood pressure responses ranging from -13 to +33 mm Hg and diastolic blood pressure responses ranging from -15 to +15 mm Hg. There was a significant relationship between the metoprolol-induced change in systolic blood pressure and the maximum lymphocyte beta 2-receptor cAMP production (y = 0.47x-7.79; r2 = 0.49, p < 0.05) such that those with the highest maximum cAMP production had the greatest blood pressure increases during metoprolol therapy. There was no relationship between S-metoprolol concentration and blood pressure response. Mean oral clearance values for S- and R-metoprolol were 1320 and 2346 ml/minute, respectively., Conclusions: Lymphocyte beta 2-receptor data suggest that individuals most responsive to beta-receptor stimulation may be at greatest risk of blood pressure elevation during beta 2-receptor blockade. The metoprolol enantiomer kinetic data are markedly different from previously published data and may represent racial differences in pharmacokinetics.

Twelve hypertensive black males completed the study, which was conducted to evaluate the effect of metoprolol on 24-h ambulatory blood pressure (ABP). Study participants took 50 mg to 100 mg metoprolol twice daily for a minimum of 3 weeks. Metoprolol had no significant effect on blood pressure (147/90 +/- 11/8 mm Hg v 151/88 +/- 16/8 mm Hg, baseline v treated, respectively) in spite of causing significant reductions in heart rate (87 +/- 9 beats/min v 69 +/- 7 beats/min, P < .001). Only one subject had a > or = 10 mm Hg decrease in 24-h diastolic blood pressure. The nighttime fall in blood pressure was minimized by metoprolol and clinically significant increases in daytime or nighttime blood pressure were noted in 58% of patients. Metoprolol therapy failed to lower blood pressure and eliminated the normal nighttime decline in blood pressure. Since the nighttime decline in blood pressure is thought to protect against target organ damage, it may be important to identify antihypertensive agents which preserve or enhance the nighttime blood pressure dip.