title: Volume expansion during acute angiotensin II receptor (AT(1)) blockade and NOS inhibition in conscious dogs.
abstract: The responses to AT(1)-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester 30 microg small middle dot kg(-1) small middle dot min(-1)) were investigated in separate experiments in normal dogs. AT(1) blockade decreased arterial pressure (106 +/- 4 to 96 +/- 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 +/- 3 to 116 +/- 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT(1) blockade and NOS inhibition (21 +/- 4 mmHg). Volume expansion during AT(1) blockade elicited marked natriuresis (26 +/- 11 to 274 +/- 55 micromol/min) that was severely reduced by concomitant NOS inhibition (10 +/- 3 to 45 +/- 11 micromol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 +/- 1 to 23 +/- 7 micromol/min). Volume expansion during AT(1) blockade increased GFR (+30%), less so during combined AT(1) blockade and NOS inhibition (+13%), but it did not increase GFR significantly (P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT(1) blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute AT(1) blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.
authors.affiliation: Department of Medical Physiology, University of Copenhagen, DK-2200, Denmark.
authors.forename: Jens Lundbaek
authors.initials: JL
authors.lastname: Andersen
authors.forename: Niels C F
authors.initials: NC
authors.lastname: Sandgaard
authors.forename: Peter
authors.initials: P
authors.lastname: Bie
mesh_terms: D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001798:Blood Proteins / Q000378:metabolism; D001810:Blood Volume / Q000502:physiology*; D003243:Consciousness; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009994:Osmolar Concentration; D011188:Potassium / Q000097:blood; D044140:Receptor, Angiotensin, Type 1; D012964:Sodium / Q000097:blood / Q000652:urine; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D012964:Sodium; D019001:Nitric Oxide Synthase; D011188:Potassium; C081643:candesartan; D019331:NG-Nitroarginine Methyl Ester