Biomedical subjects

L G Navar

Publications and source records attributed to L G Navar.

At least 73 records · Page 4Linked to original sources

PubMed1997

Plasma renin activity and metabolic clearance rate of angiotensin II in the unstressed aging rat.

We conducted studies in conscious chronically catheterized, trained young (3-5 months) and old (18-20 months) rats to assess the impact of aging on baseline renin activity (PRA) and metabolic clearance rate (MCR) of angiotensin II (ANG II). We observed that under unstressed conditions the baseline values of PRA and plasma ANG II were no different in young versus old rats (1.8 +/- 0.2 versus 1.5 +/- 0.2 ng Al/ml/h and 18 +/- 3 versus 15 +/- 2 fmol/ml, respectively). Values of PRA in the present study were similar to those reported by others for old rats, but our young rat values were lower than usually reported. This probably reflects our use of an unstressed preparation. We also observed a blunted increase in PRA in old rats in response to acute converting enzyme inhibition. Overall, our observations suggest that old rats may lose their ability to increase PRA in response to acute stimuli, including perhaps, the stress of blood drawing in emotionally or surgically stressed preparations. We also observed that the MCR of ANG II increased with age, despite similar baseline plasma ANG II concentrations in young and old. This suggests that with aging, an increase occurs in the rate of synthesis of ANG II. These results emphasize the importance of establishing true baseline values for indices of the renin-ANG II system in aging.

Aging↗

PubMed1997

Nitric oxide in the mediation of pressure natriuresis.

1. Recent studies have indicated that nitric oxide (NO) production in the kidney contributes to the regulation of renal haemodynamics and excretory function. Inhibition of nitric oxide synthase (NOS) reduces renal blood flow by approximately 25% and markedly reduces sodium excretion without reductions in filtered load. In particular, inhibition of NO synthesis markedly suppresses the slope of the arterial pressure-mediated response in sodium excretion. 2. Further studies have shown that constant intrarenal infusion of a NO donor in dogs treated with a NOS inhibitor produced diuretic and natriuretic responses but failed to restore the slope of the pressure-induced natriuretic response. These data indicate that an alteration in intrarenal NO activity, rather than the simple presence of NO during changes in arterial pressure is required for full expression of pressure natriuretic responses. 3. In support of the hypothesis that NO is involved in the mediation of pressure natriuresis, we also recently demonstrated a direct relationship between changes in arterial pressure and urinary excretion rate of sodium as well as nitrate and nitrite (a marker for endogenous NO activity) in the presence of efficient autoregulation of cortical and medullary blood flow. 4. The direct inhibitory actions of NO on tubular sodium reabsorption have also been observed in cultured tubular cells as well as isolated, perfused cortical collecting duct segments. 5. Thus, the collective data suggest that acute changes in arterial pressure induce changes in intrarenal NO production, which may directly alter tubular reabsorptive function to manifest the phenomenon of pressure natriuresis.

Animals↗

PubMed1997

Immunohistochemical localization of ANG II AT1 receptor in adult rat kidney using a monoclonal antibody.

Molecular and functional studies have suggested that AT1 receptors are present in most nephron segments, yet direct demonstration of AT1 at these sites is lacking. The present study was performed to determine the intrarenal localization of the AT1 receptor utilizing a monoclonal anti-peptide (amino acid residues 8-17) antibody (6313/G2) in adult male Sprague-Dawley rats. Western blot analysis of kidney protein extracts showed a predominant 41-kDa immunoreactive band corresponding to the molecular weight of the deduced cDNA sequence. To determine optimal fixation conditions, kidney tissues were immersion fixed in Bouin's solution, 10% buffered Formalin, or 4% paraformaldehyde. Specificity of immunostaining was documented by preadsorption of the antibody with the immunogenic peptide sequence. Prominent AT1 immunostaining was visualized in the proximal tubule brush-border and basolateral membranes. In addition, distal tubules, cortical and medullary collecting ducts, and the renal arterial vasculature exhibited specific immunoreactivity. Glomerular staining for AT1 was observed in mesangial cells and podocytes. Macula densa cells stained positively. Similar localization of the AT1 receptor was obtained using the three tissue fixation methods, although the intensity of vascular and glomerular staining was highest in Bouin-fixed tissues. The present study demonstrates that the AT1 receptor is more widely distributed along the nephron than previously described and includes renal vascular smooth muscle and proximal and distal epithelial sites.

Amino Acid Sequence↗

PubMed1997

Role of renal nerves in afferent arteriolar reactivity in angiotensin-induced hypertension.

The objective of this study was to determine the contribution of renal nerves to the enhanced afferent arteriolar reactivity observed in angiotensin II (Ang II)-induced hypertension. Uninephrectomized Sprague-Dawley rats were divided into four groups: sham rats, renal-denervated rats, Ang II-infused (at 40 ng/min for 13 days) rats, and Ang II-infused+renal-denervated rats. With the use of an implanted arterial catheter, mean arterial pressure (MAP) was monitored in conscious rats. Ang II infusion resulted in a progressive increase in MAP from 98 +/- 1 (day 0) to 166 +/- 7 mm Hg (day 13). This increase in MAP was attenuated in denervated rats and averaged 136 +/- 3 mm Hg on day 13. Kidneys were harvested on day 13 for microcirculatory experiments or measurement of intrarenal Ang II levels. Basal afferent arteriolar diameter was similar in all groups, and group averages ranged from 19.6 to 20.7 microns. Chronic Ang II infusion increased intrarenal Ang II levels. Renal denervation did not alter this effect. Increasing perfusion pressure from 100 to 160 mm Hg reduced afferent arteriolar diameter significantly by 11.2 +/- 0.6% in the sham group and by a similar degree in the remaining three groups. Superfusion with Ang II (10 nmol/L) reduced afferent arteriolar diameter by 34.3 +/- 2.0% in the sham group. This response was enhanced in Ang II-infused (62.3 +/- 3.4%) but not in renal-denervated or Ang II-infused+renal-denervated rats. Additionally, the enhanced afferent arteriolar reactivity to Ang II was not influenced by adrenergic receptor blockade. The afferent arteriolar response to norepinephrine was enhanced in renal-denervated, Ang II-infused, and Ang II-infused+renal-denervated rats compared with sham controls. Administration of the calcium ionophore A23187 decreased afferent arteriolar diameter similarly in all four groups. These results indicate that renal nerves contribute to the development of hypertension and to the enhanced afferent arteriolar responsiveness to Ang II elicited by chronic Ang II infusion.

Angiotensin II↗

PubMed1997

Pressure natriuresis and renal medullary blood flow in dogs.

In the present study, we evaluated the effects of changes in arterial pressure on regional renal blood flows and sodium excretion in anesthetized dogs during control conditions and after 5% volume expansion with isotonic saline. Medullary and cortical blood flow responses were determined with laser-Doppler needle flow probes inserted into the midmedullary and midcortical regions, and whole-kidney blood flow was assessed with an electromagnetic flow probe. Volume expansion in six dogs caused marked increases in urine flow (20.2 +/- 5.5 to 82.5 +/- 22.7 microL.min-1.g-1) and sodium excretion (3.2 +/- 0.5 to 11.1 +/- 2.7 mumol.min-1.g-1), with slight increases in glomerular filtration rate (0.92 +/- 0.03 to 1.01 +/- 0.02 mL.min-1.g-1) but no significant changes in total renal blood flow (4.7 +/- 0.3 to 5.2 +/- 0.6 mL.min-1.g-1), medullary blood flow (+6 +/- 9%), or cortical blood flow (+12 +/- 10%). During stepwise reductions in renal arterial pressure (150 to 75 mm Hg) elicited with a renal arterial occluder, both before and after volume expansion, medullary, cortical, and total renal blood flows as well as glomerular filtration rate exhibited efficient autoregulation, with slopes not significantly different from zero over this range of arterial pressure. Ther were marked increases in the slopes of the relationships between arterial pressure and urine flow (0.18 +/- 0.05 to 0.78 +/- 0.27 microL.min-1.g-1.mm Hg-1) as well as sodium excretion (0.03 +/- 0.004 to 0.10 +/- 0.03 mumol.min-1.g-1.mm Hg-1) during volume expansion. These data demonstrate that medullary blood flow is efficiently autoregulated in dogs during control and volume-expanded states and indicate that the mechanism responsible for the arterial pressure-induced changes in sodium excretion does not depend on coincident alterations in medullary blood flow.

Animals↗

PubMed1997

Renal responses to AT1 blockade in angiotensin II-induced hypertensive rats.

Previous studies have shown that uninephrectomized rats infused chronically with low doses of angiotensin II (Ang II) develop progressive hypertension that is prevented by coadministration of losartan in the drinking water. The present study was performed to contrast the effects of chronic and acute losartan treatment in reversing the Ang II-mediated actions on arterial pressure and renal function. Ang II was infused subcutaneously via osmotic minipumps (40 ng/min) for 13 days in two groups (N = 10 and N = 6); one group also received losartan in the drinking water (30 mg/kg.day) throughout this period. Untreated rats (N = 6) and rats (N = 6) receiving only losartan served as control groups. Ang II-infused rats had higher mean arterial pressures (153 +/- 7 versus 107 +/- 3 mm Hg) and lower GFR (0.7 +/- 0.04 versus 0.98 +/- 0.06 mL/min.g) than Ang II-infused rats receiving losartan chronically. The Ang II-infused rats responded to acute doses of losartan (10 mg/kg) with progressive reductions in arterial pressure and significant increases in cortical blood flow (34 +/- 12% increase), renal plasma flow, GFR, and sodium excretion; however, the increases in renal blood flow and GFR were not sustained as systemic arterial pressure decreased. Because Ang II-infused rats receiving losartan chronically still exhibited decreases in RBF in response to a bolus dose of Ang II, further studies evaluated the effects of acute losartan treatment in rats treated chronically with losartan. Although arterial pressure decreased only slightly, demonstrating adequate systemic vascular blockade, there were still substantial and sustained increases in renal plasma flow, cortical blood flow (20 +/- 4% increase), GFR, and sodium excretion. In summary, the modest responses to acute losartan in Ang II-infused rats indicate that chronic Ang II infusions lead to alterations in renal function that are only partially reversible by acute losartan treatment. In contrast, chronic treatment with losartan prevents the Ang II-induced decrease in GFR. The renal responses to acute losartan in the Ang II-infused rats treated chronically with losartan suggest that substantive intrarenal actions of Ang II can be maintained even when the systemic vascular AT1 receptors are effectively blocked.

Analysis of Variance↗

PubMed1997

Cardiovascular research support by the American Heart Association in Louisiana.

The American Heart Association (AHA) was founded in 1924 by a group of physician-scientists to promote the exchange of research ideas in an era when the treatment of heart disease was extremely frustrating. The organization has evolved to include education and community service in its mission, but the support and promotion of quality research has remained at the AHA's core. Research support by the AHA has been responsible for major advances in cardiovascular medicine, including the development of diuretics, pacemakers, artificial heart valves, defibrillators, cardiopulmonary resuscitation, hypercholesterolemia therapy, and artificial surfactant. Working to ensure the efficient distribution of funds, the AHA has distributed nearly $1.4 billion in support of quality research for graduate and medical students, post-doctoral fellows, and beginning and established investigators. Such support has assisted in the career development of four Nobel Prize winners. While cardiovascular disease remains America's leading cause of death, the activities of the AHA continue to support advances in its diagnosis and treatment.

American Heart Association↗

PubMed1997

Intrarenal production of angiotensin II.

The intrarenal renin-angiotensin system plays a critical role in the paracrine regulation of renal hemodynamics and tubular transport function. Much of the intrarenal angiotensin II (ANG II) is formed locally as evidenced by intrarenal ANG II contents that are much greater than can be explained from the circulating ANG II concentration. Intrarenal ANG II is formed from systemically delivered ANG I and from intrarenally formed ANG I derived from systemically delivered angiotensinogen as well as locally synthesized angiotensionogen. There is a regional distribution of intrarenal ANG II in that the medullary content per gram of tissue is four to five times higher than the cortical content. In addition, most of the cortical ANG II is compartmentalized in the renal interstitial fluid and in the tubular fluid. Proximal tubule cells contain all the components of the renin-angiotensin system necessary for synthesis and secretion of ANG II. Proximal tubule concentrations of ANG II as well as ANG I and angiotensinogen support the concept that the proximal tubule cells secrete ANG II or precursors of ANG II into the tubular fluid. The intratubular concentrations of ANG II are in the nanomolar range, indicating a substantial capability to influence luminal ANG II receptors on the tubule cell membranes. Thus, much of the ANG II-dependent actions on tubular transport functions could be due to specific effects of locally synthesized ANG II on luminal ANG II receptors. Experimental evidence shows that the intratubular ANG II concentrations are regulated independently of the circulating concentrations, but the specific mechanisms responsible remain to be delineated.

Angiotensin I↗

PubMed1996

Interactions between arterial pressure and sodium excretion.

Recent developments have led to renewed interest in the mechanisms that mediate the changes in sodium excretion in response to changes in arterial pressure, a phenomenon termed pressure-natriuresis. Pressure-natriuresis occurs in the absence of changes in filtered load and thus, the changes in sodium excretion are caused by changes in net tubular sodium reabsorption. Both proximal and distal nephron segments have been implicated as the sites of altered reabsorption. The specific mechanism responsible for pressure-natriuresis remains unresolved. One proposal suggests that changes in renal interstitial fluid pressure which may be due, in part, to a less efficient autoregulation of the renal medullary circulation than of the cortex, alter sodium reabsorption. Alternatively, recent studies indicate that increases in arterial pressure increase endothelial nitric oxide formation which inhibits sodium reabsorption via direct effects on the tubules as well as hemodynamically mediated effects.

Animals↗

PubMed1996

Renal responses to intra-arterial administration of adrenomedullin in dogs.

The present study was undertaken to evaluate the renal responses to intra-arterial infusion (12.5 pmol.kg-1.min-1) for 30 min of adrenomedullin (ADM) in denervated kidneys of anesthetized dogs (n = 8). Total renal blood flow (RBF) was measured with an electromagnetic flow probe, and two single-fiber laser-Doppler needle flow probes were used to measure relative changes in cortical (CBF) and medullary blood flow (MBF). ADM administration resulted in decreases in renal vascular resistance (32.3 +/- 4.9 to 22.3 +/- 3.0 mmHg.ml-1.min.g) and increases in RBF (4.5 +/- 0.5 to 6.0 +/- 0.6 ml.min-1.g-1), CBF (33 +/- 1.3%, n = 41, and MBF (32 +/- 5.7%, n = 5) without changes in glomerular filtration rate. There were also substantial increases in urine flow (11.3 +/- 1.9 to 28 +/- 4.8 microliters.min-1.g-1), as well as in sodium excretion (1.8 +/- 0.2 to 4.2 +/- 0.6 microliter.min-1.g-1). After cessation of ADM infusion, partial recovery of these responses was observed within a 30-min period. Responses to ADM were attenuated during inhibition of nitric oxide (NO) synthesis by nitro-L-arginine (50 micrograms.kg-1.min-1). These findings indicate that renal vasodilator, diuretic, and natriuretic responses to ADM may be mediated by the release of endogenous NO and suggest that ADM could play a role in regulating water and electrolyte excretion by the kidney.

Adrenomedullin↗

PubMed1996

Medullary blood flow responses to changes in arterial pressure in canine kidney.

Although it is well recognized that whole kidney and cortical blood flow exhibit efficient autoregulation in response to alterations in renal arterial pressure (RAP), the autoregulatory behavior of medullary blood flow (MBF) has remained uncertain. We have evaluated MBF responses to stepwise reductions in RAP for both short-term (2 min, n = 6) and longer periods (15 min, n = 7) using single-fiber laser-Doppler flowmetry with needle probes inserted into the mid-medullary region in denervated kidneys of 13 anesthetized dogs. The changes in cortical blood flow (CBF) were assessed with either a surface probe or a needle probe inserted into the cortex. Control total renal blood flow (RBF), assessed by electromagnetic flow probe in these dogs, was 5.2 +/- 0.3 ml.min-1.g-1, and glomerular filtration rate was 0.97 +/- 0.05 ml.min-1.g-1 (n = 7). RBF, MBF, and CBF all exhibited efficient autoregulatory behavior during changes in RAP from 150 to 75 mmHg. The slopes of RAP vs. RBF, CBF, as well as MBF, were not significantly different from zero within this range of RAP. Below RAP of 75 mmHg, all indexes of blood flow showed linear decreases with reductions in pressure. The data indicate that blood flow in the renal medulla of dogs exhibits efficient autoregulatory behavior, similar to that in the cortex.

Animals↗

PubMed1996

Afferent arteriolar response to arachidonic acid: involvement of metabolic pathways.

Arachidonic acid (AA) metabolites have been implicated in the control of renal hemodynamics, but the nature of the metabolites produced by renal cells when AA is released has remained uncertain. Experiments were performed using the in vitro perfused juxtamedullary nephron preparation to examine the effects of perfusion and superfusion of AA on the renal microvasculature. Extraluminal exposure of the vessels by superfusion with solutions containing 0.1, 1.0, and 10 microM AA decreased afferent arteriolar diameter by 8 +/- 2, 16 +/- 3, and 20 +/- 3%, respectively. The same doses of AA added to the perfusate produced a similar afferent arteriolar vasoconstriction. Inhibition of the major enzymatic pathways unmasked differential responses of AA that were dependent on the direction from which the vasculature was exposed to AA. 17-Octadecynoic acid (1 microM), an inhibitor of the cytochrome P-450 pathway, eliminated the vasoconstrictor response to superfused AA but had little effect on the response to perfused AA. Lipoxygenase inhibition with baicalein (0.5 microM) did not alter the afferent arteriolar vasoconstriction during superfusion with AA but did attenuate the vasoconstrictor response to perfused AA by 34%. Cyclooxygenase inhibition with 10 microM indomethacin reduced the afferent arteriolar response to superfusion with 10 microM AA by 46%, but the responses to perfusion with AA were reversed, leading to the unmasking of a 17% afferent arteriolar dilation. The AA-induced vasorelaxation observed during cyclooxygenase inhibition was prevented by the subsequent addition of a P-450 inhibitor. Additionally, after endothelial removal with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), the vasodilatory response reverted to a vasoconstriction. The results of this study demonstrate that in the rat, AA metabolites exert predominant actions on afferent arterioles, but differential responses are mediated via different enzymatic pathways depending on the origin of AA. Increased AA availability of intraluminal origin leads to production of cyclooxygenase-derived vasoconstrictor metabolites and also to endothelial-derived cytochrome P-450 vasodilatory metabolites. In contrast, increased AA availability of interstitial origin leads to production of vasoconstrictor cytochrome P-450 metabolites.

Animals↗

PubMed1996

Pressure-mediated vasoconstriction of juxtamedullary afferent arterioles involves P2-purinoceptor activation.

This study was conducted to examine the hypothesis that P2 purinoceptors contribute to pressure-induced autoregulatory adjustments of afferent arteriolar caliber. Experiments were performed in vitro using the blood-perfused juxtamedullary nephron technique. Afferent arteriolar diameter averaged 19.2 +/- 0.6 microns (n = 51) at control perfusion pressure of 100 mmHg and decreased when perfusion pressure was increased. Desensitization of P2 purinoceptors abolished the alpha, beta-methylene ATP-mediated afferent vasoconstriction and prevented pressure-dependent autoregulatory adjustments in afferent diameter. P2-purinoceptor saturation significantly decreased afferent caliber and attenuated pressure-induced autoregulatory responses. To block P2 receptors, afferent arterioles were treated with the P2-purinoceptor antagonists, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid or suramin. P2-receptor blockade prevented the afferent arteriolar vasoconstriction evoked by increasing perfusion pressure from 100 to 130 and 160 mmHg. These data demonstrate that inhibition of P2 purinoceptor-dependent responses through receptor desensitization, receptor saturation, or purinoceptor blockade impairs normal autoregulatory behavior in rat juxtamedullary afferent arterioles. The results are consistent with the hypothesis that P2 purinoceptors participate in mediating autoregulatory adjustments in afferent arteriolar diameter.

Adenosine Triphosphate↗

PubMed1996

Paracrine regulation of the renal microcirculation.

There has been an explosive growth of interest in the multiple interacting paracrine systems that influence renal microvascular function. This review first discusses the membrane activation mechanisms for renal vascular control. Evidence is provided that there are differential activating mechanisms regulating pre- and postglomerular arteriolar vascular smooth muscle cells. The next section deals with the critical role of the endothelium in the control of renal vascular function and covers the recent findings related to the role of nitric oxide and other endothelial-derived factors. This section is followed by an analysis of the roles of vasoactive paracrine systems that have their origin from adjoining tubular structures. The interplay of signals between the epithelial cells and the vascular network to provide feedback regulation of renal hemodynamics is developed. Because of their well-recognized contributions to the regulation of renal microvascular function, three major paracrine systems are discussed in separate sections. Recent findings related to the role of intrarenally formed angiotensin II and the prominence of the AT1 receptors are described. The possible contribution of purinergic compounds is then discussed. Recognition of the emerging role of extracellular ATP operating via P2 receptors as well as the more recognized functions of the P1 receptors provides fertile ground for further studies. In the next section, the family of vasoactive arachidonic acid metabolites is described. Possibilities for a myriad of interacting functions operating both directly on vascular smooth muscle cells and indirectly via influences on endothelial and epithelial cells are discussed. Particular attention is given to the more recent developments related to hemodynamic actions of the cytochrome P-450 metabolites. The final section discusses unique mechanisms that may be responsible for differential regulation of medullary blood flow by locally formed paracrine agents. Several sections provide perspectives on the complex interactions among the multiple mechanisms responsible for paracrine regulation of the renal microcirculation. This plurality of regulatory interactions highlights the need for experimental strategies that include integrative approaches that allow manifestation of indirect as well as direct influences of these paracrine systems on renal microvascular function.

Animals↗

PubMed1996

Renal accumulation of circulating angiotensin II in angiotensin II-infused rats.

Previous studies have demonstrated that low-dose angiotensin II (Ang II) infusion for 14 days mimics two-kidney, one clip Goldblatt hypertension and increases intrarenal Ang II levels. The objective of the present study was to determine whether the augmented intrarenal Ang II is due to intrarenal accumulation of the infused Ang II and/or to an increase in intrarenal formation of endogenous Ang II. Male Sprague-Dawley rats were uninephrectomized and divided into three groups: control (N=6), those infused with [Ile5]Ang II (endogenous form) (N=6), and those infused with [Val5]Ang II (n=8). [Ile5]Ang II or [Val5]Ang II was infused at 40 ng/min via an osmotic minipump implanted subcutaneously. By day 12, systolic blood pressure increased significantly in both [Val5]Ang II-infused rats (197 +/- 7 mm Hg) and [Ile5]Ang II-infused rats (173 +/- 3 mm Hg). Blood and kidney samples were harvested, subjected to high-performance liquid chromatography to separate [Val5]Ang II from [Ile5]Ang II, and then measured by radioimmunoassay. Plasma renin activity was markedly suppressed in both [Ile5]Ang II- and [Val5]Ang II-infused rats. Plasma Ang II levels were elevated in rats infused with both [Ile5]Ang II (121 +/- 24 fmol/mL) and [Val5]Ang II (119 +/- 14 fmol/mL) compared with controls (69 +/- 15 fmol/mL). Both [Ile5]Ang II- and [Val5]Ang II-infused rats exhibited an enhancement of total intrarenal Ang II. Only [Ile5]Ang II (358 +/- 53 fmol/g) was detected in the kidneys of rats infused with -Ile5-Ang II. In [Val5]Ang II-infused rats, a significant portion of total renal Ang II (371 +/- 57 fmol/g) was in the form of [Val5]Ang II (256 +/- 44 fmol/g). Renal [Ile5]Ang II levels were maintained in the [Val5]Ang II-infused rats (116 +/- 15 fmol/g) compared with control rats (116 +/- 11 fmol/g) despite marked suppression of renin release. These results support the hypothesis that infused circulating ANG II is bound to receptor or taken up intrarenally in a manner that protects against degradation.

Angiotensin II↗

PubMed1996

Receptor-mediated intrarenal angiotensin II augmentation in angiotensin II-infused rats.

Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.

Angiotensin II↗

PubMed1996

Actions of epoxygenase metabolites on the preglomerular vasculature.

Epoxygenase metabolites of arachidonic acid are produced by the kidney and have been implicated in the control of renal blood flow. This study examined the preglomerular actions of various epoxyeicosatrienoic acids (EET). By use of the in vitro blood-perfused juxtamedullary nephron preparation, interlobular and afferent arteriolar diameter responses to 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET were determined. Diameters of interlobular and afferent arterioles preconstricted with 0.5 microM norepinephrine averaged 24 +/- 1 microns (N = 27) and 17 +/- 1 microns (N = 32), respectively, at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.01 to 100 nM 11,12-EET caused graded increases in diameters of the interlobular and afferent arterioles. At a dose of 100 nM, 11,12-EET increased the diameters of the interlobular and afferent arterioles by 18 +/- 2% (N = 10) and 20 +/- 3% (N = 9), respectively. The vasodilatory response to 11,12-EET was stereoselective because 11,12(R,S)-EET but not 11,12(S,R)-EET increased the diameters of the interlobular and afferent arterioles. 14,15-EET had a much smaller effect and increased the diameters of the these vessels by 10%; 8,9-EET did not significantly affect vascular diameters. In contrast, 5,6-EET constricted the interlobular and afferent arterioles by 16 +/- 3% (N = 6) and 21 +/- 3% (N = 7), respectively. The corresponding diols, 5,6-DIHETE and 11,12-DIHETE, had no effect on diameters of the interlobular and afferent arterioles at concentrations up to 1 microM. The vasodilatory response to 11,12-EET was not affected by removal of the endothelium or by inhibition of cyclooxygenase with indomethacin. In contrast, the vasoconstrictor response to 5,6-EET was abolished by both removal of the endothelium or cyclooxygenase inhibition. The thromboxane/ enderoperoxide receptor inhibitor, SQ 29,548, resulted in a 60% attenuation of the afferent arteriolar vasconstriction to 5,6-EET. These results indicate that the preglomerular vasoconstriction to 5,6-EET is cyclooxygenase dependent and requires an intact endothelium, whereas the vasodilation to 11,12-EET is stereoselective and is the result of direct action of the epoxide on the preglomerular vascular smooth muscle.

8,11,14-Eicosatrienoic Acid↗

PubMed1996

Renal cortical and medullary microvascular blood flow autoregulation in rat.

Previous studies have demonstrated the critical role of the afferent arteriole in autoregulation of nephron blood flow in response to changes in perfusion pressure. The present study focused on the responses of postglomerular vascular segments to alterations in renal arterial pressure. Afferent arterioles, efferent arterioles and outer medullary descending vasa recta of juxtamedullary nephrons were visualized using the in vitro blood-perfused juxtamedullary nephron technique. Simultaneous measurements of inside vessel diameter and centerline erythrocyte velocity were made in order to determine single vessel blood flow. Blood flow measured in afferent arterioles (N = 13) displayed efficient autoregulation of blood flow and afferent arterioles responded actively with decreases in arteriolar diameter during stepwise elevations of renal perfusion pressure from 100 to 150 mm Hg. Similarly, blood flow measured at efferent arterioles (N = 9) exhibited autoregulation during increases in renal perfusion pressure. However, efferent arteriolar diameters were not altered during increases in perfusion pressure. During superfusion with the calcium channel blocker, diltiazem (10 microM), which primarily dilates afferent arterioles, efferent arteriolar blood flow (N = 7) increased and responded to changes in perfusion pressure. Nevertheless, efferent arteriolar diameter remained unchanged and did not respond to increases in perfusion pressure. Outer medullary descending vasa recta (N = 7) diameter, centerline erythrocyte velocity and calculated blood flow were also not significantly altered following stepwise increases in pressure to 125 and 150 mm Hg. These data demonstrate effective autoregulation of postglomerular blood flow, measured at efferent arterioles and at outer medullary descending vasa recta, over a perfusion pressure range of 100 to 150 mm Hg. There was no dissociation of arteriolar and outer medullary descending vasa recta blood flow responses to increases in renal perfusion pressure indicative of efficient autoregulation in both cortical and medullary postglomerular circulations of the rat.

Animals↗