Orthostatic Hypertension: When Pressor Reflexes Overcompensate

Joshua Fessel; David Robertson


Nat Clin Pract Nephrol. 2006;2(8):424-431. 

In This Article

Pathophysiology of Orthostatic Hypertension

The pathophysiology underlying orthostatic hypertension remains relatively poorly understood (Figure 1). This is due in part to an underappreciation of the phenomenon and in part to the diverse clinical conditions that can have orthostatic hypertension as a feature. As discussed above, Streeten et al. described a process of excessive venous pooling in the lower extremities upon standing, which leads to a decrease in cardiac output, a vigorous activation of the sympathetic nervous system, and excessive arteriolar vasoconstriction.[22] This process may be analogous in some ways to the mechanism proposed for POTS by Streeten et al.[34] and Jacob et al.,[35] which involves a partial dysautonomia in the lower extremities as an immediate upstream cause for excessive venous pooling. There must be substantive differences, however, as patients with POTS do not always exhibit orthostatic hypertension.

Figure 1.

Pathophysiological mechanisms proposed to underlie orthostatic hypertension.

The underlying mechanisms for orthostatic hypertension in extreme dipper patients are especially unclear. Kario et al. suggest that orthostatic hypertension in this patient population may involve enhanced arteriolar vasoconstriction that is mediated by the sympathetic nervous system.[23] It is plausible that the orthostatic hypertension in these patients is in fact the result of sympathetic activation, though the specifics are not understood. For example, it is unknown whether the phenotype is primarily due to central or peripheral sympathetic activation. Further clouding the picture is the finding by Kario and Shimada that circulating levels of vasopressin in extreme dippers are higher following a head-up tilt challenge than in dippers and non-dippers, but extreme dippers did not have significantly higher levels of norepinephrine or plasma renin activity.[24] It also seems plausible that there is some mechanistic connection between orthostatic hypertension and the unusually large drop in SBP that is the defining feature of the extreme dipper phenotype, though what the connection may be remains obscure.

The connection between orthostatic hypertension and type 2 diabetes mellitus is similarly obscure. Yoshinari et al. suggest that hypersensitivity of the baroreflex may be the underlying cause for orthostatic hypertension in these patients.[31] In support of this hypothesis, they point out that the patients with orthostatic hypertension also had evidence of neuropathy; however, the coefficient of variation of the RR interval on electrocardiograms of patients with orthostatic hypertension was higher than that of those without. This coefficient is known to decrease with parasympathetic dysfunction, and parasympathetic dysfunction precedes sympathetic dysfunction in diabetic patients. These investigators suggest that the disconnect between clinical evidence of neuropathy and the elevated coefficient of variation of the RR interval could point to baroreflex hypersensitivity as a contributing factor to orthostatic hypertension in type 2 diabetes. The mechanism underlying baroreflex hypersensitivity, however, is not at all clear.

There is some experimental evidence in animal models that orthostatic hypertension is sympathetically mediated. Raffai et al. exposed normotensive and experimentally hypertensive (via blockade of nitric oxide production) rats to either repeated or sustained 45-degree head-up tilt.[36] Both normotensive and hypertensive rats responded to head-up tilt with an increase in blood pressure. This response was blocked by the administration of prazosin, an alpha-1 adrenergic receptor antagonist, or a subanesthetic dose of chloralose. The conclusion of these authors was that the hypertensive response of these rats to head-up tilt was likely due to stress-mediated activation of the sympathetic nervous system. The anesthetic reduced the animals' stress, while the prazosin prevented the increase in blood pressure at the level of the vasculature. While this model differs substantially from orthostatic hypertension observed in humans, it offers a potential mechanism at work in patients that can be tested with currently available pharmacologic tools.


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