In 40 to 50% of renin dependent essential hypertensives, normal modulation of angiotensin II (Ang II) response with changes in sodium intake is absent or lost. When salt replete, they have abnormally low renal plasma flows (RPF) and blunted declines in RPF in response to exogenously administered Ang II. When salt deplete, their expected aldosterone response to exogenous Ang II is markedly attenuated. Treatment with angiotensin converting enzyme inhibitors (CEI) corrects these abnormalities and ameliorates the hypertension with an associated Na+ diuresis. It is hypothesized that nonmodulating hypertension is caused by either a change in Ang II receptor-effector coupling leading to enhanced Ang II sensitivity or increased local production of Ang II. The hypothesis that genetic hypertension in spontaneously hypertensive rats (SHR) is due to an enhanced slow pressor response to Ang II is based on the observation that SHR are remarkedly more sensitive then Wistar Kyoto (WKY) rats to the slow pressor response to Ang II. We hypothesize that nonmodulating hypertension is similar to genetic hypertension in the rat. We will examine whether nonmodulators 1) CEI-pretreated exhibit an enhanced slow pressor response to Ang II when compared to normals and modulators, 2) CEI-pretreated can reproduce an abnormal RPF in response to Ang II selectively by a slow infusion of Ang II, and 3) in the forementioned maneuver is associated with a new accumulation of Na+. Caffeine, an adenosine antagonist, enhances the slow pressor response to Ang II in the WKY rat, probably by facilitation of norepinephrine (NE) release. We hypothesize that failure of adenosine release might explain the abnormalities in nonmodulating hypertension. We will determine if 1) caffeine administration converts modulators into nonmodulators and 2) CEI- pretreated nonmodulators and modulators, caffeine abolishes the expected difference in the slow pressor response to Ang II. In salt replete hypertensives, the forearm blood flow (FBF) response to isoproterenol (INE) is abnormally attenuated. Salt restriction corrects this. We hypothesize that nonmodulators might demonstrate an exaggerated Ang II facilitation of NE release when salt replete and an inappropriate down-regulation of vascular beta-2-responsiveness. We will determine whether 1) the abnormal attenuation of the FBF response to INE is limited to salt replete nonmodulators, 2) CEI restores the vascular responsiveness to normal, and 3) in CEI-pretreated nonmodulators, chronic infusion of Ang II unmasks an abnormal attenuation of FBF.
| Braren, V; West Jr, J C; Boerth, R C et al. (1988) Management of children with hypertension from reflux or obstructive nephropathy. Urology 32:228-34 |
