Role of angiotensin II in L-NAME-induced systemic and renal hemodynamic effects in hydrochlorothiazide-pretreated hypertensive subjects.
BACKGROUND
Experimental evidence suggests that in conditions associated with an activated renin-angiotensin system, unopposed activity of angiotensin II underlies the marked renal vasoconstrictor response to nitric oxide synthase inhibition. In the present study, we investigated whether this holds true in hypertensive subjects pretreated with hydrochlorothiazide (HCT).


METHODS
Systemic N(G)-nitro-L-arginine methyl ester (L-NAME) infusions (12.5 microg/kg per min for 40 min) were given to eight hypertensive subjects (age 53 +/- 6 years) during placebo, and during pretreatment with HCT (25 mg once daily) or HCT and losartan (LOS) (50 mg twice daily), both for 9 days. The glomerular filtration rate (GFR) and renal plasma flow were estimated from the clearances of radiolabeled thalamate and hippuran. Renal blood flow (RBF) was calculated as renal plasma flow/1 - hematocrit and the renal vascular resistance (RVR) as mean arterial pressure (MAP) divided by RBF.


RESULTS
Compared with placebo, plasma renin increased (P < 0.001) from 15 +/- 4 mU/l during placebo to 26 +/- 7 mU/l during HCT and to 133 +/- 51 mU/l during HCT + LOS. MAP (110 +/- 3 mmHg) decreased to 102 +/- 4 mmHg during HCT and to 98 +/- 5 mmHg during HCT + LOS. RBF (579 +/- 36 ml/min), GFR (97 +/- 6 ml/min) and filtration fraction (29 +/- 2%) did not change, whereas RVR (200 +/- 15 RU) decreased to 183 +/- 13 RU during HCT and to 165 +/- 14 RU during HCT + LOS (P < 0.05). In response to L-NAME, MAP and RVR increased maximally by 10 +/- 3 and 67 +/- 9%, whereas RBF and GFR decreased maximally by 42 +/- 6 and 18 +/- 4%. Compared with these responses, the responses of MAP, RBF and RVR were not affected by pretreatment of HCT or HCT + LOS, but the L-NAME-induced decrease in GFR (26 +/- 5% during HCT and 29 +/- 5% during HCT and LOS) was enhanced (P < 0.01).


CONCLUSIONS
In hypertensive subjects with an activated renin-angiotensin system, unopposed activity of angiotensin II is not involved in L-NAME-induced pressor and renal vasoconstrictor response, whereas the L-NAME-induced decrease in GFR is enhanced, indicating greater dependency of GFR on nitric oxide-mediated vasodilator tone during sodium depletion.
van der Linde
Nicole A
NA
Erasmus Medical Center, Department opf Internal Medicine, University Hospital Dijkzigt, Rotterdam, The Netherlands.
van den Meiracker
Anton H
AH
Boomsma
Frans
F
D000804:Angiotensin II / Q000378:metabolism*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006728:Hormones / Q000097:blood; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester; D009318:Natriuresis / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D004232:Diuretics; D004791:Enzyme Inhibitors; D006728:Hormones; D049993:Sodium Chloride Symporter Inhibitors; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester