Haas, J. A.

Abstract—Chronic intravenous infusion of subpressor doses of angiotensin II causes blood pressure to increase progressively over the course of several days. The mechanisms underlying this response, however, are poorly understood. Because high-dose angiotensin II increases oxidative stress, and some compounds that result from the increased oxidative stress (eg, isoprostanes) produce vasoconstriction and antinatriuresis, we tested the hypothesis that a subpressor dose of angiotensin II also increases oxidative stress, as measured by 8-epi-prostaglandin F2α(isoprostanes), which may contribute to the slow pressor response to angiotensin II. To test this hypothesis, we infused angiotensin II (10 ng/kg per minute for 28 days via an osmotic pump) into 6 conscious normotensive female pigs (30 to 35 kg). We recorded mean arterial pressure continuously with a telemetry system and measured plasma isoprostanes before starting the angiotensin II infusion (baseline) and again after 28 days with an enzyme immunoassay. Angiotensin II infusion significantly increased mean arterial pressure from 121±4 to 153±7 mm Hg (P<0.05) without altering total plasma isoprostane levels (180.0±24.3 versus 147.0±29.2 pg/mL;P=NS). However, the plasma concentrations of free isoprostanes increased significantly, from 38.3±5.8 to 54.7±10.4 pg/mL (P<0.05). These results suggest that subpressor doses of angiotensin II increase oxidative stress, as implied by the increased concentration of free isoprostanes, which accompany the elevation in mean arterial pressure elevation. Thus, isoprostane-induced vasoconstriction and antinatriuresis may contribute to the hypertension induced by the slow pressor responses of angiotensin II.

Abstract Rapid degradation of prostacyclin (PGI 2 ) inherent to its molecular structure has long been a major limitation in assessing the natriuretic effect of this prostaglandin. The recent availability of the stable PGI 2 analogue iloprost now allows for a comparative study with prostaglandin E 2 (PGE 2 ). In the present study conducted in six anesthetized dogs, the intrarenal effects of two consecutive doses (1 and 4 ng · kg −1 · min −1 ) of PGE 2 on renal blood flow, glomerular filtration rate, and urinary sodium excretion were compared with the effects of two identical doses of iloprost. The selected doses of PGE 2 were those producing a maximal natriuretic and vasodilator response without affecting mean arterial pressure. A washout period was allowed between administration of PGE 2 and iloprost. PGE 2 infusion significantly increased fractional sodium excretion from 0.69±0.1 to 2.79±1.1% and 4.27±1.2%% ( P <.05), respectively. These changes in fractional sodium excretion induced by PGE 2 were associated with significant increases in renal blood flow from 151.1±62 to 185±64.3 and 185.6±64.3 mL/min ( P <.05), respectively; however, no significant alterations were seen in glomerular filtration rate, from 29.5±9.4 to 35.2±12.2 and 32.7±7.8 mL/min (NS), and mean arterial pressure, from 117.6±26 to 113.9±24.1 and 112.3±24.1 mm Hg (NS) during control and PGE 2 infusion. At identical doses, sequential infusion of PGI 2 had no effect on renal blood floww and glomerular filtration rate, producing natriuresis only at the highest dose, a fractional sodium excretion from 0.69±0.1 to 0.8±0.28 mm Hg (NS) and 1.05±0.34% ( P <.05), respectively. In conclusion, the present study confirms that PGE 2 exerts a natriuretic effect during increases in renal blood flow. In contrast, PGI 2 had no hemodynamic effect, and the natriuresis was markedly blunted.

Flow of tubule fluid to the macula densa is part of a proposed feedback loop for autoregulation of glomerular filtration rate. In the present study, autoregulation of single nephron filtration rate was tested in the presence and the absence of flow to the macula densa in the rat. Filtration rates were measured at elevated arterial blood pressures caused by carotid occlusion and vagal section and at reduced renal perfusion pressures caused by partial aortic constriction. Measurements of single nephron filtration rate in the presence and the absence of flow to the macula densa were obtained by complete volume collections from the distal nephron beyond the macula densa and from the proximal tubule, respectively. Mean blood pressure was 130 ± 4 (SE) mm Hg for the initial collections, and renal perfusion pressure was 100 ± 1 mm Hg for the repeat collections (nine rats). Distal single nephron filtration rate was 42 ± 1 nliters/min at elevated perfusion pressure and 41 ± 1 nliters/min at reduced perfusion pressure; proximal single nephron filtration rate was 41 ± 1 nliters/min at elevated perfusion pressure and 41 ± 1 nliters/min at reduced perfusion pressure. Similarly, glomerular filtration rate was 4.6 ± 0.4 ml/min kg -1 body weight and 4.7 ± 0.3 ml/min kg -1 body weight at elevated and reduced perfusion pressures, respectively. Additional studies in seven dogs showed good correlation between autoregulation of single nephrons in the absence of flow to the macula densa and autoregulation of the micropunctured kidney. It is concluded that autoregulation of single nephron filtration rate is unaltered by interruption of tubule fluid flow to the macula densa.

Oxygen consumption beyond the proximal tubule is mainly determined by active solute reabsorption, especially in the thick ascending limb of the Loop of Henle. Furosemide-induced suppression of oxygen consumption (FSOC) involves inhibition of sodium transport in this segment, which is normally accompanied by a marked decrease in the intrarenal deoxyhemoglobin detectable by blood oxygen level-dependent (BOLD)-magnetic resonance imaging (MRI). This study tested the hypothesis that the magnitude of BOLD-MRI signal change after furosemide is related to impaired renal function in renovascular hypertension. In 16 pigs with unilateral renal artery stenosis, renal hemodynamics, function, and tubular function (FSOC and fluid concentration capacity) were evaluated in both kidneys using MR and multidetector computerized tomography (MDCT) imaging. Animals with adequate FSOC (23.6 ± 2.2%, P > 0.05 vs. baseline) exhibited a mean arterial pressure (MAP) of 113 ± 7 mmHg, and relatively preserved glomerular filtration rate (GFR) of 60 ± 4.5 ml/min, comparable to their contralateral kidney (66 ± 4 ml/min, P > 0.05). In contrast, animals with low FSOC (3.1 ± 2.1%, P = NS vs. baseline) had MAP of 124 ± 9 mmHg and GFR (22 ± 6 ml/min) significantly lower than the contralateral kidneys (66 ± 4 ml/min, P < 0.05). The group with preserved GFR and FSOC showed an increase in intratubular fluid concentration as assessed by MDCT that was greater than that observed in the low GFR group, suggesting better preservation of tubular function in the former group. These results suggest that changes in BOLD-MRI after furosemide can differentiate between underperfused kidneys with preserved tubular function and those with tubular dysfunction. This approach may allow more detailed physiologic evaluation of poststenotic kidneys in renovascular hypertension than previously possible.

We examined whether interactions between angiotensin II (Ang II), endothelin (ET), nitric oxide (NO), and prostaglandins (PGs) differentially regulate perfusion to distinct vascular beds. For this, we blocked either angiotensin AT 1 or ET receptors or both and then sequentially inhibited NO and PG synthesis in anesthetized dogs. Blocking Ang II or ET had similar effects on systemic hemodynamics: Mean arterial pressure fell slightly without altering cardiac output. Blocking both caused a synergistic fall in mean arterial pressure and increased cardiac output. Pulmonary vascular resistance was not altered by blocking Ang II, ET, or both but progressively increased during NO and PG blockade in group 2 (which had unblocked ET receptors), suggesting that endogenous ET exerts pulmonary vasoconstriction that is tempered by NO and PGs. In the kidney, blocking Ang II increased regional blood flow (RBF), glomerular filtration rate (GFR), and fractional excretion of sodium (FENa). In contrast, blocking ET did not alter RBF, and it decreased GFR and FENa. Combined Ang II and ET blockade markedly increased RBF without altering GFR, and FENa was maintained at the levels as when only ET was blocked. Sequentially inhibiting NO and PGs decreased RBF when Ang II or ET were blocked but had little effect when both were blocked. Finally, Ang II or ET blockade did not alter iliac blood flow. Inhibiting NO and PGs decreased iliac blood flow when Ang II or ET but not both were blocked. These results suggest that regional differences in the interactions between endogenous Ang II, ET, NO, and PGs are important determinants in systemic, pulmonary, and regional hemodynamics.