Sexual Dysfunction in Patients with Hypertension: Implications for Therapy

Carlos M. Ferrario, MD, Pavel Levy, MD

Disclosures
In This Article

Evolving Role of ANG II As a Mediator of Erectile Dysfunction

While the physiology of erection is a complex, neurovascular event regulated by psychologic and hormonal factors,[30] corporal and vascular smooth muscle tone and contractility play a key role in modulating penile blood flow and, hence the erectile process. Erection occurs due to nitric oxide-mediated relaxation of corporal and arterial smooth muscle, allowing increased blood flow into the sinusoidal spaces (Figure 2).[30] Nitric oxide, released from the endothelium and from nonadrenergic, noncholinergic cavernous nerves during sexual stimulation, appears to be the principal mediator of erection, although vasoactive polypeptide and prostaglandins may also be involved.[30,36]

Schema depicting the possible role of angiotensin II (AII) as a regulator of penile erection through contractile effects on corporal and vascular smooth muscle. By blocking the effects of AII, the AII antagonist losartan produces a dose-dependent increase in cavernosal pressure and relaxation of smooth muscle, and hence, development of an erection. Losartan may therefore potentially offer a new therapeutic option to prevent and/or correct erectile dysfunction in patients with hypertension.[13,30,44]ACE=angiotensin-converting enzyme; cGMP=cyclic guanosine monophosphate; AIIR=angiotensin II receptor; NO=nitric oxide

Recent evidence suggests that ANG II may play an important role in detumescence and possibly erectile dysfunction.[13,44] ANG II has been identified in human corpus cavernosum (primarily in endothelial cells lining blood vessels and smooth muscle bundles within the corpus cavernosum), where its tissue concentration is 200 times higher than plasma levels and 10 times higher than in aortic or mesenteric vessels.[13] Superfused cavernosal tissue from human subjects undergoing penile prosthesis implantation synthesizes (presumably via local endothelial ACE) and spontaneously secretes ANG II. Local ACE may therefore regulate smooth muscle tone in a paracrine fashion via production of ANG II, which in turn stimulates contraction of corporal and vascular smooth muscle via an ANG II receptor. This constricts blood flow through the penile arteries and reopens the venous plexus, thereby allowing penile flaccidity to return. This mechanism is consistent with a recent study indicating that the ACE DD genotype (a deletion polymorphism in the ACE gene associated with high circulating and tissue levels of ACE) may represent an important risk factor for vasculogenic erectile dysfunction.[44]

The potential involvement of ANG II in regulating erectile function is illustrated by the results of Kifor and colleagues,[13] who utilized a canine model of penile erection. Intracavernosal administration of ANG II terminated spontaneous erections in anesthetized dogs, an effect similar to that obtained with epinephrine. Administration of the AIIA in the same model resulted in a dose-dependent increase in cavernosal pressure and relaxation of smooth muscle, and thus the development of an erection (Figure 3). These intriguing studies suggest that ANG II may be an important mediator of erectile function and may offer a mechanistic explanation for the improvement in erectile function as well as satisfaction and frequency of sexual activity observed in clinical studies in male hypertensive patients with sexual dysfunction.[11]

Administration of 1 mg losartan (representing 1/30th of the dose producing a 10% decrease in blood pressure) in an experimental model of penile erection produced an immediate increase in intracavernosal pressure, followed by multiple waves of increased pressure. The increase in intracavernosal pressure was significantly correlated with losartan dose (p<0.001). Data derived from J Urol. 1997;157(5):1920-1925.[13]

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