title: Peripheral sympatholytic actions of four AT1 antagonists: are they relevant for long-term antihypertensive efficacy?
abstract: BACKGROUND
  Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities.
  
  
  OBJECTIVE
  The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists.
  
  
  METHODS
  Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan.
  
  
  METHODS
  In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II.
  
  
  RESULTS
  Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (-42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity.
  
  
  CONCLUSIONS
  AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic Schleswig-Holstein, Campus Luebeck, Luebeck, Germany. dendorfe@medinf.mu-luebeck.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
authors.forename: Peter
authors.initials: P
authors.lastname: Dominiak
authors.forename: Klaus
authors.initials: K
authors.lastname: Tempel
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017779:Sympathetic Fibers, Postganglionic / Q000502:physiology; D013565:Sympatholytics / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D013565:Sympatholytics; D013777:Tetrazoles; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan; D000077405:Irbesartan; D019808:Losartan; C081643:candesartan; D009638:Norepinephrine