Diversity in supercoupling of beta 2-adrenergic receptors in orthostatic hypotension

Orthostatic hypotension is a clinical condition that frequently involves abnormal adrenergic control of cardiovascular function. Adrenergic function was studied in six patients with symptomatic orthostatic hypotension and in 11 age-matched healthy subjects. The patients demonstrated higher supine mean arterial pressures (MAP; 103 +/- 8 versus 86 +/- 4 mm Hg) and orthostatic hypotension (delta MAP -70 +/- 5 versus +15 +/- 2 mm Hg, p less than 0.001) compared with normal subjects. The delta MAP in phase II of the Valsalva maneuver was significantly greater (-31 +/- 4 versus -7 +/- 4 mm Hg, p less than 0.002) and phase IV heart rate response was blunted (-5 +/- 3 versus -30 +/- 8 beats/min, p less than 0.02) in these patients. More isoproterenol was required to increase heart rate by 25 beats per minute in patients with hypotension (810 +/- 670 versus 3.1 +/- 1.3 micrograms, p less than 0.05), indicating marked chronotropic hyposensitivity. Leukocyte beta 2-adrenergic receptor densities were similar in patients and controls. beta 2-Adrenergic receptor coupling, however, was elevated in patients with hypotension when compared with control subjects (ratio of the low-affinity and high-affinity dissociation constants [KL/KH] 140 +/- 7.4 versus 66 +/- 4.3, p less than 0.001). There were negative correlations between the KL/KH value and the dose of isoproterenol required to decrease MAP by 20 torr (p less than 0.02) and between the KL/KH value and the product of the hormone receptor and MAP (p less than 0.01). However, the patients could be subdivided into a group who could mount a nearly normal hormone receptor times MAP response on standing (group 1A), and a group who could not (group 1B). The group 1A patients had elevated plasma norepinephrine responses associated with milder beta 2-adrenergic receptor supercoupling, whereas group 1B patients had essentially no orthostatic plasma norepinephrine response and had much higher KL/KH values. Thus, though a state of biochemical supersensitivity existed in both patient subgroups, diminished catecholamine exposure was associated, as expected, with beta 2-adrenergic hypersensitivity in group 1B, whereas there was no diminution of catecholamine exposure in the beta 2-adrenergic hypersensitivity observed in group 1A patients.