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From the Departments of Urology and Physiology & Biophysics, Institute for Smooth Muscle Biology, Albert Einstein College of Medicine, Bronx, New York.
| Correspondence to: George J. Christ, PhD, Professor, Departments of Urology and Physiology & Biophysics, Ben Marden Distinguished Scholar in Urology, Director, Institute for Smooth Muscle Biology, Room 744, Forchheimer Bldg, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461 (e-mail: christ{at}aecom.yu.edu). |
| Received for publication May 2, 2002; accepted for publication May 16, 2002. |
Strategies for the Development of Organ/Tissue-Specific Treatments
for Erectile Dysfunction
In the post-Viagra era, the quest for orally administered, penile-selective
enhancers/restorers of erectile capacity has become the gold standard for the
development of improved therapeutic agents for the treatment of erectile
dysfunction. However, the relatively serendipitous discovery of the utility of
Viagra for the treatment of erectile dysfunction highlights the fact that
there is currently no established algorithm/paradigm for identifying relevant
molecular targets for the "next generation" of improved treatment
of erectile dysfunction. As outlined below, there are 3 obvious approaches to
do so:
Certainly, the overall approach here is quite straight-forward. The idea is to begin by utilizing any of the numerous new molecular technologies available to perform analysis of gene expression (ie, gene chip microarrays) and establish whether or not there is evidence for tissue-specific expression of relevant molecular targets. Such an approach can seem daunting in light of the fact that gene chips contain upward of 7–10 000 genes. However, the recommended approach is to start by mining the tissue/cell-specific genomic database for genes that are already known to be important modulators of corporal smooth muscle cell tone (ie, K channel modulators). Such "directed" gene-based discovery methods are quite efficient for identifying suspected targets, as well as for "screening" potentially novel targets. However, since differential expression does not guarantee differential function, target validation is required, and the recommended experimental path is outlined in Figure 1. If a gene relevant to the control of corporal smooth muscle cell tone is only expressed, or perhaps even preferentially expressed, in the corporal myocyte, then developing a small molecule to activate this target is certainly feasible.
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If taking advantage of tissue-specific expression is not possible, then leveraging differences in tissue-specific function is another option. More specifically, just because a given target is expressed in more than one tissue does not imply that it functions similarly in those distinct tissues. The goal here was to evaluate the contribution of a given target to contraction and relaxation of corporal smooth muscle. Thus, the ability to conduct pharmacological experiments in vivo and in vitro on human corporal tissue strips and to compare the results obtained with similar experiments conducted in appropriate animals models make this approach feasible. Again, by analyzing information obtained at a variety of experimental levels (see Figure 1), one can verify or refute the relevance of suspected targets. In short, the multiplicity of experimental approaches that can be applied to the study of corporal smooth muscle make erectile physiology/dysfunction an ideal model system for identification and validation of molecular targets.
Finally, perhaps it is intuitively obvious that if neither tissue-specific expression nor function of a suspected target is relevant under normal circumstances, then age- or disease-related changes in cell/tissue/organ function produce a suitable target(s). Nonetheless, target validation using the algorithm outlined in Figure 1 would still be required.
Rationale for the Utility of Ion Channels as Molecular Targets for
the Treatment of Erectile Dysfunction
In light of the importance of the corporal smooth muscle cell to the
propagation of the species, it is not surprising that regulation of the degree
of tone of this specialized vascular smooth muscle cell is intrinsically
complex (Christ et al, 1997,
1999;
Christ, 2000c). Numerous
intracellular processes are known to govern corporal myocyte tone (see
Figure 2). They include calcium
mobilization (Christ et al,
1992; Zhao and Christ,
1995) and calcium sensitization
(Chitaley et al, 2001; Mills et al, 2001; Rees et al,
2001,
2002). Nonetheless, ion
channels, the integral membrane spanning proteins found on the surface of
corporal smooth muscle cells, represent an important convergence point for
directly or indirectly affecting virtually all forms of cellular signaling.
Ion channels provide an obligate mechanism for regulating cellular
excitability (see Figures 2,
3,
4). The ion channels most
commonly found in corporal smooth muscle—namely potassium, calcium, and
chloride channels—are so named according to their selective permeability
to K+, Ca2+, and Cl-, respectively. This
report focuses on the functionally antagonist role that exists between K and
Ca channels and the degree of corporal smooth muscle cell tone.
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The Role of K and Ca Channels in Modulating Corporal Smooth Muscle
Cell Tone
The pivotal role of ion channels in modulating membrane potential and
corporal smooth muscle cell tone is conferred by the anisotropic distribution
of their respective ionic species across the cell membrane. The effects of
alterations in K and Ca channel activity on corporal smooth muscle cell tone
are therefore a reflection of the standing electrochemical ionic gradients
that are maintained by a host of cellular metabolic and biochemical processes
(see Figures 3 and
4). Although a detailed review
of this subject matter is well beyond the scope of this report, the opening of
K channels will, in short, lead to the efflux of K+ down its
electrochemical gradient and out of the corporal smooth muscle cell.
Meanwhile, the opening of Ca channels will produce exactly the opposite
effect, that is, the influx of Ca2+ down its electrochemical
gradient. The former moves positive charge out of the corporal smooth muscle
cell and leads to hyperpolarization (ie, decreased membrane potential), and
thus, reduced cellular excitability, primarily by virtue of the corresponding
inhibition of transmembrane calcium flux through L-type voltage-dependent Ca
channels (see Figure 4). The
latter, or the opening of Ca channels, moves positive charge inside the
corporal smooth muscle cell, leading to cellular depolarization (ie, increased
membrane potential) and increased cellular excitability (see
Figure 3).
The common physiologic link between these 2 functionally antagonistic ion channels, the one that permits them to differentially modulate smooth muscle cell tone, is their respective effects on the free intracellular calcium concentration. In fact, it is now well established that alterations in the free intracellular calcium concentration are an absolute prerequisite to changes in smooth muscle cell tone. More specifically, with respect to the corporal smooth muscle cell, not only are increases in intracellular calcium required for increased contractility, but additionally, sustained contraction of corporal smooth muscle is dependent on continuous transmembrane calcium flux through L-type voltage-dependent calcium channels. The main physiologic implication of the aforementioned interrelationships is that K channels, by virtue of their central physiological location and mechanism of action, provide an ideal molecular target for the treatment of disorders that are characterized by increased smooth muscle cell tone.
Which K Channels Provide the Best Targets?
As observed for other smooth muscle cell types, corporal smooth muscle
cells express several distinct K channel subtypes. In addition to the large
conductance calcium-sensitive K channel subtype (maxi-K) and the metabolically
regulated K channel subtype (KATP), previous studies also provide
evidence for at least 2 other K channel subtypes
(Christ et al, 1993;
Malysz et al, 2001). These are
an A-type K current, as well as a delayed rectifier current. Although the
KATP and maxi-K channel subtypes apparently account for much of the
outward currents observed in cultured and freshly isolated human corporal
smooth muscle cells, it would not be surprising if additional K channel
subtypes were identified. There is also recent evidence for
electrophysiological heterogeneity in the corporal smooth muscle cell
population per se (Malysz et al,
2001), and this could have important implications in erectile
dysfunction and its therapy. In this report, however, we have focused our
investigations on the 2 best characterized and, moreover, arguably the 2 most
physiologically relevant K channel subtypes to the regulation of corporal
smooth muscle cell tone, namely the KATP and the maxi-K channel
subtypes.
The Presence of Corporal Smooth Muscle Cell Networks Ensures the
Tolerance/Efficiency of Heterogeneous Cellular Responses
A series of publications has documented the presence and physiological
relevance of gap junctions to the coordination of contraction and relaxation
responses among the corporal smooth muscle cells connexin43 (Christ et al,
1997,
1999;
Brink et al, 2000; Christ,
2000a,b).
Although there are 16 known mammalian gap junction proteins (ie, connexins),
the dominant one in human corporal smooth muscle is undoubtedly connexin43.
The presence of these aqueous intercellular channels provides partial
cytoplasmic continuity between coupled smooth muscle cells and ensures the
intercellular transit of most of the known second-messenger molecules/ions
that regulate corporal smooth muscle cell tone
(Figure 5). Thus, not all
smooth muscle cells in the corpus cavernosum need to be directly activated in
order to elicit a rapid and syncytial relaxation or contractile response. That
is, the smooth muscle cells of the corpus cavernosum function as a syncytial
smooth muscle cell network. A correlate of these facts is that not all
corporal smooth muscle cells may, or even need to, express the same cellular
phenotype. Of direct relevance to this report is that, even if a molecular
target is heterogeneously expressed in corporal myocytes, it can still provide
an attractive therapeutic target if a sufficient number of cells express that
phenotype (eg, this provides an important "safety factor" for the
potential success of gene therapy; see below). Theoretical calculations of the
number of activated/responsive cells required in order to produce syncytial
tissue responses have been previously described
(Ramanan et al, 1998).
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The Rationale for Pursuing Orally Administered,
Organ/Tissue-Selective K Channel Modulators
As reviewed elsewhere, the therapeutic potential of KATP channel
activators to treat vascular disease (ie, increased peripheral resistance) has
been established for more than 2 decades
(Lawson, 1996). The relatively
limited clinical efficacy profile of the KATP channel modulators is
most certainly related to the ubiquitous distribution of the KATP
channel in smooth, skeletal, and cardiac muscle
(Lawson, 1996), as well as in
numerous other tissues/cell types.
There is some, albeit limited, clinical experience with K channel modulators for the treatment of erectile dysfunction. For example, an orally available maxi-K channel opener was being evaluated in phase 2a study (BMS-223131; Bristol-Myers Squibb, New York, NY), but the outcome of those studies remains uncertain (Pryor and Redmon, 2000). In addition, the possibility of surmounting untoward systemic side effects by utilizing intracavernous injection of a KATP channel modulator for the treatment of erectile dysfunction (PNU83757; Upjohn, Peapack, NJ) has also been attempted but has yielded somewhat disappointing clinical results as well (Pryor and Redmon, 2000).
Although the initial clinical results are not encouraging, there is reason to believe that a renaissance in the therapeutic utility of K channel activators may soon occur. Such an approach would obviously have to leverage tissue-specific or disease-related changes in corporal smooth muscle K channels. A brief summary of the salient molecular features of the KATP and maxi-K channel subtypes is therefore given below.
Molecular Composition of the KATP and Maxi-K Channel
Subtypes
Both the KATP and the maxi-K channels are formed from
heteromultimer alpha (
, pore forming) and beta (ß, regulatory)
subunits (Figure 6). The
KATP channel has 2 known Kir (Kir; inward rectifier) isoforms
(Kir6.1 and Kir6.2) and 4 known regulatory subunits, SUR1, SUR2A, SUR2B, and
SUR2C (sulfonylurea receptors [SURs];
Aguilar-Bryan et al, 1998; Babenko et al, 1998;
Inagaki and Seino, 1998;
Seino, 1999). For example,
there are the cardiac-specific (SUR2A/Kir6.2), the pancreatic-specific
(SUR1/Kir6.2), and the smooth muscle-specific (SUR2B/Kir6.2 and SUR2B/Kir6.1)
complexes that could be targeted by novel, selective KATP channel
openers (Lawson, 2000;
Lawson and Dunne, 2001). With
respect to the maxi-K channel, only a single isoform of the subunit
has been identified, and only a single ß subunit is present in smooth
muscle. But there is evidence of significant physiological distinctions among
splice variants in the subunit; furthermore, there is evidence that
the subunit splice variants exhibit both tissue-specific
(Knaus et al, 1995; Wallner et al, 1995; Jones et
al, 1998,
1999;
Toro et al, 1998; Giangiacomo et al, 2000) and
disease-related (Xie and McCobb,
1998) changes.
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Disease-related alterations in ion channel function per se have been referred to as "ion channelopathies"—in this case, K channelopathies (Ashcroft, 2000; Lawson and Dunne, 2001). As used herein, the term "K channelopathy" refers to alterations in K channel expression, activity, regulation, or function that provide the mechanistic basis for pathological cellular function—in this case, altered smooth muscle cell tone. The observed tissue-specific expression patterns in the heteromultimer composition of the KATP or maxi-K channels, as discussed above, are consistent with the possibility that chemical entities may be identified that can leverage these tissue-specific differences in K channel expression or function. Furthermore, if there are disease-related K channelopathies (ie, diabetes), then such an observation may provide a rationale to develop a mechanism-based, patient-specific therapeutic strategy for the treatment of erectile dysfunction. Recent data obtained from human corporal tissue strips have documented the importance of the maxi-K (Spektor et al, in press) and KATP channels (Venkateswarlu et al, in press) in the contraction and relaxation of human corporal smooth muscle and, furthermore, have suggested that K channelopathy may have an impact on the physiology of human diabetic corporal smooth muscle (Venkateswarlu et al, in press).
So, Can Orally Administered K Channel Activators Provide a Potential
Therapy for Erectile Dysfunction?
The activity of the maxi-K and KATP channel subtypes in corporal
smooth muscle is quite low at physiological membrane potentials in the absence
of endogenous neurally mediated relaxation (ie, at 40–50 mV, the open
probabilities are estimated to be less than 1%; Lee et al,
1999a,b).
Moreover, recent studies have documented that the open probabilities of both K
channel subtypes are dramatically increased in activity by the addition of
prostaglandin E1 (PGE1) (open probability approaches 1 with 33
µM PGE1; Lee et al,
1999b) and pinacidil (10 µM), respectively. The apparent
quiescence of these channels in this cell type during flaccidity, and yet the
ability of physiologically relevant stimuli to increase their activity so
dramatically (Lee et al,
1999a,b;
Wang et al, 2000), make them
attractive molecular targets.
The real question, then, is whether or not it is possible to administer K channel activators systemically at concentrations that would have a greater impact on corporal smooth muscle K channels than on, for example, the vascular K channels in resistance vessels. Stated more succinctly, the real challenge is to identify a therapeutic window that simultaneously satisfies 2 conditions. First, the K channel modulator concentration would have to be low enough so as not to adversely affect the vascular K channels in resistance vessels (ie, no change in blood pressure). Second, the concentration of the K channel modulator achieved in the corporal vascular sinuses would have to be sufficient to ensure that when the K channels are activated by neural signals, an enhanced hyperpolarization and a corporal smooth muscle cell relaxation occur. Preliminary data in our rat model in vivo, using intravenous administration of pinacidil (a selective KATP channel activator) and NS1619 (a putative selective maxi-K channel activator), are consistent with such a possibility (data not shown). Briefly, intravenous administration of both compounds (0.1–1.0 mg/kg) produced a physiologically relevant increase in the intracavernous pressure response (ICP) to submaximal current stimulation (0.2–0.5 mA) in anesthetized rats. In both cases, prior to administration of the compounds, the nerve-stimulated ICP was insufficient to elicit an erection (ICP = 20–50 cmH2O), whereas afterward, visible erectile responses were observed in the majority of animals (ICP = 60–100 cmH2O). Although further experiments are required, these preliminary observations do provide "proof of concept" that such an approach is feasible. As more information is gleaned about the effects of age and disease on the molecular and biophysical properties of these K channel subtypes in physiologically distinct smooth muscles, it may be possible that one can indeed develop orally activated, tissue-selective K channel activators.
Gene Therapy for Erectile Dysfunction
A recent publication documented that expression of hSlo (the
, or pore-forming subunit of the human maxi-K channel; see
Figure 6) in a fraction of the
specialized vascular smooth muscle cells of the rat corpus cavernosum (ie,
corporal myocytes) restored the age-related decline in the nerve-stimulated
ICP typically observed in older rats
(Christ et al, 1998). Similar
observations have been made following 8–12 weeks of experimental
diabetes using the streptozotocin-diabetic F-344 rats (Christ,
1998b,
2000b;
Melman and Christ, 2001). In
both cases, the mechanism of action was hypothesized to be related to the
enhanced hyperpolarizing ability of the corporal smooth muscle cell network
provided by hSlo in response to cellular activation by released
neurotransmitters (eg, nitric oxide; see Figures
2 through
4). The fact that relatively
low-level hSlo transfection rates produced dramatic changes in
erectile capacity (ie, intracavernous pressure) was presumed related to the
presence and physiological relevance of the intercellular pathway provided by
the connexin43-derived gap junction channels (see
Figure 5). Thus, not every
corporal smooth muscle cell needed to be genetically modified to achieve
global affects on tissue function, permitting a certain degree of inefficiency
in gene transfer. This inefficiency in gene transfer will likely prove
valuable to the safety profile of this novel form of therapy; the smaller the
degree of genetic modification required to produce a physiologically relevant
effect nominally, the lower the likelihood there will be any untoward effects
of the therapy.
Our preliminary observations indicate that the physiologically relevant effects of a single intracavernous injection of naked DNA (ie, hSlo/pVAX or pcDNA3) can last for up to 4 months in the diabetic rat (ie, longer time points were not examined) and up to 6 months in the aged rat model. The implication is that a patient could be effectively treated for erectile dysfunction by 1–2 visits to a urologist per year. Certainly, such a therapy would provide clear advantages over other forms of currently available therapy and perhaps over other forms of gene therapy as well (Schenk et al, 2001). Moreover, many impotent men may require no other form of therapy. The increased sensitivity of their corporal smooth muscle cells conferred by expression of the gene product now makes it responsive to the extant neural pathways, whereas prior to gene therapy, the endogenous neural stimulus was insufficient. Even if gene therapy itself were insufficient to restore erectile capacity, the patient could then be placed on other available forms of therapy (ie, Viagra), presumably at lower concentrations, thus minimizing the side effect profile. Such a rationale could well establish a safe and effective gene therapy approach as a first-line treatment for erectile dysfunction and perhaps even as a prophylactic treatment to prevent the onset of impotence.
Summary and Conclusions
K channels appear to provide an ideal molecular target for regulating
corporal smooth muscle cell tone and therefore erectile capacity. They do so
by virtue of the central role they play in integrating cellular signals and
furthermore, because alterations in their activity are commensurate with the
modulation, but not ablation, of smooth muscle cell tone. Since both
tissue-specific expression and tissue-specific function are characteristics of
the multisubunit complexes that comprise the maxi-K and KATP
channel subtypes, significant potential exists for developing novel chemicals
that can selectively activate these channels in target tissues. Moreover, the
quiescence of these channels during flaccidity and the robust increase in
their activity levels during endogenous stimulation bode well for their
potential as erectogenic agents. Finally, the ability of intercellular
communication through gap junctions to efficiently spread K channel-mediated
hyperpolarizing signals throughout the corporal smooth muscle cell network
implies that low-efficiency gene transfer techniques will provide a unique
circumstance in which high-efficacy treatments can be locally delivered to the
penis, thus further minimizing the potential for systemic side effects.
Appendix
Question 1—
About 4–5 years ago, your group reported on gene therapy using maxi-K
channels for the treatment of erectile dysfunction. Where are we now in regard
to National Institutes of Health (NIH) support and clinical trials?
Answer— There are several other groups working on gene therapy. We have now submitted this protocol to the advisory committee of the NIH and to our institutional review board and hope to recruit human patients sometime later this year.
Question 2— How confident are you that these transfection methods will produce physiologically regulated responses? In other words, could you overdo the response by changing the amount of your channels?
Answer— What I did not show you is that there is a dose-response relationship. If you drop the concentration of transfected gene down to 10 µg, the smooth muscle effect does not last very long. In regard to basal intracavernosal pressure responses, none of the animals we have injected so far had any pathologic effects up to 6 months. We looked at the distribution of the gene in different tissues after intracavernous injections and observed it in the corpus cavernosa and several other places, but within a week, it was gone everywhere else and was expressed at a very low level in the corpus cavernosa. We believe this is a kind of reverse gene therapy. Most researchers working on gene therapy desire the most efficient, most potent, and longest-acting integrative gene they can procure. What we are trying to do is exactly the opposite. We are attempting to achieve the lowest level of expression, counting on the fact that the cells are interconnected by gap junctions and that a small push in the right direction will produce a physiological response during stimulation without any undue adverse effects.
Question 3— Have you seen any priapism in your rat model?
Answer— No.
Acknowledgments
This work was supported in part by NIH USPHS grants DK46379 and DK55076.
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