Madeleine Dupont

Sodium and angiotensin in hypertension induced by long-term nitric oxide blockade.

The influence of dietary sodium restriction and angiotensin II blockade on hypertension induced by a 25-day period of administration of the inhibitor of nitric oxide synthesis NG-nitro-L-arginine-methyl ester (10 mg/kg twice daily by gavage) was assessed in Wistar rats fed a normal or low sodium diet. In addition, the angiotensin II receptor blocker losartan (30 mg/kg once daily by gavage) was administered before and during NG-nitro-L-arginine-methyl ester in rats fed the normal sodium diet. At the end of the studies, conscious systolic arterial pressure increased similarly in NG-nitro-L-arginine-methyl ester-treated groups maintained on normal or low sodium intake. Moreover, a 25% reduction in cardiac output due to a decrease in stroke volume was observed in both groups. A slight but significant cardiac hypertrophic response was observed in hypertensive rats irrespective of sodium intake. At the completion of studies, plasma renin activity was similar to corresponding controls in the hypertensive groups on normal or low sodium intake. Losartan totally prevented the development of hypertension as well as the decrease in stroke volume and cardiac hypertrophy associated with NG-nitro-L-arginine-methyl ester treatment in rats on normal sodium intake. In conclusion, hypertension resulting from long-term blockade of nitric oxide synthesis was not affected by dietary sodium restriction. A crucial role for the renin-angiotensin system was demonstrated in this new model of hypertension.

Preglomerular Sudanophilia in L-NAME Hypertensive Rats: Involvement of Endothelin

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.

Evidence for a postsynaptic effect of captopril in isolated perfused rabbit kidney

The influence of captopril (SQ 14225) on the vascular and norepinephrine-releasing responses to nerve stimulation (2, 5 and 10 Hz) was assessed in isolated blood-free perfused rabbit kidney. At a concentration of 0.23 and 0.46 mM in the perfusion medium, captopril markedly attenuated the vasoconstrictor response but did not influence the release of norepinephrine produced by nerve stimulation. These results suggest that captopril may act as an alpha-antagonist at a postjunctional level.

6 Development of sudanophilic lesions along the renal preglomerular vasculature during prolonged NG-nitro-L-arginine methyl ester-induced hypertension in rats

Methods: The morphology of renal pregiomerular vessels was studied in normotensive male Wistar rats (controls) and in rats in which hypertension was induced by oral administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20mg/kg per day) for 5, 10 and 25 days. Large, mostly intact, portions of the pregiomerular vasculatures consisting of arcuate (ArcA), interlobular arteries (ILA) and afferent arterioles were isolated from the kidneys using a recently developed maceration-dissection technique [1]. For comparison, vessels were similarly isolated from cardiac and cerebral tissue. Systolic blood pressure was measured by tail-cuff manometry before and after 5, 10 and 25 days of treatment. Results: Systolic blood pressure (mean±SEM) significantly increased by 18±2% (n = 5), 21±2% (n = 6) and 49±9% (n = 7), respectively. Controls showed no significant variations in sys-tolic blood pressure over the 25 days. Microscopic observation of hypertensive renal vessels revealed the presence of focal, granular deposits within the media of ArcA and ILA. These deposits showed a general orientation parallel to that of smooth muscle cells and were associated with increased wall thickness. The frequency of focal deposits increased in a time-dependent manner. Focal deposits were never observed along afferent arterioles, cardiac or cerebral vessels in hypertensive rats. No renal, cardiac or cerebral deposits were observed in the controls. Granular deposits could not be immunostained for renin but were stained with the lipophilic dye Sudan black. Conclusion: L-NAME-induced hypertension is associated with a rapid and progressive development of sudanophilic lesions along pre-afferent vessels. Our results suggest that renal atherosclerosis is associated with L-NAME-induced hypertension.