Collecting duct-derived endothelin regulates arterial pressure and Na excretion via nitric oxide.
Mice with a collecting duct-specific deletion of endothelin-1 are hypertensive and have impaired Na excretion. Because endothelin-1 activates NO synthase (NOS) in the collecting duct, we hypothesized that impaired renal NO production in knockout mice exacerbates the hypertensive state. Control and knockout mice were treated chronically with N(G)-nitro-l-arginine methyl ester, and blood pressure (BP) and urinary nitrate/nitrite excretion were assessed. On a normal Na diet, knockout systolic BP was 18 mm Hg greater than in controls. N(G)-nitro-l-arginine methyl ester increased BP in control mice by 30 mm Hg and 10 mm Hg in collecting duct-specific deletion of endothelin-1 knockout mice, thereby abolishing the difference in systolic BP between the groups. A high-Na diet increased BP similarly in both groups. Urinary nitrate/nitrite excretion was lower in knockout mice than in controls on normal or high Na intake. In separate experiments, renal perfusion pressure was adjusted in anesthetized mice, and urinary nitrate/nitrite and Na excretion were determined. Similar elevations of BP increased urinary Na and nitrate/nitrite excretion in control mice but to a significantly lesser extent in knockout mice. Isoform-specific NOS activity and expression were determined in renal inner medulla homogenates from control and knockout mice. NOS1 and NOS3 activities were lower in knockout than in control mice given normal or high-Na diets. However, NOS1 or NOS3 protein expressions were similar in both groups on normal or high-Na intake. These data demonstrate that collecting duct-derived endothelin-1 is important in the following: (1) chronic N(G)-nitro-l-arginine methyl ester-induced hypertension; (2) full expression of pressure-dependent changes in sodium excretion; and (3) control of inner medullary NOS1 and NOS3 activity.
Schneider
Markus P
MP
Vascular Biology Center, Medical College of Georgia, Augusta, USA.
Ge
Yuqiang
Y
Pollock
David M
DM
Pollock
Jennifer S
JS
Kohan
Donald E
DE
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004231:Diuresis / Q000502:physiology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000502:physiology; D006977:Hypertension, Renal / Q000378:metabolism* / Q000503:physiopathology; D007679:Kidney Medulla / Q000201:enzymology; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000502:physiology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D012964:Sodium / Q000378:metabolism*
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D012964:Sodium; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester