Normal TGF Responsiveness During Chronic Treatment With Angiotensin-Converting Enzyme Inhibition
Role of AT1 Receptors
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Abstract—Acute inhibition of angiotensin II formation by angiotensin-converting enzyme inhibition (ACE-I) attenuates tubuloglomerular feedback (TGF) responsiveness. This has been proposed to facilitate sodium excretion, which contributes to the antihypertensive effects of ACE-I. However, in previous experiments in spontaneously hypertensive Fawn-hooded rats, TGF responses were normal during chronic ACE-I treatment. In the present study, we investigated TGF responsiveness during chronic ACE-I treatment in normotensive rats and the involvement of changes in nitric oxide or angiotensin II activity. Maximum TGF responses were assessed in control Sprague-Dawley rats and in rats acutely (acute ACE-I, 3 μg/min IV) and chronically (chronic ACE-I, 100 mg/L PO 2 to 3 weeks+acute 3 μg/min enalaprilat IV) treated with ACE-I. In all groups, TGF responses were also assessed during late proximal tubular perfusion with 1 mmol/L nitro-l-arginine. In a last group, the chronic ACE-I treatment was combined with acute ACE-I and high doses of intrarenal losartan (acute 3 μg/min enalaprilat IV+50 mg/kg losartan). The maximum TGF responses in acutely treated ACE-I rats were strongly attenuated (0.7±0.4 mm Hg versus 6.5±0.8 mm Hg in control rats, P<0.05). Mean arterial pressure was lower in the chronically treated ACE-I group (107±5 mm Hg versus 126±5 mm Hg in control rats, P<0.05); however, TGF responses were normal (6.4±0.9 mm Hg). Intraluminal nitro-l-arginine infusion did not influence TGF responses during acute ACE-I (2.3±0.4 mm Hg) but enhanced TGF responses during chronic ACE-I to the same extent as in control rats (14.5±2.3 versus 16.7±1.9 mm Hg, NS). In the rats chronically treated with ACE-I with superimposed acute infusion of losartan or chronically treated with losartan, TGF responses were significantly attenuated (1.8±0.8 mm Hg and 2.6±0.8 mm Hg, respectively; P<0.05 versus chronic ACE-I and control). Prolonged administration with ACE-I is associated with normal TGF responses. This phenomenon appears to be mediated by AT1 receptors, because acute treatment with losartan in rats chronically treated with ACE-I and chronic treatment with losartan lead to strong attenuation of TGF responses.
- Received November 1, 1999.
- Revision received December 30, 1999.
- Accepted May 10, 2000.