Chronic nitric oxide inhibition model six years on.
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Animals↗
Biomedical subjects
C Baylis
Publications and source records attributed to C Baylis.
The aging kidney: insights from experimental studies.
The rat provides a useful experimental model to study of the mechanisms of kidney aging. As in man, a wide diversity in the renal response to aging occurs in the rat, and because of this variability it is important to always specify experimental conditions, i.e., strain, gender, diet, and environment. Most aging rats display chronic progressive nephrosis, although the rate at which injury develops is highly variable. There are a number of known risk factors that potentiate injury, including male gender, genetic background, obesity, high protein/high calorie diet, and environmental exposure to pathogens. The causes of age-dependent glomerulopathy are multifactorial and include an imbalance between synthesis and degradation of extracellular matrix products, as well as hemodynamic alterations. Of importance, this damage is not inevitable and can be dissociated from normal kidney aging when optimal conditions for successful aging are provided. There is complex and sometimes contradictory information on vasoactive factors. It is, likely, however, that the activity of intrarenal AngII is somehow upregulated in the aging kidney of some, but not all, strains, and alpha 1-dependent renal nerve activity may also be enhanced. The endothelial vasodialtory prostaglandins and NO exert an increasingly important role in the maintenance of renal perfusion with advancing age, although their production may be diminished. In the future, we anticipate that comparison of rats with different genetic backgrounds will help to dissociate true aging from disease.
Aging↗
Beta-adrenoceptor-stimulated renin release is blunted in old rats.
Plasma renin activity (PRA) was similar in young versus old male Sprague Dawley rats under unstressed conditions (1.3 +/- 0.2 versus 1.8 +/- 0.3 ng angiotensin I/ml per min). Airjet stress increases PRA in young but not old rats (13.9 +/- 3.8 versus 2.9 +/- 0.8 ng angiotensin I/ml per min), respectively. This response is ablated in young rats by beta-adrenoceptor blockade, suggesting that the increased PRA is mediated by beta-adrenoceptors, and this response was blunted in old rats.
Aging↗
Recent insights into the roles of nitric oxide and renin-angiotensin in the pathophysiology of preeclamptic pregnancy.
Normal pregnancy involves marked maternal hemodynamic adaptations; these are suppressed in preeclampsia, leading to serious complications for mother and baby. The cause of preeclampsia is unknown, but may involve primary pathology at the maternal/fetal interface. However, the systemic manifestations of the disease are associated with widespread maternal vascular endothelial damage and dysfunction. There has been considerable recent interest in the possible roles for nitric oxide (NO) deficiency and for alterations in the renin angiotensin system (RAS) in the pathophysiology of preeclampsia. The following is an overview of the hemodynamic responses to normal pregnancy, an evaluation of the possible roles of NO and the RAS in these adaptations, and a review of the important aspects of these systems in preeclampsia.
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Circulation and hemodynamics.
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Journal Article↗
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↗
Sensitivity of the segmental renal arterioles to angiotensin II in the aging rat.
With advancing age the old rat kidney becomes tonically vasoconstricted by endogenous angiotensin II (ANGII) (C. Baylis. Am. J. Kid. Dis., (1993) 842). The present study was designed to investigate the sensitivity of the cortical glomerular microvasculature of the old rat kidney (19-22 months of age) to exogenous ANGII, using the in vivo micropuncture technique. In the baseline state, glomerular blood pressure (P(GC)) in old male rate was higher compared to young rats (4-5 months of age). During exogenous ANGII infusion (40 ng/kg/min), a significant rise in arterial blood pressure and renal vasoconstriction occurred in both young and old rats. In young rats, the ANGII induced fall in renal plasma flow (RPF) and glomerular plasma flow (QA) was accompanied by a rise in PGC and thus the glomerular hydrostatic pressure gradient, with little change in Kf. Therefore, the glomerular filtration rate (GFR) and single nephron GFR (SNGFR) were unchanged by ANGII infusion in young rate. In old rats, RPF and QA fell, a rise occurred in PGC and also a fall was seen in the glomerular capillary ultrafiltration coefficient (Kf), thus GFR and SNGFR fell significantly. The magnitude of the pressor and renal vasoconstriction response to ANGII were not affected by age; of interest, ANGII increased preglomerular and efferent arteriolar resistance (RA, RE) and PGC by similar accounts in young and old rats. SNGFR was reduced in old rats, due to the marked ANGII-induced decline in Kf. Neither absolute nor fractional proximal reabsorbtion were affected by ANGII infusion in either young or old rats. by 19-22 months of age, old rats had much more injured glomeruli than young rats. These data demonstrate that the afferent and efferent arterioles had similar sensitivity to exogenous pressor dose of ANGII in both young and old rats, but Kf was more sensitive to ANGII in old rats leading to a significant fall in SNGFR.
Aging↗
Impact of surgery on nitric oxide in rats: evidence for activation of inducible nitric oxide synthase.
We investigated the effect of euvolemic surgical preparation, on chemical indices of activity of the nitric oxide (NO) system, in anesthetized, acutely prepared rats. The urinary excretion of NO2+NO3 (UNOXV) and cGMP (UcGMPV) increased progressively during the experiment. Pretreatment with aminoguanidine or dexamethasone, inhibitors of inducible NO synthase (iNOS), prevented the increase in UNOXV and UcGMPV but had no impact on mean arterial pressure (BP), renal vascular resistance (RVR) or GFR. Since these variables did not change in the conscious rat, the increased UNOXV results from some aspect of the acute surgical preparation. When acutely prepared rats received L-NAME, a non-specific NOS inhibitor, BP and RVR increased but paradoxical increases in UNOXV and UcGMPV were also seen. Nonselective NOS inhibition (+L-NAME) was fatal in 50% of acutely prepared rats, causing cardiac contracture. The same dose of L-NAME produced no deaths in either conscious chronically catheterized rats or in acutely prepared rats, previously subjected to sterile surgery and acute L-NAME in the conscious state. These data indicate that acute, nonsterile surgery induces expression of iNOS, but that the additional NO generated has no obvious cardiovascular/renal actions. Acute UNOXV and UcGMPV do not predict total NO production, or "hemodynamically active" NO. Generalized NO inhibition in rats acutely stressed by surgery/anesthesia can be fatal.
Animals↗
Basal and stimulated nitric oxide in control of kidney function in the aging rat.
To investigate the activity of nitric oxide (NO) in control of renal hemodynamics during aging, studies were conducted on conscious Sprague-Dawley rats aged 3-5 mo (young, Y) and 18-22 mo (old, O). Blood pressure (BP) and renal vascular resistance (RVR) were higher in O vs. Y in control, and acute systemic NO synthesis inhibition (NOSI) increased BP and RVR, with an enhanced renal vasoconstrictor response in O. Infusion of the NO substrate L-arginine produced similar, selective renal vasodilation in both groups. The endothelium-dependent vasodilator acetylcholine caused similar falls in BP and RVR, whereas sodium nitroprusside produced an exaggerated depressor response in O vs. Y without falls in RVR in either age group. Urinary excretion of the stable NO oxidation products (NOx) decreased with age, suggesting a decline in the overall somatic NO production. In conclusion, basal tonically produced NO has a more pronounced role in maintenance of renal perfusion in aging, whereas L-arginine- and agonist-stimulated renal vasodilation is not impaired with age. NO production from some source may be reduced with aging, as indicated by falls in 24-h NOX excretion, although the similarity in pressor response and enhanced renal vasoconstrictor response to NOSI suggests that the role of NO in control of total peripheral and renal vascular resistance is maintained.
Acetylcholine↗
Biosynthesis and homeostatic roles of nitric oxide in the normal kidney.
Nitric oxide (NO) is an important molecular mediator of numerous physiological processes in virtually every organ. In the kidney, NO plays prominent roles in the homeostatic regulation of glomerular, vascular, and tubular function. Differential expression and regulation of the NO synthase (NOS) gene family contribute to this diversity of action. This review explores recent advances in the molecular and cell biology of the NOS isoforms and relates these findings to functions of NO in the control of normal renal hemodynamics, the glomerular microcirculation, and renal salt excretion. Newly recognized molecular diversity of the NOS gene products, factors governing NOS isozyme gene expression and catalytic activity, and the intrarenal distribution of the NOS isoforms are examined. Physiological data regarding the complex roles of NO in the control of renal hemodynamics and the glomerular microcirculation are analyzed, and the effects of chronic NOS inhibition on glomerular function and structure are presented. The contributions of NO to renal salt excretion as well as functional and molecular biological evidence for adaptive changes in NOS isoform expression during variations in dietary salt balance are discussed. Current investigative challenges and goals for future research of renal NO biology are presented.
Animals↗
Renal nerves do not mediate vasoconstrictor responses to acute nitric oxide synthesis inhibition in conscious rats.
Nitric oxide is a physiologically important peripheral and renal vasodilator. The studies presented here were conducted in the conscious, chronically catheterized, unstressed rat to investigate whether NO interacts with renal efferent sympathetic nerve activity in control of blood pressure, renal vascular resistance, and sodium excretion. Renal clearance studies were conducted in normal rats with innervated kidneys and in a separate group of rats with chronic, bilateral renal denervation. Acute systemic inhibition of NO synthesis with n-nitro L-arginine methyl ester (L-NAME) leads to hypertension, renal vasoconstriction, and natriuresis in rats with intact renal nerves. Chronic renal denervation does not diminish the pressor and renal vasoconstrictor response to NO synthesis inhibition, although the natriuretic response is prevented. Stimulation of renal NO synthesis with the substrate L-arginine produces selective renal vasodilation and a marked osmotic diuresis in the innervated kidney. Renal denervation has little impact on the responses to L-arginine. These studies suggest that in the normal, conscious, chronically catheterized rat in which the sympathetic nervous system is operating at basal levels, renal nerve activity does not contribute to the pressor or renal vasoconstrictor response to NO inhibition or the renal vasodilator response to NO stimulation. These observations contrast with earlier observations made under conditions of stress-induced activation of renal nerve activity.
Animals↗
Importance of nitric oxide in the control of renal hemodynamics.
The kidney vasculature is under tonic control by nitric oxide (NO) and in cortex, NO controls RA and Kf. Systemic NO inhibition leads to systemic hypertension, increases in RE, mediated by Ang II and ET, and direct effects on RA and Kf. The relationship between NO and other vasoconstrictor systems is variable. In the conscious relaxed animal, vasoconstrictor activity is low, yet acute NO inhibition leads to pressor and renal vasoconstrictor responses. At physiologic levels, ET unexpectedly is a renal vasodilator, possibly via NO generation at RA. When vasoconstrictor activity is high, NO is very important in maintenance of renal perfusion. Chronic L-NAME produces dose dependent systemic and glomerular capillary hypertension and eventual proteinuria and glomerular damage. NO deficiency is key in this process, although the hypertension becomes refractory to L-arginine administration and dependent on Ang II and the SNS, by mechanisms not yet defined. In contrast, the renal vasculature remains fully responsive to L-arginine, suggesting that pressor and renal vascular responses to chronic NO inhibition are separately regulated. NO generated from iNOS does not normally control BP or renal hemodynamics. The relative contributions of NO from bNOS and eNOS, and importance of NOS in different locations in the kidney, remain to be determined.
Animals↗
Impact of nitric oxide deficiency on blood pressure and glomerular hemodynamic adaptations to pregnancy in the rat.
Studies were conducted to investigate the impact of nitric oxide synthesis inhibition on blood pressure and glomerular hemodynamic adaptations to pregnancy in the rat. In normal pregnancy, urinary excretion of NO2 + NO3 (NOx), reflecting increased nitric oxide (NO) production, progressively increased. Blockade of NO production in virgin and late pregnant Sprague-Dawley rats caused systemic hypertension, increased renal vascular resistance (RVR), reductions in RPF but GFR remained unchanged. In cortical nephrons, preglomerular and efferent arteriolar resistance (RA and RE) were elevated and glomerular capillary blood pressure (PGC) increased markedly. Glomerular plasma flow (QA) and the glomerular capillary ultrafiltration coefficient, Kf, were reduced without change in single nephron glomerular filtration rate (SNGFR) because of the large elevation in PGC. The pressor and glomerular hemodynamic responses to NO blockade were similar in virgins and pregnancy. Urinary NOx excretion was markedly reduced in all groups with chronic NO blockade. Inhibition was incomplete in pregnancy, however, and a level of NO production that was adequate for normal BP and renal function in virgins, led to severe vasoconstriction in pregnancy. The present studies suggest that chronic NO deficiency leads to derangement of the hemodynamic adaptations of pregnancy.
Animals↗
Nitric oxide (NO) in renal physiology and pathophysiology.
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Animals↗
Nitric oxide and blood pressure: effects of nitric oxide deficiency.
Nitric oxide plays several crucial roles in control of blood pressure and kidney function and in the dietary response to salt in normal humans and animals. Nitric oxide deficiency leads to hypertension and renal damage in experimental animals and may be related to the development of some hypertensive disorders in people.
Animals↗
Relationship between basal NO release and cyclooxygenase products in the normal rat kidney.
We investigated the physiological regulation of renal function by nitric oxide (NO) and its interactions with the endothelial cyclooxygenase products in the conscious, chronically catheterized rat. A subpressor dose of NO inhibitor nitro-L-arginine methyl ester (L-NAME) produced renal vasoconstriction that was unaffected by cyclooxygenase inhibition with indomethacin (Indo). Acute, high-dose L-NAME produced a pressor response of approximately 40 mmHg and marked renal vasoconstriction. Indo selectively amplified the renal vasoconstriction, whereas inhibition of the thromboxane-endoperoxide receptor had no effect. Chronic NO inhibition for 5 wk led to sustained hypertension and renal vasoconstriction; the latter was amplified by acute Indo. These data suggest that in the normal, conscious rat the kidney is under important NO-dependent tone. There is no obvious interaction between NO and the cyclooxygenase products in control of basal renal function. When systemic NO inhibition is produced with either acute or chronic high-dose L-NAME, the kidney is severely vasoconstricted. The renal vasoconstriction is not ameliorated by thromboxane-endoperoxide antagonism but is exacerbated by cyclooxygenase blockade, suggesting that vasodilator cyclooxygenase products compensate for the renal hypoperfusion because of severe NO deficiency.
Animals↗
Hypothalamic lesions induce obesity and sex-dependent glomerular damage and increases in blood pressure in rats.
Placement of two symmetrical lesions in the ventromedial hypothalamus of the rat causes massive overeating and obesity. We have studied male (n=8) and female (n=5) Munich-Wistar rats 7 months after induction of obesity and compared them with age-matched controls. Body weight and kidney weight were greater in control males versus females (396 +/- 7 and 1.5 +/- 0.1 g versus 229 +/- 4 and 1.0 +/- 0.1 g, respectively; both P <.001). Both obese males and females were heavier than lean counterparts (592 +/- 30 and 361 +/- 19 g, both P <.001), whereas kidney weight was similar between obese and control rats of each sex (obese males, 1.5 +/- 0.1 g; obese females, 1.1 +/- 0.1 g). Blood pressure was higher in obese versus control males; there was no differences between other groups. Single-nephron glomerular filtration rate was similar in control females and males and obese females but depressed in obese males. Glomerular blood pressure was normal in all groups. Urinary protein excretion and the percentage of sclerosed glomeruli were similar in control females and males and obese females but elevated in obese males. Plasma triglyceride levels were elevated in obesity, particularly in males. We conclude that hypothalamic lesioning induces overeating and obesity and selectively in the male causes hypertension and glomerular damage as well as declines in renal function. This injury is not hemodynamically mediated (glomerular blood pressure is normal) but may be related to the elevation in plasma triglyceride levels, which has previously been causally linked to glomerular damage in genetically obese rats.
Animals↗
The aging glomerulus.
Glomerular filtration rate (GFR) decreases with advancing age, particularly in men, although the rate of decrease in GFR is highly variable. Renal vasoconstriction contributes to the decrease in GFR because of increased renal nerve activity, angiotensin II, endothelin, and decreases in vasodilatory prostacyclin levels. Intrarenal nitric oxide activity may be enhanced during aging, perhaps as part of a compensatory response. The atrial natriuretic peptide system is altered during aging, but there is probably no net change in intrarenal hemodynamic actions. Glomerular damage also contributes to age-dependent decreases in GFR. The primary mechanisms are unknown, but they involve a buildup of mesangial extracellular matrix materials. Increases in vasoconstrictor, growth promoting factors, and/or decreases in vasodilator, growth inhibiting factors may contribute. Androgens provide a risk factor. Glomerular hypertension and/or hypertrophy are not primary factors in the development of age-dependent glomerulopathy, but will worsen the process when present.
Aging↗