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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania

The present study determined the effects of the angiotensin-converting enzyme (ACE) inhibitor captopril and angiotensin II receptor subtype 1 (AT₁-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 ± 0.8 mm Hg) than the WKY (14.7 ± 0.9 mm Hg), which was associated with the higher levels of angiotensin II (Ang II) in plasma (50.3 ± 0.9 pg/ml) and in muscle bath perfusates (72.7 ± 11.8 pg/ml) compared with the WKY (p < 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 AT₁-R in the internal anal sphincter (IAS) of SHR. Ang II caused concentration-dependent contraction of IAS smooth muscle strips from WKY (pEC₅₀ = 8.5 ± 0.1) and SHR (pEC₅₀ = 8.6 ± 0.2). Losartan (100 nM) significantly (p < 0.05) inhibited this effect. From these data, we conclude that 1) hypertensive IAS in SHR is primarily the result of renin-angiotensin system up-regulation, 2) ACE inhibitors and AT₁-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 AT₁-R antagonists.

Address correspondence to: Dr. Satish Rattan, Jefferson Medical College, Thomas Jefferson University, 1025 Walnut St., Room 901 College; Philadelphia, PA 19107. E-mail: satish.rattan{at}jefferson.edu

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