title: Potentiation of L-NAME-induced systemic and renal vasoconstrictor responses by alpha1-adrenoceptor antagonism.
abstract: BACKGROUND
  Acute inhibition of nitric oxide synthase results in systemic and renal vasoconstriction, which might be attributable to unopposed activity of the sympathetic nervous (SNS) and the renin-angiotensin system (RAS). We studied the effects of N-nitro-L-arginine methyl ester (L-NAME) during alpha1-adrenoceptor blockade and concomitant angiotensin II type 1 (AT1)-receptor blockade in hypertensive individuals pretreated with hydrochlorothiazide (Hct; 25 mg once daily).
  
  
  METHODS
  Thirteen individuals (47 +/- 9 years) were studied during administration of placebo, and after pretreatment with Hct + doxazosin (Dox; 8 mg twice daily for 9 days), with Hct + Dox + losartan (Los; 50 mg twice daily for 9 days), or (n = 5) with doxazosin or Dox + Los without hydrochlorothiazide. Mean arterial pressure (MAP) and cardiac output were derived from the finger blood pressure signal recorded by Finapres. Systemic vascular resistance (SVR) was calculated as MAP/cardiac output. Five renal clearance studies of 40 min were performed. Renal vascular resistance (RVR) was calculated as MAP divided by renal blood flow (RBF). L-NAME (12.5 microg/kg per min intravenously) was given during the third clearance period.
  
  
  RESULTS
  MAP was 113 +/- 11 mmHg at baseline and decreased to 99 +/- 10 mmHg during the administration of Hct + Dox and to 92 +/- 10 mmHg during Hct + Dox + Los. This decrease in MAP was caused by a decrease in SVR (P = 0.0009). Pretreatment with Hct + Dox or Hct + Dox + Los had no effect on glomerular filtration rate or RBF. Infusion of L-NAME during the administration of Hct + Dox resulted in an augmented (P < 0.0001) increase in MAP (18%), SVR (61%) and RVR (70%) compared with those observed with placebo (8, 30 and 49%, respectively). This augmentation was abolished by losartan.
  
  
  CONCLUSIONS
  L-NAME-induced systemic and renal vasoconstrictor responses are potentiated during alpha1-adrenoceptor blockade. This potentiation was abolished by AT1-receptor antagonism. In man, unopposed activity of the SNS or SNS and RAS is not involved in the systemic and renal vasoconstriction induced by L-NAME.
authors.affiliation: Erasmus MC, Department of Vascular and Metabolic Diseases, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
authors.forename: Nicole Aj
authors.initials: NA
authors.lastname: van der Linde
authors.forename: Frans
authors.initials: F
authors.lastname: Boomsma
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D012079:Renal Circulation / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000804:Angiotensin II; D019331:NG-Nitroarginine Methyl Ester