REGULATION OF α‐ AND β‐ADRENOCEPTOR RESPONSIVENESS. STUDIES IN PATIENTS WITH CHRONIC AUTONOMIC FAILURE

1 Seven patients with severe orthostatic hypotension due to peripheral autonomic neuropathy were studied. 2 In four patients, heart rate did not change after the β‐adrenoceptor antagonists propranolol or metoprolol. After the partial β‐adrenoceptor agonist pindolol heart rate rose in a dose‐dependent manner. After α‐adrenoceptor antagonists phentolamine and yohimbine heart rate and blood pressure did not change, which confirmed that these patients were indeed sympathetically denervated. 3 The non‐selective β‐adrenoceptor agonist isoprenaline and the β 2 ‐selective β‐adrenoceptor agonist salbutamol increased heart rate and lowered arterial pressure, whereas the β 1 ‐adrenoceptor agonist prenalterol increased both heart rate and arterial pressure. After treatment with pindolol, the patient was desensitized for the chronotropic effects of the β‐adrenoceptor agonists in the order: salbutamol > isoprenaline > prenalterol. The desensitization of the depressor effects of the β‐adrenoceptor agonists was in the order isoprenaline > salbutamol. These data suggest preferential cardiovascular β 2 ‐adrenoceptor sensitization in patients with chronic autonomic failure, which can be reversed by treatment with pindolol. They also provide in vivo evidence for the existence of cardiac chronotropic β 2 ‐adrenoceptors in man. 4 The α‐adrenoceptor agonists methoxamine, phenylephrine, noradrenaline, clonidine and guanfacine increased arterial pressure. The vascular reactivity for the different α‐adrenoceptor agonists differed markedly, as was shown by the declining steepness of the dose‐response curves in the order methoxamine and phenylephrine > noradrenaline > clonidine > guanfacine. The pressor profiles of these agonists were also different. These data suggest, that different α‐adrenoceptor populations are involved in the contractile responses to these α‐agonists, being methoxamine and phenylephrine a 1 , noradrenaline α 1 > α 2 and clonidine and guanfacine α 2 > α 1 . 5 Two patients were treated with clonidine, slow release, 250 μg daily, which increased supine and standing arterial pressure and relieved orthostatic symptoms. In one patient the pressor‐depressor response to adrenaline was converted to a pure pressor response after clonidine, which contrasted with a pure pressor response to adrenaline after treatment with pindolol. Treatment with clonidine shifted the dose‐response curves of the α‐adrenoceptor agonists in the order clonidine > noradrenaline > phenylephrine, suggesting preferential α 2 ‐adrenoceptor desensitization by clonidine in this patient. 6 These data provide further evidence for the view that α 1 ‐β 1 and α 2 ‐β 2 ‐adrenoceptor sensitivity and/or responsiveness are independently regulated and lend support to the hypothesis that peripheral α 2 ‐β 2 ‐adrenoceptors are not innervated.