Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans.
Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 μg·kg-1·min-1NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP (P< 0.005 vs. baseline), -10% GFR, -20% RBF, -49% UNaV (P< 0.001), and +120% U8-iso-PGF2αV (P< 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME (P> 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA,P> 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (-6%), RBF (-12%), and UNaV (-34%) were blunted vs. PL + l-NAME and LOS + l-NAME (P< 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%,P> 0.05 vs. baseline;P< 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.
Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; alberto.montanari@unipr.it.
Alberto
A
Montanari
Prevention and Rehabilitation Unit at the Don Gnocchi Foundation and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; and.
Davide
D
Lazzeroni
Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy.
Giovanna
G
Pelà
Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy.
Antonio
A
Crocamo
Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Yuliya
Y
Lytvyn
Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy.
Luisa
L
Musiari
Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy.
Aderville
A
Cabassi
Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
David Z I
DZI
Cherney
D000328:Adult; D062186:Arterial Pressure / Q000187:drug effects; D015415:Biomarkers / Q000652:urine; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D004095:Dihydropyridines / Q000008:administration & dosage*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D064368:Healthy Volunteers; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000201:enzymology; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D009318:Natriuresis / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009578:Nitrobenzenes; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines; D012079:Renal Circulation / Q000187:drug effects*; D013997:Time Factors
D015415:Biomarkers; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D009578:Nitrobenzenes; D010879:Piperazines; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; C054218:manidipine; D015237:Dinoprost; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester
NG-nitro-l-arginine methyl ester; losartan; manidipine; nitric oxide; renal hemodynamic function