[Sar1, Ala8]-Angiotensin II

The biological effects of 1-Sarcosine, 8-Threonine angiotensin II ([Sar1, Thr8]ANG II) on blood pressure, plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were investigated in six normal subjects on an unrestricted diet, and compared with those of 1-Sarcosine, 8-Isoleucine ANG II ([Sar1, Ile8]ANG II) and 1-Sarcosine, 8-Alanine ANG II ([Sar1, Ala8]ANG II). All three ANG II analogues (AIIA) showed agonistic pressor activity, that of [Sar1, Ile8]ANG II being greater than that of [Sar1, Thr8]ANG II or [Sar1, Ala8]ANG II. The antagonistic effect of [Sar1, Thr8]ANG II on blood pressure was less than [Sar1, I1e8]ANG II or [Sar1, Ala8]ANG II. Both [Sar1, Ile8]ANG II and [Sar1, Ala8]ANG II increased PAC and blocked the steroidogenic action of ANG II, while [Sar1, Thr8]ANG II showed little effect on PAC. All three AIIA caused similar suppression of PRA and showed no inhibitory effect on the decrease in PRA produced by ANG II. These results indicate that [Sar1, Thr8]ANG II is an AIIA with weak agonistic pressor action and that it has vascular selective properties. It is also suggested that ANG II receptors in a variety of target organs are heterogeneous.

Experiments were done in normal rats to assess kidney, single nephron, and tubuloglomerular feedback responses during control conditions and during renin-angiotensin blockade with the angiotensin II (ANG II) antagonist [Sar1,Ala8]angiotensin II (saralasin, 20 micrograms.kg-1.min-1). Plasma renin activity was increased fourfold during saralasin infusion. Glomerular filtration rate (GFR) and renal blood flow increased in parallel from 1.09 +/- 0.04 to 1.26 +/- 0.05 ml/min and from 6.4 +/- 0.5 to 7.6 +/- 0.5 ml/min, respectively. Absolute and fractional sodium excretion were increased sixfold during ANG II blockade. Hydrostatic pressures in proximal tubules, peritubular capillaries, and distal tubules were unchanged. Estimates of nephron GFR (SNGFR) based on collections of distal tubular fluid were increased from 21.6 +/- 1.2 to 24.3 +/- 0.9 nl/min during ANG II blockade. Increases in SNGFR and decreases in fractional absorption at micropuncture sites beyond the late proximal tubule during saralasin administration resulted in increases of flow rate and Cl- delivery at the early distal tubule. Tubuloglomerular feedback activity, assessed by measuring changes in proximal tubule stop-flow pressure in response to alterations in orthograde microperfusion rate from late proximal tubule sites, was significantly attenuated over the range of physiological flow rates for the late proximal tubule during blockade of the renin-angiotensin system. Acute blockade of ANG II in this rat model results in attenuated tubuloglomerular feedback activity and associated changes of hemodynamic and excretory behavior by the kidney.