Orthostatic hypotension due to diabetic neuropathy is difficult to manage, because the standing BP should be raised without at the same time raising supine BP. The proposed causes of orthostatic hypotension include damaged sympathetic vasoconstrictor fibres, and impaired baroreceptor function.1 Few papers have described the treatment of diabetic orthostatic hypotension with β-blockers.2 Combined β1 and β2 blockade has been reported to reduce the fall of SBP on standing up, but in one study a cardio-selective β1-blocker was not effective.2 The successful use of a β1-blocker in diabetic orthostatic hypotension has not been reported. β-Blockers have been reported to have paradoxical pressor effects while standing in patients with orthostatic hypotension,3 but they have not been widely used in hypotensive patients because it has also been reported that they can cause congestive heart failure without having pressor effects.4 We here describe a case of severe orthostatic hypotension with diabetic neuropathy successfully treated with a once daily bedtime dose of a β1-blocker.
A 54-year-old man with diabetes was referred to the Hypertension Clinic in Jichi Medical School Hospital with symptoms of dizziness and orthostatic intolerance. In 2002, he started insulin therapy (Hemoglobin A1c 9 %), and in 2004, he was started on a once daily dose of valsartan 80 mg for hypertension. He sometimes complained of dizziness and fainting while standing. On 13 February 2005, he fell down while riding a bicycle. As the clinic BP was 84/60 mm Hg on 14 March, and the valsartan was stopped. He was referred to otolaryngology and neurology, but no significant abnormalities were detected.
On 19 April, he was referred to our Hypertension Clinic. Laboratory data were: hemoglobin A1c 8.6%, postprandial glucose 12.1 mmol/l, serum creatinine 84.0 μmol/l and urinary protein 2+. During a head-up tilt test, BP decreased 50 mm Hg systolic and 27 mm Hg diastolic, and the patient complained of dizziness (Figure 1a); orthostatic hypotension was diagnosed. After the atenolol was started, with a dose of 6.25 mg on 20 April, the dizziness was relieved, and the dose of atenolol was gradually increased.
A second head-up tilt test (12 July, Figure 1b) showed improvement of the average supine BP (decreased from 173/93 to 147/82 mm Hg) and pulse rate (PR – decreased from 100 to 67 bpm) without any symptoms. By contrast, the standing BP remained essentially unchanged (from 123/65 to 121/67 mm Hg). A second ambulatory BP monitoring showed significant reduction of sleep BP and PR (170/96 mm Hg, PR 93 bpm on 19 April; 149/85 mm Hg, PR 70 bpm on 13 July) and flattening of the circadian BP pattern. The variability (s.d.) of awake SBP/DBP was also reduced (from 18/12 to 12/8 mm Hg). A Valsalva maneuver showed a dysautonomic pattern (a lack of compensatory increase of PR in phase II and overshoot of BP in phase IV) and remained unchanged after the β1-blocker therapy. Although a brain MRI showed multiple cerebral and cerebellar infarctions, single photon emission computed tomography (SPECT) did not show any ischemic lesions. Echocardiography showed a cardiac ejection fraction of 84%, but no left ventricular hypertrophy.
A cardio-selective β1-blocker (atenolol) effectively reduced the orthostatic BP changes in this patient with severe orthostatic hypotension due to diabetic autonomic neuropathy, and the main finding was an improvement of the elevated supine BP without reducing the standing BP. This differential antihypertensive effect is ideal for a medication in orthostatic hypotension, but is very different from other reports of the effects of β-blockers, where the emphasis has been on increasing the standing pressure. Our study was unique in two ways: first, the use of 24-h ambulatory monitoring; and second, we describe a potentially different mechanism whereby β-blockers may benefit patients with orthostatic hypotension, by lowering the night-time and supine BP. Several aspects of this case merit discussion.
Standard pharmacological therapy for orthostatic hypotension1 can cause side effects such as congestive heart failure and hypertension. Previous reports have described a pressor effect of β-blockers in patients with mild hypertension, orthostatic hypotension with hypertension, central autonomic neurodegenerative disorders,5 and diabetic orthostatic hypotension.2 The usual explanation for the beneficial effect of β-blockers in orthostatic hypotension is that in some patients there is a paradoxical vasodilation on standing that has been attributed to stimulation of β2 vasodilator receptors. In accordance with this, a number of studies and case reports have shown that nonselective β-blockers such as pindolol2, 6 and propranolol2, 5 may elevate the standing BP. It has also been reported that nonselective β-blockade reduced the fall in SBP on standing up, while a selective β1-blocker did not.2 However, there are other reports which do not support the effectiveness of β-blockers in orthostatic hypotension.7 None of these reports used 24 h BP recording to fully document the effects of β-blockers in orthostatic hypotension.
Considering the two proposed mechanisms of orthostatic hypotension described above, the first – impaired baroreceptor function assessed by the Valsalva maneuver and by heart rate reactivity during the tilt test1 – did not improve with atenolol in this case. The second is improvement of impaired vasoconstriction on standing, which could occur either by enhanced α-sympathetic activity3 or by blockade of vasodilator β2 receptors. While there are no reports of β-blockers actually increasing α-sympathetic activity, atenolol has been reported to cause an acute increase of sympathetic nerve activity.8 Cardio-selective β-blockers such as atenolol would not be expected to affect the β2 vasodilator effect, and we observed no increase of standing BP in our patient.
A third mechanism, which we believe has not previously been proposed, is related to the observed reduction of supine and nocturnal BP. In patients with orthostatic hypotension, supine hypertension could result from excessive cardiac output or from inappropriately high systemic vascular resistance9 driven by residual sympathetic tone acting on hypersensitive receptors, and unrestrained by the impairment of baroreflex buffering.10 As venous return is greatly increased when patients with orthostatic hypotension lie down, an increased cardiac output seems the more likely mechanism. Supine hypertension may also stimulate pressure natriuresis leading to relative volume depletion during the night, and hence worsening the orthostatic hypotension.11
In our case, the improvement of supine hypertension through prevention of the increase of cardiac output by the β1-blocker may have been the critical mechanism. This would be consistent with the observation that atenolol lowered the night-time PR from 93 to 70 bpm. Although the standing BP did not change, the reduction of supine hypertension and the change of BP during postural change, together with the reduction of BP variability, might have contributed to the relief of dizziness with the β1-blocker. Previous reports of the use of β-blockers2, 5, 6 in orthostatic hypotension have focused on the prevention of the fall of standing BP, and did not examine the circadian BP rhythm. An increased night-time BP is an important component of autonomic failure.12
In conclusion, a once-daily low dose of atenolol at bedtime improved supine hypertension and BP variability, and may be an optional method to treat severe orthostatic hypotension due to diabetic autonomic neuropathy.
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This study was supported by the grant from Jichi Medical School Young Investigator award.
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Eguchi, K., Pickering, T., Ishikawa, J. et al. Severe orthostatic hypotension with diabetic autonomic neuropathy successfully treated with a β1-blocker: a case report. J Hum Hypertens 20, 801–803 (2006). https://doi.org/10.1038/sj.jhh.1002066
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