Effects of unclipping and converting enzyme inhibition on bilateral renal function in Goldblatt hypertensive rats

Effects of unclipping and converting enzyme inhibition on bilateral renal function in Goldblatt hypertensive rats. Previous studies have demonstrated that blockade of the renin-angiotensin system in two-kidney, one clip Goldblatt hypertensive rats induced arterial pressure associated reductions in the function of the renin rich, clipped kidney even though the renin-depleted, contralateral kidney exhibited enhanced renal hemodynamics and excretory function. This study was performed to evaluate the influence of inhibition of the activity of the renin-angiotensin system on the function of each kidney following the unclipping of the clipped kidney. Renin-angiotensin system blockade was accomplished by intravenous infusion of converting enzyme inhibitor (CEI, SQ 20881, 3 mg/hr · kg), either before (group 1, N = 15) or after (group 2, N = 16) removal of the clip. CEI infusion before unclipping decreased arterial blood pressure (BP), from 157 ± 3 to 124 ± 3mm Hg and led to increases in renal blood flow (RBF), GFR, urinary volume and sodium excretion in the nonclipped kidney. When the clip was still in place, renal function decreased in the clipped kidney during CEI infusion. Upon removal of the clip, there were immediate increases in RBF and GFR, and pronounced diuresis; natriuresis and kaliuresis ensued despite a further reduction of BP from 124 ± 3 to 110 ± 3mm Hg. In group 2, unclipping of the clipped kidney prior to administration of CEI reduced BP from 161 ± 4 to 118 ± 3mm Hg within 2hr. Nevertheless, RBF, GFR, urine flow, and sodium and potassium excretion rates increased in this newly undipped kidney. Subsequent infusion of CEI decreased BP further, but RBF, GFR, and urinary excretion rates of both kidneys increased significantly. These results suggest that hemodynamic and excretory function of both the nonclipped and clipped kidneys are influenced substantially by the renin-angiotensin system; however, this influence on the clipped kidney can be unmasked only after the clip has been removed.Effets de l'ablation du clip et de l'inhibition de l'enzyme de conversion sur la fonction rénale bilatérale chez des rats hypertendus selon Goldblatt. Les études antérieures ont démontré que le blocage du système rénine-angiotensine chez des rats hypertendus selon Goldblatt à deux reins et un clip entrainait des réductions de la fonction du rein riche en rénine clippé, en rapport avec la pression artérielle, bien que le rein contralatéral, déplété en rénine, ait une augmentation de l'hémodynamique et de la fonction excrétoire rénales. Cette étude a été entreprise afin d'évaluer l'influence de l'inhibition de l'activité du système rénine-angiotensine sur la fonction de chaque rein après ablation du clip du rein clippé. Le blocage du système rénine-angiotensine a été effectué par perfusion intra-veineuse de l'inhibiteur de l'enzyme de conversion (CEI, SQ 20881, 3 mg/hr · kg) soit avant (groupe 1, N = 15) soit après (groupe 2, N = 16) ablation du clip. La perfusion de CEI avant l'ablation du clip a abaissé la pression artérielle (BP) de 157 ± 3 à 124 ± 3mm Hg, et a augmenté le flux sanguin (RBF), le GFR, le volume urinaires et l'excrétion sodée du rein non clippé. Lorsque le clip était encore en place, la fonction rénale diminuait du côté du rein clippé pendant la perfusion de CEI. Lors de l'ablation du clip, il y avait des augmentations immédiates du RBF et de GFR et une diurèse; une natriurèse et une kaliurèse prononcées se produisaient malgré une réduction supplémentaire de la BP de 124 ± 3 à 110 ± 3mm Hg. Dans le groupe 2, l'ablation du clip avant l'administration de CEI a réduit la BP du rein clippé de 161 ± 4 à 118 ± 3mm Hg en 2hr. Cependant, le RBF, le GFR, le débit urinaire, et l'excrétion de sodium et de potassium se sont élevés dans ce rein dont le clip a été récemment enlevé. La perfusion ultérieure de CEI diminuait BP plus mais RBF, GFR, et les excrétions urinaires des deux reins ont augmenté significativement. Ces résultats suggèrent que les fonctions hémodynamique et excrétoire des reins clippés et non-clippés sont substantiellement influencées par le système rénine-angiotensine; cependant, cette influence sur le rein clippé ne peut être démasquée qu'après ablation du clip

Renal Heme Oxygenase-1 Induction with Hemin Augments Renal Hemodynamics, Renal Autoregulation, and Excretory Function

Heme oxygenases (HO-1; HO-2) catalyze conversion of heme to free iron, carbon monoxide, and biliverdin/bilirubin. To determine the effects of renal HO-1 induction on blood pressure and renal function, normal control rats (n=7) and hemin-treated rats (n=6) were studied. Renal clearance studies were performed on anesthetized rats to assess renal function; renal blood flow (RBF) was measured using a transonic flow probe placed around the left renal artery. Hemin treatment significantly induced renal HO-1. Mean arterial pressure and heart rate were not different (115±5 mmHg versus 112±4 mmHg and 331±16 versus 346±10 bpm). However, RBF was significantly higher (9.1±0.8 versus 7.0±0.5 mL/min/g, P<0.05), and renal vascular resistance was significantly lower (13.0±0.9 versus 16.6±1.4 [mmHg/(mL/min/g)], P<0.05). Likewise, glomerular filtration rate was significantly elevated (1.4±0.2 versus 1.0±0.1 mL/min/g, P<0.05), and urine flow and sodium excretion were also higher (18.9±3.9 versus 8.2±1.0 μL/min/g, P<0.05 and 1.9±0.6 versus 0.2±0.1 μmol/min/g, P<0.05, resp.). The plateau of the autoregulation relationship was elevated, and renal vascular responses to acute angiotensin II infusion were attenuated in hemin-treated rats reflecting the vasodilatory effect of HO-1 induction. We conclude that renal HO-1 induction augments renal function which may contribute to the antihypertensive effects of HO-1 induction observed in hypertension models

AT1 Receptor Blockade Prevents the Increase in Blood Pressure and the Augmentation of Intrarenal ANG II Levels in Hypertensive Cyp1a1-Ren2 Transgenic Rats Fed With a High-Salt Diet

BACKGROUND: The present study was performed to determine the effects of high-salt diet on the magnitude of the increases in systolic blood pressure (SBP) and kidney tissue ANG II levels that occur following induction of ANG II-dependent malignant hypertension in Cyp1a1-Ren2 transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name: TGR (Cyp1a1Ren2)]. METHODS: Cyp1a1-Ren2 rats (n=6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension. RESULTS: Rats induced with I3C exhibited increases in (SBP) and elevations of ANG II levels in kidney cortex and medulla. In a second group of rats (n=6), high salt intake alone did not alter basal SBP; however, subsequent dietary administration of 0.3% I3C during continued high salt intake elicited a substantially greater increase in SBP than observed in rats fed a normal salt diet. ANG II levels in kidney cortex and medulla of rats induced with I3C and fed a high salt diet were elevated similarly to those in rats induced with I3C alone. Chronic administration of the AT(1) receptor antagonist, losartan (100 mg/L in drinking water, n=6), markedly attenuated the I3C-induced increase in SBP and prevented the augmentation of ANG II levels in kidney cortex and medulla in rats induced with I3C and maintained on a high salt diet. CONCLUSIONS: Activation of AT(1) receptors contributes to the augmented blood pressure and elevated kidney tissue ANG II levels that occur in Cyp1a1-Ren2 transgenic rats with malignant hypertension maintained on a high salt diet

ACE2-Mediated Reduction of Oxidative Stress in the Central Nervous System Is Associated with Improvement of Autonomic Function

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1–7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2−/y) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2−/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2−/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2−/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2−/y mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2−/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress

The legacy of Homer W. Smith: mechanistic insights into renal physiology

In 1945, Homer W. Smith published an article in the JCI that clearly demonstrated that para-aminohippuric acid is the most suitable agent for the evaluation of renal plasma flow in both humans and dogs; in addition, the paper provided detailed methodology that is still in use today. This paper is but one of many outstanding works performed by Smith and his colleagues that clearly established the clearance technique as a powerful noninvasive approach to gain mechanistic insights into intrarenal function