Elsevier

European Urology

Volume 56, Issue 6, December 2009, Pages 1055-1066
European Urology

Sexual Medicine
Smooth-Muscle–Specific Gene Transfer with the Human Maxi-K Channel Improves Erectile Function and Enhances Sexual Behavior in Atherosclerotic Cynomolgus Monkeys

https://doi.org/10.1016/j.eururo.2008.12.016Get rights and content

Abstract

Background

Despite the advent of effective oral therapies for erectile dysfunction (ED), many patients are not successfully treated, and side effects have been documented.

Objective

To further evaluate the potential utility of naked DNA-based gene transfer as an attractive treatment option for ED.

Design, setting and participants

The effects of gene transfer on erectile function and sexual behavior were evaluated in eight male cynomolgus monkeys with ED secondary to moderately severe, diet-induced atherosclerosis.

Intervention

Following establishment of baseline characteristics, animals were subjected to intracavernous injection of a smooth-muscle–specific gene transfer vector (pSMAA-hSlo) encoding the pore-forming subunit of the human large-conductance, calcium-sensitive potassium channel (Maxi-K).

Measurements

For the sexual behavior studies, 2 wk of baseline data were obtained, and then animals were placed in the presence of estrogen-implanted females (n = 2) three times per week for 30 min, and sexual behavior was recorded. The intracavernous pressure response to papaverine injection was also monitored.

Results and limitations

Dramatic changes in erectile function and sexual behavior were observed after intracorporal gene transfer. The frequency of partial (6 ± 2 to 10 ± 2) and full (2 ± 1.5 to 5 ± 1.4) erections were significantly increased, with a parallel 2–3-fold increase in the duration of the observed erections. The frequency and latency of ejaculation were increased and decreased, respectively. Frequency and duration of grooming by the female were increased, and the latency decreased. Increased latency and decreased frequency of body contact was also observed, and this is characteristic of the typical drop in consort intimacy that occurs after mating in most macaque species. In addition, an increased responsiveness to intracavernous papaverine injection was observed.

Conclusions

The data indicate that intracorporal Maxi-K–channel gene transfer enhances erectile capacity and sexual behavior; the data imply that increased erectile function per se may lead to increased sexual function.

Introduction

Although penile erection is a complex neurovascular event, the degree of corporal and arterial smooth-muscle cell tone is the primary determinant of the hemodynamic events that govern erectile capacity [1], [2]. That is, the initiation and maintenance of penile erections sufficiently rigid for sexual intercourse require a degree of smooth-muscle relaxation sufficient to ensure rapid and sustained transmission of systemic blood flow into the normally low-flow, flaccid penis. In this scenario, increased smooth-muscle contractility, or conversely, impaired smooth-muscle relaxation create a predisposition to erectile failure due to a variety of causes. Erectile dysfunction (ED) is defined as the consistent inability to obtain a penile erection sufficient for vaginal penetration. The presence of ED correlates highly in men with hypercholesterolemia, cardiovascular disease, hypertension, and diabetes mellitus [3]. In fact, inadequate blood flow to the penis is a common cause of ED, and atherosclerosis is an established risk factor for development of ED in both animal models and in humans [4], [5], [6], [7], [8], [9], [10], [11].

In this regard, a previous investigation documented the presence of ED in nonhuman primates fed an atherogenic diet for several years [4]. More specifically, Macaca fascicularis is a species of nonhuman primate that develops human-like, diet-induced dyslipoproteinemias and atherosclerotic lesions that progress both in lesion character (fatty streak to complicated plaque) and lesion distribution (aortic and coronary lesions progressing to peripheral disease) similar to that of human beings [12]. These monkeys also develop end-organ pathology (myocardial infarctions, thrombosis, peripheral artery disease) at about the same frequency as human patients, and they exhibit gender-based differences in lesion progression and development of disease similar to that of men and women [13], [14], [15], [16], [17]. Additionally, these lesions regress in response to both dietary and pharmacologic intervention [18], [19]. The foregoing similarities to human beings suggest that this species may provide an excellent model for studying the mechanistic basis for vascular ED, as well as evaluating novel therapies for vascular ED [13], [20].

The need for novel therapies, in turn, is indicated by the fact that not all ED patients are successfully treated; many patients are not candidates for existing therapies; and untoward side effects are clearly documented [21], [22], [23]. Given the central importance of smooth-muscle contraction and relaxation to the erectile process, regulation of corporal and arterial smooth-muscle cell tone remains a major focus of investigation for new therapies for ED. Potassium (K) channels provide an important mechanism for the regulation of corporal smooth-muscle cell tone [24], [25], [26], [27], and furthermore, they represent a convergence point for mediating the effects of a wide variety of endogenous neurotransmitters, neuromodulators, and hormones [28]. Although several K-channel subtypes are present in penile smooth muscle, the large-conductance, calcium-sensitive K channel (ie, Maxi-K, encoded by the Slo gene) clearly plays a prominent role in the regulation of corporal smooth-muscle cell tone, and thus, erectile capacity. Preclinical studies in rodent models and excised human erectile tissues/cells support this supposition [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. Consistent with these observations, a recently completed phase 1 clinical trial suggested that intracorporal gene transfer with the Maxi-K channel may provide a safe and effective alternative therapy for ED [33]. The goal of this study was to evaluate the ability of smooth-muscle–specific Maxi-K gene transfer to ameliorate ED in an established nonhuman primate model of atherosclerosis and atherosclerosis-related ED [4].

Section snippets

Experimental animals

A total of 10 adult cynomolgus monkeys (Macaca fascicularis) were used in this study; 8 males and 2 estrogen-implanted females. They were obtained from the Wake Forest University Primate Center. All of the eight male monkeys used in the study were fed an atherogenic diet for >4 yr: 0.75 mg of cholesterol per kilocalorie [38]. Four of these male monkeys and two ovariectomized, estrogen-implanted females were used for the sexual behavior study. Note that the four male monkeys used in the sexual

Results

A total of eight male monkeys were available for these studies. Mean values for age and weight of these eight animals were 19.5 ± 1.02 yr and 6.01 ± 0.23 kg (n = 8), respectively. The age of the two females was the same (ie, 7.74 yr), with their respective weights being 2.84 kg and 3.32 kg.

Discussion

Despite the advent of effective oral treatments for ED, there is still significant room for therapeutic advances [21], [22], [23]. In fact, the results of preclinical rodent studies [24], [25], [30], [34] and a phase 1 clinical trial [33] highlight the potential utility of pSMAA-hSlo (ie, Maxi-K) gene transfer for the treatment of ED due to a variety of causes. In our continuing pursuit of improved therapies for ED, the goal of these studies was to further extend our understanding of the

Conclusions

In conclusion, in light of recent work with this vector in rodents [34], these observations provide additional support for smooth-muscle–specific gene transfer as an attractive therapeutic approach for the amelioration of age- and disease-related impairments in erectile function and capacity in two species. Moreover, this is the first evidence we are aware of, in nonhuman primates, that suggests that gene-transfer–related enhancements in erectile function per se may lead to enhanced sexual

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