title: A prospective study of the effects of prolonged timolol therapy on alpha- and beta-adrenoceptor and angiotensin II receptor mediated responses in normal subjects.
abstract: OBJECTIVE
  Long-term treatment with beta 1-selective adrenergic antagonists gives rise to cross-sensitisation of cardiac beta 2-adrenoceptor responses, with no corresponding alteration in beta 1-adrenoceptor responses. We performed a prospective randomised double-blind placebo-controlled cross-over study of the effects of nonselective beta-blockade with timolol on alpha-adrenergic and angiotensin II receptor mediated responses in normal subjects. We also wished to study the time course of beta 1- and beta 2-adrenergic responses after withdrawal of timolol.
  
  
  METHODS
  Six healthy males received timolol 10 mg twice daily or placebo for 14 days. On day 11 of treatment, vascular alpha 1-, alpha 2- and angiotensin II receptor responses were assessed by measuring the blood pressure increases in response to intravenous phenylephrine, alpha-methylnoradrenaline and angiotensin amide respectively, following one dose of timolol 10 mg (to block the beta-adrenergic effects of phenylephrine and alpha-methylnoradrenaline). Both systolic and diastolic blood pressure increased in response to each of these drugs, but these increases were not different on timolol treatment or placebo. Following cessation of treatment with timolol or placebo, beta 1- and beta 2-adrenoceptor mediated responses were assessed by measuring the heart rate responses to treadmill exercise and intravenous salbutamol infusion respectively. Half each of the subjects underwent this 2 days and 3 days respectively, after the end of treatment.
  
  
  RESULTS
  Both exercise-induced and salbutamol-induced tachycardia were not different following placebo or 3 days following the end of timolol treatment. However, 2 days following timolol treatment, both were attenuated; the reduction in salbutamol-induced tachycardia was significant, whilst the reduction in exercise tachycardia did not reach statistical significance. We also measured metabolic responses to exercise and to salbutamol infusion. Exercise induced a rise in plasma potassium and noradrenaline. Salbutamol produced a fall in plasma potassium, a rise in plasma glucose and insulin and also a rise in plasma noradrenaline. All of these changes were not different following placebo or 3 days after the end of timolol treatment; by contrast, 2 days following timolol treatment, all were significantly attenuated, with the exception of the rise in plasma glucose. In addition, the rise in both plasma glucose and insulin in response to an oral load of 75 g glucose were not different post-placebo, 2 or 3 days post-timolol.
  
  
  CONCLUSIONS
  These results show that, following 14 days of nonselective beta-adrenoceptor blockade with timolol, there is evidence of residual beta-adrenoceptor blockade 2 days after drug withdrawal; this finding is in contrast with the known plasma profile of timolol (half-life 3-6 hours), but is consistent with our previous observations of the slow speeds of association and dissociation of timolol with beta-adrenoceptors in vitro. There is no evidence, in this study, of beta-adrenergic sensitisation following timolol withdrawal, nor of cross-regulation of vascular alpha 1-, alpha 2- or angiotensin II receptors in response to nonselective beta-adrenoceptor blockade.
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital.
authors.forename: A
authors.initials: A
authors.lastname: Ferro
authors.forename: J A
authors.initials: JA
authors.lastname: Hall
authors.forename: J E
authors.initials: JE
authors.lastname: Dickerson
authors.forename: M J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D015444:Exercise / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011446:Prospective Studies; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D013999:Timolol / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D013999:Timolol; D000420:Albuterol