Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension

Abstract

Bivol LM, Berge RK, Iversen BM. Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension. Am J Physiol Renal Physiol 293: F839-F845, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00140.2007.-The tetradecythioacetic acid (TTA) is a modified fatty acid known to exhibit pleiotropic effects. First, we compared the effect of TTA on the blood pressure in spontaneously hypertensive rats (SHR) with two-kidney, one-clip (2K1C)-hypertensive rats. Second, we examined mechanisms involved in the blood pressure reduction. TTA had minor effect on systolic blood pressure (SBP) in young SHR up to 8 wk of age. In 2K1C we confirmed the blood pressure-lowering effect of TTA (SBP: 173 Ϯ 4 before vs. 138 Ϯ 3 mmHg after TTA, P Ͻ 0.001). No effect on SBP was seen in Wistar-Kyoto rat (WKY) controls. Plasma renin activity (PRA) was low in SHR and WKY controls and TTA did not change it. PRA decreased from 22.9 Ϯ 1.3 to 16.2 Ϯ 2.2 ng ⅐ ml Ϫ1 ⅐ h Ϫ1 (P ϭ 0.02) in 2K1C. Plasma ANG II concentration declined from 101 Ϯ 3 to 81 Ϯ 5 fmol/l after TTA treatment (P ϭ 0.005). In the clipped kidney, tissue ANG I concentration decreased from 933 Ϯ 68 to 518 Ϯ 60 fmol/g tissue (P ϭ 0.001), and ANG II decreased from 527 Ϯ 38 to 149 Ϯ 21 fmol/g tissue (P Ͻ 0.001) after TTA treatment. In the nonclipped kidney, TTA did not change ANG I and moderately reduced ANG II levels. The renal blood flow response to injection of ANG II into the nonclipped kidney was blunted compared with controls and normalized with TTA treatment (10 Ϯ 2 before vs. 20 Ϯ 2%, P Ͻ 0.001). The results indicate that TTA downregulates the renin-angiotensin system in high renin animals but has no effect in low renin models. Angiotensin I; angiotensin II HYPERTENSION IS CLOSELY related to an increase in cardiovascular death and represents a major challenge in health care all over the world. The use of animal models has been of major importance in examining the mechanisms involved in the development and maintenance of high blood pressure and is widely used in studies of new antihypertensive drugs to explore the mechanisms involved in blood pressure reduction.Several rat models are used. The spontaneously hypertensive rat (SHR) is a genetic model of hypertension and is looked upon as a model for essential hypertension in humans (32). In this model, the activity of the renin-angiotensin system is normal or low (27). Despite this, the commonly used ACE inhibitor and AT1 receptor blockers lower blood pressure in SHR (16,29).The 2-kidney, 1-clip (2K1C) is a renovascular model of hypertension with increased activity of renin-angiotensin system that plays a key role in the development and maintenance of high blood pressure (17, 21). The plasma renin and ANG II concentrations are high for several weeks after clipping, a finding that may be due to increased ANG II production and/or decreased ANG II degradation (17,19). The renin concentration, as well as the levels of ANG I and II, is high in the clipped ki...

Tetradecylthioacetic acid downregulates cyclooxygenase 2 in the renal cortex of two-kidney, one-clip hypertensive rats

“…In the present study, we have also confirmed that TTA partially prevents the increase of BP in 2K1C rats, as we have shown previously (5,16). The fact that neither indomethacin nor parecoxib has any effect on BP in 2K1C rats further supports that the TTAs effect on BP is at an upstream site, Fig.…”

“…The control and 2K1C hypertensive groups were fed with standard rat chow (0.25% Na, 14.7% proteins), and the TTA group was fed standard rat chow that was sprayed with TTA dissolved in acetone (9 g TTA dissolved in 1 liter of acetone to 2.7 kg pellet). We have shown previously that TTA and acetone did not interfere with the food intake (5,16).…”

“…The first set of experiments was used for collection of renal cortex and urine (n ϭ 6 in each group). Because TTA do not affect BP in control rats, this group was not examined in the present study (5,6). One urine sample per rat was collected, as well as one tissue sample from the left kidney in the control group and one sample from each kidney in the 2K1C group.…”

“…We have recently shown that TTA prevents the development of hypertension in 2K1C by reducing the activation of the renin-angiotensin system (5,16) and, furthermore, that TTA has a strong anti-inflammatory effect (6). TTA reduces mRNA renin levels in the clipped kidney and ANG II in both clipped and nonclipped kidney (16).…”

Tetradecylthioacetic acid prevents the inflammatory response in two-kidney, one-clip hypertension

“…TTA is known to be a stimulator of all three types of peroxisome proliferator activated receptors (PPARs) (7), but also acts via PPAR-independent pathways (5). It had been shown that TTA attenuates the development of renal hypertension (8,19), but does not affect established genetic high blood pressure, as seen in the spontaneously hypertensive rat (SHR) (8).…”