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Androgenic Maintenance of Inflow and Veno-Occlusion during Erection in the Rat

^a Department of Physiology and Endocrinology and ^b Department of Surgery, Urology Section, Medical College of Georgia, Augusta, Georgia 30912-3000

	ABSTRACT

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Ongoing studies in this laboratory are designed to determine the role of androgens in the maintenance of the erectile response in the rat. Testosterone-treated castrated rats (TESTO) and untreated castrated rats (CASTRATE) were used for measurement of the rate at which blood flows into the cavernous sinuses by timed collections of blood after partial amputation of the penis. A laser Doppler flow meter was employed to determine whether androgens also regulate the veno-occlusive mechanism that controls the rate of blood flow out of the sinuses. Erection was induced by direct electrical stimulation of the autonomic ganglion that controls cavernosal blood flow in the erectile response. The results of these studies showed that blood flow into the sinuses was approximately twice as great in the TESTO animals as the CASTRATE rats. Furthermore, during ganglionic stimulation, veno-occlusion occurred in the TESTO rats but failed to occur in the CASTRATE rats. The dependence of these responses on nitric oxide (NO) was demonstrated by showing that injection of sodium nitroprusside (SNP) enhances the intracavernosal pressure response in TESTO rats but not CASTRATE animals. However, when SNP injection was combined with ganglionic stimulation, veno-occlusion did occur in the CASTRATE animals. Taken together, these studies show that both the rate of blood flow into the cavernous sinuses and the blood flow out are under androgenic regulation and may involve the actions of NO.

	INTRODUCTION

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The erectile response of the penis is associated with vascular smooth muscle in the tunica media of arteries and arterioles that carry blood into the corpora cavernosa of the penis. Of equal importance to the erection are the vascular smooth muscle cells that line the cavernous sinuses. Relaxation of these latter cells early in the erectile response permits the sinuses to expand to accommodate the increased rate of blood inflow under the driving force of the central arterial pressure. As blood fills the sinuses, they expand against the tunica albuginea; the expansion of the sinuses compresses the veins carrying blood out, and this pressure-dependent limitation of outflow constitutes the veno-occlusive process. The resulting combination of increased inflow due to arteriolar dilation and decreased outflow resulting from veno-occlusion is the basis for penile erection.

Studies from this and other laboratories have shown that penile erection is an androgen-dependent process (see [1]). Many of the published findings dealt with the hormonal control of the actions of the neurotransmitters that regulate contraction and relaxation of the cavernosal smooth muscle. The veno-occlusive mechanism, which limits the outflow, also appears to be androgen dependent [2], but this dependence has not been extensively studied. The current experiments present methods for the direct measurement of the rates at which blood flows into and out of the corpus cavernosum during erection. The techniques have been utilized in testosterone-treated castrated rats and untreated castrated rats to determine whether androgens regulate both inflow and outflow.

	MATERIALS AND METHODS

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Animals

Male Holtzman rats (Harlan, Indianapolis, IN), 6–8 mo of age, were used in these studies. Animals were castrated under ether anesthesia and implanted s.c. with a pellet (3-mm diameter, weight 3–5 mg) of testosterone (1:1, testosterone:cholesterol; group designation: TESTO) or a control pellet of cholesterol only (group designation: CASTRATE). In previous studies from this laboratory it was reported that with a single testosterone pellet implanted, blood testosterone levels are in the range of 500–1000 pg/ml while after implantation of a cholesterol control pellet, the levels of testosterone in the blood are less than 25 pg/ml [3]. The animals were used in the studies 6–8 days after surgery. All procedures were performed in accordance with the Guiding Principles in the Care and Use of Animals approved by the American Physiological Society.

Measurement of the Erectile Response

The procedure used to induce erection and measure the intracavernosal pressure (CCP) has been previously described from this laboratory [2, 4–6]. Briefly, in this method, the animals are anesthetized with ketamine and xylazine, and, using standard methods, the left carotid artery is cannulated for continuous monitoring of mean arterial blood pressure (MAP). Once this cannula is in place, the abdominal cavity is opened and the viscera are retracted and wrapped in warmed saline-soaked sponges and cellophane wrap. The right major pelvic ganglion is exposed by clearing the overlying fascia. The shaft of the penis is then freed of skin and fascia to reveal the paired corpora cavernosa distal to the crural region. The right corpus cavernosum is cannulated by insertion of a 30-gauge needle attached to PE 50 tubing, which has been drawn to a fine tip and connected to a pressure transducer to permit continuous monitoring of CCP. The left corpus cavernosum is cannulated with a 30-gauge needle attached to a 10-µl syringe via a short length of PE 10 tubing. This cannula is used for the delivery of 1–2 µl of saline containing vasoactive agents into the cavernous sinuses. Stainless steel bipolar electrodes are then placed on the major pelvic ganglion and, with the stimulator set at 5 volts, the position of the electrodes is adjusted until the maximal CCP is achieved. The duration and amplitude of the ganglionic stimulation, MAP, and CCP are continuously recorded on a polygraph recorder. Stimulatory voltage is varied in 1-volt steps from 1 to 5 volts (5-msec duration, 12-Hz frequency, 1-min duration of nerve stimulation with a 1-min rest period between subsequent stimulations).

Measurement of Intracavernosal Blood Flow (CCF)

A laser Doppler flow meter was employed in the determination of the movement of blood in the cavernous sinuses during erection. This technology has been previously used in the measurement of testicular [7] and mammary [8] blood flow in the rat. The FC 302 laser Doppler flow detection probe (PeriMed, Stockholm, Sweden) was positioned at the base of the penis lateral to the cavernosal vein of the left corpus cavernosum. Output of the flow meter was both digital (relative flow units) and audible. The proper positioning of the probe was confirmed during ganglionic stimulation when the turbulence caused by partial veno-occlusion could be heard as pulses marking the flow spurts during systole. The digital output of the flow meter was continuously recorded with the polygraph recorder. Care was taken in the positioning of this probe to ensure that movement of the penis during the erectile response was not measured as flow (movement artifact). Before each use, the laser Doppler flow meter was calibrated. The results presented in Figure 1 are based on measurements made in 7 TESTO and 12 CASTRATE animals.

Measurement of Blood Flow into the Cavernous Sinuses

To measure the rate at which blood flowed into the corpus cavernosum, the distal end of the penis was amputated just proximal to the os penis while the penis was in the non-erect state. At the cut end, the corpus spongiosum and dorsal vein were ligated with microsurgical clips so that only blood from the corpora cavernosa emerged from the remaining portion of the shaft. By timing the interval required to collect 100 µl of blood into a capillary tube, the flow rate in ml/min could be determined. For very low flow rates, blood was collected for 1 min into a tared capillary tube and the tube was weighed to determine the volume of blood that had been collected. These measurements of the rates of inflow were completed for non-erect penises from 6 TESTO and 7 CASTRATE rats and during ganglionic stimulation at 1 through 5 volts.

Effect of Sodium Nitroprusside on CCP and CCF

After completion of the voltage-response and blood flow studies, the effect of sodium nitroprusside (SNP) on MAP, CCP, and CCF was investigated. In this experiment, there was an initial 5-volt, 1-min stimulation of the major pelvic ganglion during which the CCP and CCF were continuously measured. Immediately after discontinuation of this ganglionic stimulation, SNP (8 µg/kg BW in 1–2 µl saline) was injected into the left corpus cavernosum and, after a period of 3 min during which CCP and CCF were continuously recorded, the 5-volt simulation was repeated for 1 min. Thus, in this sequence, CCP and CCF were measured during erection induced by ganglionic stimulation only, during erection resulting from SNP stimulation only, and during erection induced by a combination of ganglionic stimulation and SNP. This study employed 5 TESTO and 9 CASTRATE rats.

Computation of Pressure and Flow Rates

Since the output of the laser Doppler flow meter was in relative perfusion units, the flow and pressure data were analyzed by integrating each of the response curves. This was accomplished by scanning the polygraph recordings into computer memory and then electronically overlaying a grid that divided each response curve into 23 segments, each of which was equivalent to 3.8 sec. The magnitude of each CCP and CCF response was determined by summing the response areas in each of the 3.8-sec segments. The results of this analysis are expressed as relative cavernosal pressure units (CPU) and relative cavernosal flow units (CFU).

Statistical Analysis

Results of these experiments are expressed as means ± 1 SEM. Changes in CPU, CFU, and MAP were analyzed using one-way and two-way ANOVA with post hoc analysis by Newman-Keuls test [9]. Statistical significance was set at p < 0.05. In order to determine when veno-occlusion occurred in the studies of ganglionic stimulation and SNP treatment, the following procedure was used. The first three CFU measurements, made before the start of ganglionic stimulation, were averaged for each animal and then compared statistically (t-test) to the average of three measurements made after 30 sec of ganglionic stimulation. Veno-occlusion is defined as the lack of a significant difference between the measurements made before and those made during ganglionic stimulation. If the flow is significantly elevated above prestimulation levels during ganglionic stimulation, then veno-occlusion failed to occur. A similar analysis was completed for the CPU measurements at the same time points.

	RESULTS

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In prior studies from this laboratory [4, 10], circulating levels of testosterone in castrated rats receiving a single 3-mm pellet of 50% testosterone (TESTO) have been approximately 1 ng/ml, while in untreated castrated rats (CASTRATE) the levels are about 20 pg/ml. Although 1 ng/ml is less than levels measured in intact rats, the replacement with testosterone pellets has maintained the erectile response at levels not different from the response measured in intact rats [2]. In the present study, blood was not collected for the measurement of testosterone, but at necropsy the sizes of the ventral prostate, the dorsolateral prostate, and the seminal vesicles were always noted. Since these are androgen-sensitive tissues, the size and apparent secretory activity of these organs served to confirm that the blood testosterone levels in the CASTRATE group were very low as compared to levels in the animals receiving pellet implants of testosterone.

Figure 1 shows the CPU and CFU results for TESTO and CASTRATE rats during ganglionic stimulation varying from 1 to 5 volts. In full agreement with our prior findings, the CPU in TESTO animals at 3, 4, and 5 volts was greater than the response in CASTRATE animals. The CFU also show an important difference between TESTO and CASTRATE rats: at low voltages (1 and 2 volts), CFU appeared to be greater in TESTO than in CASTRATE rats. However, as the ganglionic stimulation was increased to 3 and 4 volts, CFU declined in the TESTO group but remained elevated in the CASTRATE animals. At 5 volts, the patterns in TESTO and CASTRATE animals were dissimilar; in the androgen-treated rats, the rate of flow rose over the first few seconds of ganglionic stimulation and then declined to levels that were not different from the prestimulation levels, indicating that the veno-occlusive mechanism had been activated and outflow was impeded. In the CASTRATE rats, CCF remained high at 5 volts, indicating little or no veno-occlusion. Thus, veno-occlusion, as indicated by the initial rise followed by a sharp decline in flow at 5 volts, appears to be a characteristic of the androgen-maintained erectile response.

View larger version (32K): [in this window] [in a new window]   FIG. 1. Intracavernosal pressure (CPU, open circles) and intracavernosal flow (CFU, solid circles) measurements made in TESTO and CASTRATE rats during progressive ganglionic stimulation from 1 to 5 volts. At each voltage, stimulation was continued for 1 min (hatched bar) followed by a 1-min rest period. At 4 and 5 volts, the CPU was greater in TESTO than in CASTRATE rats. The tracings are based on measurements made in 12 CASTRATE and 7 TESTO animals. Error bars have been omitted from this graph for clarity.

The next experiment was designed to measure directly the rate at which blood flowed into the corpus cavernosum during erection. These measurements were accomplished by amputating the distal end of the penis so that the veno-occlusive mechanisms were inoperative. The results in Figure 2 clearly demonstrate that at 3, 4, and 5 volts, the rate of blood flow into the erectile tissue was significantly greater in the TESTO than in the CASTRATE animals.

View larger version (16K): [in this window] [in a new window]   FIG. 2. The rate of blood flow into the corpora cavernosa of TESTO (solid circles) and CASTRATE (open circles) rats. The distal portion of the penis was amputated, and the rate at which blood emerged from the cut end was determined before stimulation of the major pelvic ganglion (resting) and during stimulation at 1-5 volts. The mean values are based on measurements made in 7 CASTRATE and 6 TESTO rats, with brackets representing 1 SEM. Asterisks indicate significant differences between TESTO and CASTRATE at the same voltage.

A clear difference having been established between TESTO and CASTRATE rats in both the rate of blood flow into the cavernous sinuses and the veno-occlusive response during erection, the next series of experiments was designed to determine whether the reduced rate of inflow could account for the failure of the veno-occlusive mechanism in the CASTRATE rats. These studies show that in response to the initial ganglionic stimulation only, there was a greater CPU response in TESTO (Fig. 3a) than in CASTRATE rats (Fig. 3b). Figure 3 also shows clear evidence of veno-occlusion in TESTO (Fig. 3c) but not in CASTRATE rats (Fig. 3d) during the initial ganglionic stimulation. When these same animals received an intracavernosal injection of the nitric oxide (NO) donor drug, SNP, there were two important differences between the responses in TESTO and CASTRATE animals. Firstly, the CPU response to the SNP was significantly greater in the TESTO rats (Fig. 3a) than in the CASTRATE group (Fig. 3b). The higher CPU response seen in the TESTO rats (Fig 3a) was accompanied by lower CFU (Fig. 3c), indicating a greater limitation of blood outflow in the rats. The second difference between TESTO and CASTRATE rats was apparent in the CPU and CFU response to ganglionic stimulation after SNP injection. The CASTRATE rats, which showed no evidence of veno-occlusion to ganglionic stimulation before SNP, showed clear evidence of veno-occlusion after SNP administration (Fig. 3d). In this way, the response in CASTRATE rats with additional NO mimicked the response seen in the TESTO animals before SNP. It would appear from this experiment that the addition of exogenous NO, via an SNP injection, changed the intracavernosal flow pattern in CASTRATE animals to one that closely resembled the TESTO pattern. In addition, ganglionic stimulation after SNP injection caused a significant elevation in CPU in the CASTRATE (Fig. 3b) but not in the TESTO animals (Fig. 3a).

View larger version (35K): [in this window] [in a new window]   FIG. 3. The effect of ganglionic stimulation and the administration of SNP, singly and in combination, on the erectile response in TESTO and CASTRATE rats. After the initial period of ganglionic stimulation at 5 volts (hatched bar), each animal received an intracavernosal injection of SNP (, 8 µg/kg BW in 1-2 µl saline), and after 3 min, the ganglionic stimulation was repeated. a) Shows the intracavernosal pressure (CPU) response in TESTO rats while b shows the CPU response in CASTRATE animals. Intracavernosal flow of blood (CFU) is shown in TESTO (c) and CASTRATE (d) rats. Mean values are based on measurements made in 9 CASTRATE and 5 TESTO rats, with brackets representing 1 SEM. A statistically significant difference between the CPU or CFU measurement made immediately before and during the ganglionic stimulation is indicated by an asterisk (*).

	DISCUSSION

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Reports from several laboratories point to the role of androgens in the maintenance of the erectile response. Using a variety of ex copula penile responses (penile flip, quick flip, etc.), Hart and colleagues showed that the erectile response in spinal-sectioned rats declined within 24 h after castration [11] but that with 24-h testosterone replacement, the response partially returned. Gray et al. [12] also reported that erections declined after castration but increased after testosterone replacement and that treatment with an anti-androgen blocked the testosterone maintenance of the erections. Studies from this and other laboratories have shown that there is a measurable decline in the CCP during electrically induced erection within 1 day after castration and that the decline is nearly maximal after 7 days [2]. When the androgen is replaced, the erectile response fully recovers [6, 13]. In men, erectile dysfunction and low blood testosterone levels are problems in patients undergoing renal dialysis [14], men with prolactin-secreting pituitary adenomas [15], and during some anti-androgen treatments [16–19]. After treatment with androgens, hypogonadal, impotent men reported an increase in the number of erections, nocturnal penile tumescence, episodes of masturbation [20], and sexual desire [21]. Several other authors related blood levels of testosterone to the erectile response and libido [22, 23].

The primary site of androgenic regulation of the erectile response is widely held to be the NO synthetic activity in the autonomic nerve fibers that supply the corporal smooth muscle of the cavernosal arterioles and sinuses [24–26]. Studies from this laboratory have demonstrated that NO synthase gene expression is lower in cavernosal tissue obtained from CASTRATE rats than from TESTO animals [4]. Our studies also indicate that non-NO-dependent pathways may be androgen sensitive in the erectile response [10] and that sensitivity to -adrenergic stimulation is higher in CASTRATE rats than in TESTO [5]. Published reports using the dog [27] or rabbit [28] models also point to an involvement of NO in erection and a regulatory role of androgens in the process. However, from these prior studies, it is not clear whether the androgens act only to regulate the rate of blood flow into the erectile tissue. The actions of testosterone on the veno-occlusive mechanism have not been widely examined. Studies from this laboratory used cavernosometry to show that, in order to achieve veno-occlusion, the rate of saline infusion was nearly twice as great in CASTRATE than in TESTO rats [2]. The present study extends our prior findings with the use of a laser Doppler flow meter to show changes in the intracavernosal movement of blood during erection. We find that blood continues to move within the cavernous sinuses during erection in the CASTRATE animals, while in TESTO rats the intracavernosal movement declines during erection, indicating that veno-occlusion has taken place. When additional NO is added with the injection of SNP, veno-occlusion occurs in the CASTRATE group, suggesting that the failure to veno-occlude in the CASTRATE rats is due to inadequate NO synthesis. What is not clear from this experiment, however, is the location of the smooth muscle that responds to the elevated NO levels. With injection of the drug directly into the cavernous sinuses, the intracavernosal smooth muscle cells would be primarily affected, but an action on the smooth muscle in the tunica media of the arterioles is not ruled out. Our finding that the rate of inflow is lower in the CASTRATE rats supports an action of testosterone in the maintenance of NO production in the cavernosal arterioles.

In considering the present results, it must be remembered that increased inflow and veno-occlusion are both critical to the success of the erectile response. Our prior experiments used cavernosometry to investigate the androgen dependence of veno-occlusion in the rat erection [2]. The deficiency in veno-occlusion in CASTRATE could be due to a deficient production of NO so that the smooth muscle cells lining the cavernous sinuses achieve a lesser degree of relaxation. Since this would permit a higher rate of outflow, veno-occlusion would not occur. When exogenous NO is administered (with SNP injection), the veno-occlusive response improves, but the CCP increase with ganglionic stimulation and SNP falls short of the response seen in TESTO rats. This finding suggests that there is another site of androgenic action in addition to the maintenance of NO production. Androgens could support the cGMP mechanism that is activated by NO. Another possibility is that testosterone is responsible for the maintenance of the physical properties of the tunica albuginea. If castration leads to a progressive breakdown of the collagen matrix of the tunica, the tissue could become more compliant and veno-occlusion less likely. The studies from Hatzichristou and coworkers [29] point to the importance of the physical properties of the tunica for complete erectile response in men.

Our studies show that the pressure within the cavernous sinuses during erection in the CASTRATE rats is largely dependent on the rate of inflow, since there is little evidence that a significant degree of veno-occlusion occurs during erection in the animals. With the addition of exogenous NO (SNP injection), it is likely that the rate of inflow increases, although we have not measured the effects of SNP after amputation of the distal portion of the penis. It is also possible that the additional NO caused a greater degree of relaxation of the smooth muscle lining the cavernous sinuses and that this increased degree of relaxation permitted veno-occlusion to occur. Possibly, a combination of deficient NO production and a more compliant tunica albuginea exists in the CASTRATE rats. Another possibility is that the sympathetic tone is greater in the cavernous tissue of the CASTRATE rats than in those receiving testosterone replacement. Our prior experiments have demonstrated that the erectile response in CASTRATE rats is more sensitive to the actions of -adrenergic stimulation than the response in the TESTO rats [5]. If sympathetic tone is higher in the CASTRATE rats, then a greater degree of vasodilatory stimulation would be required to achieve the same degree of erection.

	FOOTNOTES

 
¹ Correspondence. FAX: 706 721 7299; tmills{at}mail.mcg.edu

Accepted: July 28, 1998.

Received: May 26, 1998.

	REFERENCES

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