While the physiology of the normal carotid baroreflex is reasonably well established, the pathophysiology of carotid sinus hypersensitivity (CSH) remains obscure. It has been proposed that central α₂ adrenoceptor upregulation provides the substrate for the changes in baroreflex gain which manifest as CSH.¹ This hypothesis suggests that carotid sinus stiffness resulting from age related cardiovascular disease causes relative diminution of afferent baroreceptor neural traffic, with compensatory brain stem post-synaptic α₂ adrenoceptor upregulation. This physiologic denervation hypersensitivity then causes the overshoot bradycardia and hypotension following carotid sinus stimulation that is clinical CSH. Though widely quoted, this hypothesis has no evidence base, and no attempts have been made to date to test it. If α₂ adrenoceptor hypersensitivity was the major pathophysiological defect in CSH, a centrally active α₂ adrenoceptor antagonist should abolish or attenuate the effects of carotid sinus massage (CSM) in such individuals.^1,2 In order to test this hypothesis we studied the effects of the central α₂ adrenoceptor antagonist yohimbine³ on the vasodepressor response to CSM in syncopal subjects with CSH, in a randomised, double blind, placebo controlled study, utilising a crossover design.

Eighteen consecutive patients with syncope caused by CSH, who had been referred for permanent pacemaker implantation through our syncope facility and had a minimum reproducible vasodepressor response of 20 mm Hg during CSM post-pacemaker, participated in this study. While a 50 mm Hg fall in systolic blood pressure (SBP) during CSM defines vasodepressor CSH,⁴ a previous study has shown that during supine CSM in healthy subjects, mean vasodepression was 19 mm Hg on the right, and 14 mm Hg on the left.⁵ Subjects were studied post-pacemaker implantation so that the fixed cardiac pacing rate avoided the confounding effects of hypotension secondary to variable bradycardic or asystolic responses to CSM. The investigation had local ethical approval. Following informed, written consent, 10 ml solutions of intravenous yohimbine hydrochloride (0.063 mg/kg) and normal saline were infused over two minutes into each subject via antecubital cannulae, on separate days, in random, double blind fashion with a minimum 48 hours between injections to ensure adequate washout of the active drug (distribution half life 0.4–18 minutes, elimination half-life 15–150 minutes) (fig 1​1).³

Of 18 subjects, nine were female and the mean age was 73.9 (8.31) years. None of the subjects were on medications that interacted with α₂ adrenoceptors or yohimbine. Seven (39%) subjects experienced side effects following yohimbine infusion which included tremulousness, anxiety, teeth chattering, and cold sweat; one subject experienced a headache after receiving the placebo. The rise in SBP following yohimbine injection (37 mm Hg) was significantly greater than that following saline injection (15 mm Hg, 95% confidence interval (CI) 8.12 to 35.54; p = 0.0037), a difference of 22 mm Hg (fig 2​2).). Vasodepressor responses and time to SBP nadir with CSM are detailed in table 1​1 and fig 3​3 (vasodepressor responses only).

We found no evidence of a critical role for central α₂ adrenoceptor upregulation in the pathogenesis of CSH. If the hypothesis were correct, the powerful central α₂ adrenoceptor antagonist yohimbine should have attenuated the vasodepressor response to CSM; it did not. Criticism could be levelled at the small vasodepressor response (less than the usual SBP criteria for vasodepressor CSH), but its previous validation as an abnormal response,⁵ reproducibility and the within subjects control factor afforded by the crossover design, make this unlikely. Furthermore, the use of patients with a pure vasodepressor response to CSM (that is > 50 mm Hg fall in SBP with CSM) may have increased the risk of watershed type neurological complications, particularly given the repeated episodes of CSM in each patient. Patients with a pacemaker already implanted, controlled for the potentially confounding effects of bradycardia/asystole on blood pressure. O’Mahony suggested pre-medication with apraclonidine before yohimbine injection to ensure only central α₂ adrenoceptor blockade.¹ While the hypertension and other hyperadrenergic side effects experienced by study participants clearly demonstrate the adequacy of central α₂ adrenoceptor blockade, the vasodepressor response to CSM during yohimbine administration was unchanged, arguing strongly against a significant role for these receptors in CSH.