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

doi:10.1016/S0047-6374(97)00053-5

Mechanisms of Ageing and Development

Volume 97, Issue 2, August 1997, Pages 163-171

https://doi.org/10.1016/S0047-6374(97)00053-5 Get rights and content

Abstract

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 plasma 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 the indices of the renin–ANG II system in aging.

Introduction

It is widely reported that in man and rats plasma renin activity (PRA) declines with advancing age 1, 2, 3, 4, 5, 6. The mechanism of this decline in PRA is unknown, although it is related to declines in renal renin content rather than loss of functional nephrons 4, 5. Nevertheless, angiotensin converting enzyme inhibitors (ACEIs) are potent antihypertensive agents in older patients 7, 8and also lower blood pressure and preserve kidney and vascular structure in aging rats 6, 9, 10, 11, 12. One explanation that reconciles these observations is that the plasma angiotensin II (ANG II) and/or intrarenal ANG II levels may not be diminished in parallel with the falls in PRA. For example, a reduction in the metabolic clearance rate (MCR) of ANG II in aging would lead to increased ANG II levels and feedback suppression of PRA and would explain why ACEI is antihypertensive/renal protective in aging 6, 9, 10, 11, 12. This possibility was suggested by our earlier observation that activity of the proximal tubule brush border membrane neutral metalloprotease (NEP; endopeptidase 24.11), is diminished in old rats [13]. This metalloprotease plays a role in degrading various peptide hormones including ANG II [14].

Accordingly the present study was conducted in young adult (3–5 months old) and old (18–20 months old), conscious chronically catheterized male Sprague Dawley rats to investigate the impact of aging on the MCR of ANGII. At 3–5 months of age, rats are sexually mature and exhibit no renal injury or dysfunction. By 18–20 months of age male Sprague Dawley rats have developed substantial renal pathology and glomerular function is beginning to decline [15]; 50% mortality occurs by 24 months of age in male rats of this strain. In the present study, some experiments were conducted on rats who also received NEP inhibitor to determine whether NEP plays any role in ANG II metabolism and whether alterations in NEP activity influence MCR ANG II in aging. These studies also allowed us to re-evaluate the impact of aging on baseline PRA, obtained under unstressed conditions.

Section snippets

Methods

All studies were conducted in chronically catheterized male Sprague Dawley rats (Harlan Sprague Dawley) aged 3–5 months (young) or 18–20 months (old) of age. Throughout the study, the rats were maintained on ad libitum rat chow (sodium 0.4%) and tap water. Under short acting barbiturate anesthesia (Brevital, Eli Lilly) and using a full sterile technique, vascular catheters were placed in the femoral artery and vein and urinary bladder, as previously described [16]. Rats were allowed at least 7

Results

Old rats were heavier than young rats (BW=551±7 versus 364±119; P<O.001). The major findings are summarized in Table 1. The most striking observation is that in this setting, baseline PRA values were no different between young and old rats. This was due to the low values of PRA in the young animals, which probably reflects the use of the unstressed conscious preparation. PRA values measured in anesthetized rats are higher, even when blood samples are collected without delays or experimental

Discussion

Although it is widely reported that PRA declines with advancing age 1, 2, 3, 4, 5, 6, the present study shows that when the trained unstressed rat is used, both young and old rats display similarly low values of PRA. We further observed that baseline plasma ANG II concentrations are the same in old and young rats. It is interesting that our values of PRA in old rats are close to other published values whereas the values we obtained for young rats are substantially lower 4, 6, 19, 20, 21.

Acknowledgements

This study were supported by a grant from the Baxter Extramural Grant Program (to CB) and NHLBI No. 26371 (to LGN). The gift of the ACEI Enalapril from Dr C. Sweet, Merck and the NEP inhibitor SCH 32615 from Dr E. Syberk, Schering Plough, are gratefully acknowledged.

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