Mechanisms of Ischemia-Induced Cavernosal Smooth Muscle Relaxation Impairment in a Rabbit Model of Vasculogenic Erectile Dysfunction

No AccessJournal of UrologyInvestigative Urology1 Dec 1998MECHANISMS OF ISCHEMIA-INDUCED CAVERNOSAL SMOOTH MUSCLE RELAXATION IMPAIRMENT IN A RABBIT MODEL OF VASCULOGENIC ERECTILE DYSFUNCTION KAZEM M. AZADZOI, IRWIN GOLDSTEIN, MIKE B. SIROKY, ABDUL M. TRAISH, ROBERT J. KRANE, and INIGO SAENZ DE TEJADA KAZEM M. AZADZOIKAZEM M. AZADZOI More articles by this author , IRWIN GOLDSTEINIRWIN GOLDSTEIN More articles by this author , MIKE B. SIROKYMIKE B. SIROKY More articles by this author , ABDUL M. TRAISHABDUL M. TRAISH More articles by this author , ROBERT J. KRANEROBERT J. KRANE More articles by this author , and INIGO SAENZ DE TEJADAINIGO SAENZ DE TEJADA More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(01)62299-7AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: To determine the effects of hypercholesterolemia and atherosclerosis-induced chronic cavernosal arterial insufficiency on cavernosal smooth muscle tone, nitric oxide synthase (NOS) activity and cavernosal tissue synthesis of constrictor eicosanoids. To study whether inhibition of the cyclooxygenase pathway by indomethacin and tissue treatment with nitric oxide (NO) precursor L-arginine improve hypercholesterolemia and ischemia-induced impaired endothelium-dependent and neurogenic relaxation of cavernosal tissue. Materials and Methods: New Zealand White rabbits were divided into control (n = 10, fed a regular diet), hypercholesterolemia (Hch, n = 13, fed a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 14) groups. The CCI group underwent balloon de-endothelialization of iliac arteries and received a diet containing 0.5% cholesterol. After 16 weeks, we examined the effects of Hch and balloon de-endothelialization induced arterial occlusive disease on iliac arterial blood flow, reactivity of cavernosal tissue, cavernosal NOS activity and cavernosal tissue synthesis of constrictor eicosanoids. Results: Histology revealed significant atherosclerotic arterial occlusive disease in the CCI group. Iliac artery blood flow in the CCI group was significantly reduced compared with the control and Hch groups. In the Hch and CCI groups, endothelium-dependent relaxation of cavernosal tissue to acetylcholine was significantly reduced compared with the control group. Electrical field stimulation-induced neurogenic relaxation and cavernosal NOS activity were significantly reduced in the CCI group but not in the Hch group. The basal release of cavernosal constrictor eicosanoids, prostaglandin F2 alpha (PGF2 alpha) and thromboxane A2 (TXA2) was significantly increased in the CCI group. Indomethacin increased endothelium-dependent relaxation in all groups and neurogenic relaxation in the CCI group, but failed to normalize the differences in relaxation between treated and control groups. In the presence of indomethacin, L-arginine improved endothelium-dependent relaxation of cavernosal tissue in the Hch group but did not normalize endothelium-dependent or neurogenic relaxations in the CCI group. Relaxation to NO donor sodium nitroprusside and papaverine was similar in cavernosal tissue from all groups. Conclusions: Impairment of endothelium-dependent relaxation by Hch occurs secondary to disruption of the NO formation in cavernosal endothelium. Improvement of endothelium-dependent relaxation by L-arginine may suggest lack of availability of L-arginine in cavernosal tissue from the Hch animals. Impairment of endothelium-dependent and neurogenic relaxation by CCI occurs secondary to disruption of the NO formation due to an alteration in the expression or activity of NOS and increased output of constrictor eicosanoids in cavernosal tissue. These studies show that Hch and atherosclerosis-induced chronic cavernosal arterial insufficiency, beyond decreasing cavernosal perfusion pressure, also adversely affect smooth muscle relaxation mechanisms in cavernosal tissue. References 1 : Functional anatomy and mechanism of penile erection. In: Contemporary Management of Impotence and Infertility. Edited by . Baltimore: Williams 321: 1648. Google Scholar 4 : Nitric oxide and cyclic GMP formation upon electrical stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun.1990; 170: 843. Google Scholar 5 : A nitric oxide-like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J. Clin. Invest.1991; 88: 112. Google Scholar 6 : Endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone. J. Urol.1992; 147: 220. Link, Google Scholar 7 : Is impotence an arterial disorder? A study of arterial risk factors in 400 impotent men. Lancet1985; 1: 181. Google Scholar 8 : Arteriogenic impotence: findings in 195 impotent men examined with selective internal pudendal angiography. Radiology1990; 174: 1043. Google Scholar 9 : Erectile dysfunction due to atherosclerotic vascular disease: the development of an animal model. J. Urol.1992; 147: 1675. Link, Google Scholar 10 : Study of etiologic relationship of arterial atherosclerosis to corporal venoocclusive dysfunction in the rabbit. J. Urol.1996; 155: 1795. Link, Google Scholar 11 : Relationship between cavernosal ischemia and corporal veno-occlusive dysfunction in an animal model. J. Urol.1997; 157: 1011. Link, Google Scholar 12 : Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J. Urol.1990; 146: 238. Google Scholar 13 : Contraction and relaxation induced by some prostanoids in isolated human erectile tissue and cavernous artery. J. Urol.1985; 134: 1245. Link, Google Scholar 14 : Prostacyclin synthesis in corpora cavernosa of the human penis: evidence for muscarinic control and pathological implications. Prostaglandins Leuko. Med.1986; 23: 211. Google Scholar 15 : Intracavernous injection of prostaglandin E1 in impotent men. J. Urol.1988; 140: 66. Google Scholar 16 : Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. USA1990; 87: 682. Google Scholar 17 : Regulation of nitric oxide synthase synthase by nitric oxide. Molecular Pharm.1993; 44: 124. Google Scholar 18 : Protein measurement with the folin phenol reagent. J. Biol. Chem.1951; 193: 265. Google Scholar 19 : Relationship between atherosclerosis-induced cavernosal hypoxia and erectile dysfunction in the rabbit. Int. J. Impot. Res.1996; 8: 104. Google Scholar 20 : Hypoxia inhibits expression of NOS via transcriptional and posttranscriptional mechanism. Am. J. Physiol.1994; 267: H1921. Google Scholar 21 : Prostaglandin-nitric oxide interactions in the microcirculation. Adv. Prostaglandin Thromboxane Leuko. Res.1995; 23: 485. Google Scholar 22 : Prostaglandin E2 regulates inducible nitric oxide synthase in the murine macrophage cell line J774. Prostaglandins1995; 49: 105. Google Scholar 23 : Prostaglandin-mediated inhibition of nitric oxide production by bovine aortic endothelium during hypoxia. Cardiovasc. Res.1995; 30: 345. Google Scholar 24 : Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats. Hepatology1996; 23: 123. Google Scholar 25 : Effect of large doses of the nitric oxide precursor, L-arginine on erectile dysfunction. Int. J. Impotence Res.1994; 6: 33. Google Scholar 26 : In vitro profile of UK-92,480, an inhibitor of cyclic GMP specific phosphodiesterase 5 for the treatment of male erectile dysfunction. J. Urol.1996; 155: 676A. Google Scholar 27 : Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int. J. Impotence Res.1996; 8: 47. Google Scholar From the Departments of Urology, Pathology and Laboratory Medicine, and Biochemistry, Boston University School of Medicine, and the Department of Urology, Boston VA Medical Center, Boston, Massachusetts© 1998 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byBurnett A (2018) Erectile DysfunctionJournal of Urology, VOL. 175, NO. 3S, (S25-S31), Online publication date: 1-Mar-2006.AZADZOI K, SHINDE V, TARCAN T, KOZLOWSKI R and SIROKY M (2018) Increased Leukotriene and Prostaglandin Release, and Overactivity in the Chronically Ischemic BladderJournal of Urology, VOL. 169, NO. 5, (1885-1891), Online publication date: 1-May-2003.SIROKY M and AZADZOI K (2018) Vasculogenic Erectile Dysfunction: Newer Therapeutic StrategiesJournal of Urology, VOL. 170, NO. 2S, (S24-S30), Online publication date: 1-Aug-2003.Kershen R, Azadzoi K and Siroky M (2018) Blood Flow, Pressure and Compliance in the Male Human BladderJournal of Urology, VOL. 168, NO. 1, (121-125), Online publication date: 1-Jul-2002.SIMOPOULOS D, GIBBONS S, MALYSZ J, SZURSZEWSKI J, FARRUGIA G, RITMAN E, MORELAND R and NEHRA A (2018) CORPOREAL STRUCTURAL AND VASCULAR MICRO ARCHITECTURE WITH X-RAY MICRO COMPUTERIZED TOMOGRAPHY IN NORMAL AND DIABETIC RABBITS: HISTOPATHOLOGICAL CORRELATIONJournal of Urology, VOL. 165, NO. 5, (1776-1782), Online publication date: 1-May-2001.AZADZOI K, KRANE R, SAENZ DE TEJADA I, GOLDSTEIN I and SIROKY M (2018) RELATIVE ROLES OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE PATHWAYS IN ISCHEMIA-INDUCED INCREASED CONTRACTION OF CAVERNOSAL SMOOTH MUSCLEJournal of Urology, VOL. 161, NO. 4, (1324-1328), Online publication date: 1-Apr-1999.AZADZOI K, TARCAN T, KOZLOWSKI R, KRANE R and SIROKY M (2018) OVERACTIVITY AND STRUCTURAL CHANGES IN THE CHRONICALLY ISCHEMIC BLADDERJournal of Urology, VOL. 162, NO. 5, (1768-1778), Online publication date: 1-Nov-1999. Volume 160Issue 6 Part 1December 1998Page: 2216-2222 Advertisement Copyright & Permissions© 1998 by American Urological Association, Inc.MetricsAuthor Information KAZEM M. AZADZOI More articles by this author IRWIN GOLDSTEIN More articles by this author MIKE B. SIROKY More articles by this author ABDUL M. TRAISH More articles by this author ROBERT J. KRANE More articles by this author INIGO SAENZ DE TEJADA More articles by this author Expand All Advertisement PDF downloadLoading ...