Angiotensin-Converting Enzyme and Angiotensin II Receptor Subtype 1 Inhibitors Restitute Hypertensive Internal Anal Sphincter in the Spontaneously Hypertensive Rats

Abstract

The present study determined the effects of the angiotensinconverting enzyme (ACE) inhibitor captopril and angiotensin II receptor subtype 1 (AT 1 -R) antagonist losartan on the internal anal sphincter pressures (IASP) in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto rats (WKY). The SHR had significantly higher IASP (21.7 Ϯ 0.8 mm Hg) than the WKY (14.7 Ϯ 0.9 mm Hg), which was associated with the higher levels of angiotensin II (Ang II) in plasma (50.3 Ϯ 0.9 pg/ml) and in muscle bath perfusates (72.7 Ϯ 11.8 pg/ml) compared with the WKY (p Ͻ 0.05). Captopril and losartan decreased the IASP in SHR and WKY, but they were more potent in SHR. Captopril and losartan normalized the IASP in the SHR, whereas these agents may compromise rectoanal continence in the WKY. Reverse transcriptase-polymerase chain reaction and Western blots showed higher levels of angiotensinogen, renin, ACE, and AT 1 -R in the internal anal sphincter (IAS) of SHR. Ang II caused concentration-dependent contraction of IAS smooth muscle strips from WKY (pEC 50 ϭ 8.5 Ϯ 0.1) and SHR (pEC 50 ϭ 8.6 Ϯ 0.2). Losartan (100 nM) significantly (p Ͻ 0.05) inhibited this effect. From these data, we conclude that 1) hypertensive IAS in SHR is primarily the result of renin-angiotensin system upregulation, 2) ACE inhibitors and AT 1 -R antagonists simply relieve the hypertensive IAS, and 3) the differential effect of these inhibitors in the hypertensive versus the normotensive IAS may explain the lack of incontinence as a side effect in hypertensive patients receiving ACE inhibitors and AT 1 -R antagonists.Earlier studies from our laboratory have put forward evidence for the role of angiotensin II (Ang II) biosynthesis in the spontaneous myogenic tone of the internal anal sphincter (IAS) of rats (De Godoy et al., 2004). The studies show the expression of key components of the renin-angiotensin system (RAS

Is Cardiac Hypertrophy in Spontaneously Hypertensive Rats the Cause or the Consequence of Oxidative Stress?

“…In this regard, it is worth noting a previous report that an increase of SOD pharmacology potency by lecithinization is able to protect endothelial cells against alterations induced by ROS (64). Another explanation for the observed differences would be related to angiotensin II content, which appears to be involved in the genesis of oxidative stress in tissues other than cardiac tissue in SHR (65). This hypothesis is supported by recent experiments performed using the vascular tissue of stroke-prone SHR (44,45), in which the inhibition of angiotensin receptors or the angiotensin-converting enzyme system reduced ROS production.…”

Oxidative Damage in Cardiac Tissue from Normotensive and Spontaneously Hypertensive Rats: Effect of Ageing

“…In this regard, it is worth noting a previous report that an increase of SOD pharmacology potency by lecithinization is able to protect endothelial cells against alterations induced by ROS (Igarashi et al, 1992). Another explanation to the differences observed would be related to angiotensin II content, which appears involved in the genesis of oxidative stress in another tissue than heart in the SHR model (De Godoy & Rattan, 2006). This hypothesis was supported by the recent experiments performed in vascular tissue of stroke-prone SHR (Takai et al, 2005;Tanaka et al, 2005) in which the inhibition of angiotensin receptor or angiotensin-converting enzyme system produced a reduction of ROS production.…”

Regulatory Effect of Hydrogen Sulfide on Vascular Collagen Content in Spontaneously Hypertensive Rats

“…Disturbances in the regulation of upstream modulators, such as Src, phosphatidyl inositol 3 (PI3) kinase, or other kinases, could contribute to altered growth signaling by Ang II in cells from genetically hypertensive rats. Ang II-induced activation of Src is increased in SHRs, and Src-dependent regulation of p38 MAPK and ERK1/2 is altered in VSMCs from SHRs (37 (38). Thus, VSMCs from SHRs might have an intrinsic genetic abnormality in the control of VSMC proliferation.…”