The Effect of Cigarette Smoking on Penile Erection

0022-534 7/87 /1382-0438$02.00/0 Vol. 138, August

THE JOURNAL OF UROLOGY

Copyright© 1987 by The Williams & Wilkins Co.

Printed in U.S.A.

THE EFFECT OF CIGARETTE SMOKING ON PENILE ERECTION KLAUS-PETER JUENEMANN, TOM F. LUE,* JIAN-AN LUO, NEAL L. BENOWITZ, MOHAMED ABOZEID AND EMIL A. TANAGHO From the Department of Urology, University of California School of Medicine, and the Clinical Pharmacology Unit, Medical Service, San Francisco General Hospital, San Francisco, California

ABSTRACT

Clinical observations suggest that cigarette smoking impairs erectile function in patients with moderate arterial insufficiency. To evaluate the effects of smoking on the physiology of erection, we studied six healthy adult mongrel dogs in which bipolar cuff electrodes were implanted around the cavernous nerves. After threshold stimulation parameters for penile erection were established, cigarette smoke collected in a 60-ml. syringe was released slowly near the dog's mouth, to be inhaled by natural breathing. Stimulation of the cavernous nerve was repeated and blood samples for nicotine, cotinine and blood gases were obtained before and after each cigarette. The systolic and intracorporeal pressure, flow through the internal pudenda! artery, a1J;,d venous flow from the corpora cavernosa were recorded at baseline and with each electrostimulatio'n after smoke inhalation. Five of the six dogs were unable to achieve full erection after inhalation of smoke from two to three cigarettes. Some decrease of flow through the internal pudendal artery occurred and the venous restriction ability was almost completely abolished by smoking. Further, when nicotine was injected intravenously into two additional dogs, the same phenomenon was observed. These findings support the idea that cigarette smoking may contribute to impotence in some patients. (J. Ural., 138: 438441, 1987) Restoration of potency after patients discontinued cigarette smoking has been reported by Forsberg et al. 1 We have recently noted a change in the erectile response to intracorporeal pa paverine injection after cigarette smoking. 2 Although numerous studies have been performed on the effect of smoking on cardiovascular, metabolic and neurophysiologic function, 3- 8 the effect on penile erection has not been investigated. Taking advantage of recent advances in erection physiology and investigative techniques, 2• 9- 14 we examined the effect of cigarette smoking on penile erection in a canine model. MATERIALS AND METHODS

Animal preparation and surgical procedures. Six healthy adult mongrel dogs, weighing 16 to 30 kg., were premedicated with acepromazine (0.5 mg./kg. body weight) subcutaneously and anesthetized with intravenous sodium pentobarbital (30 mg./ kg. body weight with bolus injections of 25 to 50 mg./hr. as needed to maintain an adequate level of anesthesia and spon taneous respiration). Fluid maintenance consisted of intravenous infusion of normal saline solution (2 ml./kg./hr.). The animal was placed in a supine position and the abdomen was opened through a midline incision. The internal pudenda! artery was exposed unilaterally and an ultrasonic blood-flow probe (Transonics Systems, Inc., Ithaca NY) was placed around the vessel, caudal to the branching of the urogenital artery, to measure the arterial blood flow to the penis. The cavernous nerve was identified by neurostimulation and a cuff-electrode (Avery Laboratories) was placed around the nerve bundle unilaterally to induce erection by electrostimulation (0.1 to 6V, 33 Hz).13 The entire penis was then denuded, both corpora cavernosa were exposed, and two 21-gauge scalp-vein needles were placed into each corpus, one proximally for intracorporeal pressure recording (connected to a Statham pressure transAccepted for publication April 1, 1987. * Requests for reprints: Dept. of Urology, U-518, University of California, San Francisco, CA 94143. Supported by USPHS grant HL29476, grant R01-HD19640 from the National Institute of Child Health and Human Development, and an award from B. Braun Stiftung, Melsungen, Federal Republic of Germany. 438

ducer) and one distally for controlled saline perfusion of the penis (Harvard perfusion pump). A Statinsky clamp was placed on the infrarenal aorta so that the blood supply to the penis could be interrupted temporarily. By clamping the aorta while perfusing the corpus cavernosum with saline solution at a constant rate (0.9 or 1.9 ml./min.), we were able to study the penile venous system before, during, and after erection. 12• 13 In addition, a 16-gauge cannula was placed in either one of the femoral arteries for blood pressure monitoring. Once all monitoring and stimulating devices were in place, the dogs were anticoagulated with a 1000-U bolus of sodium heparin intravenously and maintained with 50 U/hr. to ensure that all pressure recording cannulae remained unobstructed. A "smoking-pipe" was created by cutting the tip of a 60-ml. syringe so that a commercially available cigarette could fit the "pipe" opening. Cigarette smoke could be collected in the syringe and released slowly near the dog's mouth to be inhaled by natural breathing. The brand of cigarette used delivered 21.2 mg of tar, 1.4 mg. of nicotine, and 12.9 mg. of carbon monoxide per cigarette (FTC report of January 1985 for levels in machinedelivered smoke). Once surgery was completed and all monitoring devices were in place, the baseline readings for the arterial responses to electrostimulation-induced erection were recorded. The aorta was then clamped and the penis was perfused with normal saline at a constant rate (0.9 or 1.9 ml./min., depending on the size of the penis) to define the venous outflow restriction response of the penis to neurostimulation. The clamp was released for five to 10 minutes after each venous study to allow adequate blood perfusion of the erectile tissue. After threshold stimulation parameters for penile erection were established, each dog was exposed to cigarette smoke. The smoke was collected repeatedly in the 60-ml. syringe until the cigarette had burned down completely. The smoke was then released slowly over a period of seven to 12 min. near the dog's mouth. Changes of arterial flow and intracorporeal pressure during cavernous nerve stimulation were recorded after each cigarette. Arterial blood samples for nicotine and cotinine analysis were obtained before and after smoke inhalation. One

EFFECT OF' CIGAFtETTE 3M0I(E O_N PEI~JILE ERECTION'

or two cigarette-equivalents of smoke were given for inhalation every hour until changes in erection were noted. The arterial flow study was performed in ail six dogs. In addition, two of the six dogs underwent a venous study. After the aorta was clamped, the changes in intracorporeal pressure were recorded after saline perfusion at a fixed rate before and after neurostimulation. This procedure was repeated several times after exposure to cigarette smoke. In two additional dogs, nicotine bitartrate was administered intravenously over one minute in graduated doses (200 µg. to 10 mg.). Blood concentrations of nicotine and cotinine (the major metabolite of nicotine) were measured by gas chromatography.15 The paired Student's t test was used to analyze the data. RESULTS

Arterial flow studies. After neurostimulation was initiated, the arterial flow to the penis increased markedly (fig. 1). With a delay of three to eight seconds the corporeal pressure went up to an average peak level of 127 cm. H20 (table 1) and stabilized at this plateau as long as stimulation was continued (two minutes). This plateau phase is the full erection phase, whereas the delay is the latent phase in neurostimulationinduced penile erection, as described by Lue et al. 12 At full erection the flow was only slightly higher than the prestimulation level. After the dog was exposed to cigarette smoke, the arterial response to neurostimulation was recorded at various times. The arterial baseline flow dropped slightly to an average of 6.5 ml./min. after exposure to one to two cigarettes (four dogs) or more than three cigarettes (two dogs) and rose to a mean peak level of 48.3 ml./min. during stimulation (p <0.02). The baseline intracorporeal pressure did not change (table 1), whereas the full erection response due to stimulation of the cavernous nerve disappeared within 15 to 60 minutes after a varied number of cigarette-equivalent exposures (table 2). When neurostimulation was initiated, the corporeal pressure rose up to an average peak level of 66.5 cm. H 2 0 and could not be maintained while neurostimulation was continued (table 1). In two dogs who smoked one or two cigarettes, the erection response recovered after three to four hours (table 2). In five of the six animals, arterial blood samples were drawn before each stimulation study. The average peak levels measured within the first five minutes after smoking one to six cigarettes were 38.5 ng./ml. for nicotine and 14.4 ng./ml. for cotinine (table 1). Interestingly, at the time when the erection failure occurred, the blood levels for nicotine and cotinine had already decreased to 17.l and 11.6 ng./ml., respectively. Blood gases were analyzed in two animals before smoke exposure (minute 0) and at 5, 10, 30 and 105 minutes after; no significant changes were found (table No blood pressure changes were noticed during the entire study.

a_

0 N

0 I

o

E

.s

t

Stimulation on (lV, 33Hz)

t

Minutes Stimulation

5

off

Fm. 1. Arterial response to cavernous nerve stimulation before and after cigarette smoke exposure in one representative dog (IP A internal pudenda! artery; CCP = corpus cavernosum pressure).

439

L Jllfean arterial flow and corporeal pressure responses to neurostimulation before and after cigarette smoking in 6 dogs

TABLE

Corporeal Pressure Baseline

Arterial Flow

Peak

Baseline

Plasma* Nicotine

Peak

(cm. H 20) (ml./min.) Before 11.5 ± 4.18 127.3 ± 27.8 9.0 ± 3.9 70.6 ± 27.1 Aftert 12. 7 ± 5.6 66.5 ± 51.9:j: 6.5 ± 3.2 48.3 ± 24.8§


Cotinine

(ng./ml.)
Values± S.D.

* The plasma levels were analyzed in

5 dogs only; peak levels were measured after 5 minutes. t Failure to achieve full erection by neurostimulation occurred after dogs inhaled 1 to 6 cigarettes. None of the 6 animals could maintain the erection within 5-55 min after cigarette smoke exposure. :j: P <0.01 when compared with levels before smoke exposure. (The pressure could not be maintained despite continuous stimulation.) § P <0.02 when compared with levels before smoke exposure.

TABLE

2. Relationship between cigarette-equivalents inhaled and

erectile failure during neurostimulation Weight (kg.)

Dog

1 2 3

29.6 21 15.6 28.5 28.6 29

4

5 6

(+)

Number of Cigarettes

Peak Recovery

0

2

+ + + + +

5

6

Nicotine

-

-

+3 hours

+ +

-

+4 hours

+

+

4

3

+

+

+

Cotinine

(ng./ml.) 27.9 14.7 51.6 8.1 20.3 87

8.0
= Normal erectile response to neurostimulation.

(-) = Unable to achieve or maintain full erection during neurostimulation. TABLE

3. Blood gas analysis before and after cigarette smoke exposure in 2 dogs

Time Dog 1 Omin 10 30 Dog 2 Omin 5 30 105

Number of Cigarettes

Erection Response

pH

pC0 2

pO,

HCO,

BE

0 1 1

+

7.40 7.46 7.43

33 26 32

93 101 98

20 18 21

-3 -3 -2

0 5 5 5

+

7.36 7.38 7.38 7.34

34 26 32 30

98 101 90 78

19 15 19 16

-5 -7

±

-5 -8

Arterial blood samples were drawn from the femoral artery. (+) = full erection; (±) = unable to maintain erection; (-) no erection achievable.

Venous outflow studies. Changes of intracorporeal pressure were recorded during normal saline perfusion of the penis at a constant flow rate after the aorta was temporarily clamped. At the low rates used (0.9 or 1.9 ml./min.), the intracorporeal pressure either showed no change or a transient rise and returned quickly to baseline. Addition of neurostimulation during perfusion at a constant rate resulted in a rapid increase of pressure off the scale until either neurostimulation or saline perfusion was terminated. This clearly demonstrated the restriction of venous flow induced by neurostimulation. After the dogs were exposed to the cigarette smoke, two striking changes were observed: 1) the peak pressure attainable was significantly less (p <0.05); and 2) this pressure could noi be maintained with the same saline perfusion rate and the sami neurostimulation parameters (fig. 2). This indicates that th, venous outflow restriction phenomenon during erection wa almost abolished by smoke inhalation. Blood levels of nicotine and cotinine were measured befo1 each venous study (table 4). The peak levels for nicotine (57 ng./ml.) and cotinine (18.6 ng./ml.) were achieved within ti

440

JUENEMANN AND ASSOCIATES

Mean arterial flow and corporeal pressure responses to neurostimulation before and after nicotine in 2 dogs*

200

0-9. ur o ~

TABLE 5.

- - Before cigarette ••••·•·•• 35 Minutes after 2 cigarettes 100

Corporeal Pressure

~==;:--:=·---~·-·····=········==·······:=········==········:=···=====···=········:::--::;·······:::-:-:········:::::=;········

t

t

Pump

t

Minutes

Stimulation on

Stimulation off

(6V 33 Hz)

t

Pump off

FIG. 2. Venous flow response to cavernous nerve stimulation before and after cigarette smoke exposure in one representative dog (aorta occluded) (CCP = corpus cavernosum pressure).

4. Mean intracorporeal pressure response to saline infusion without and with neurostimulation before and after cigarette smoke exposure in 2 dogs*

TABLE

Corporeal Pressure

Erection Response

Baseline

Peak

(cm. H 2 0) Before smoking Without stimulation With stimulation After smoking Without stimulation With stimulation

20 ± 5.7

Plasma Nicotine Cotinine

Before nicotine After nicotine

<1

<1

Yes; well main- 38 ± 31.1 182 ± 65.1 tained

<1

<1

No

19

25

46.3

17.6

No; not maintained

15

76 ± 39.6t

57.5:j:

18.6 peak

Peak

(cm. H 2 0) 7.0 ± 1.4 152 ± 39.6 10.5 ± 5 96 ± 53.7t

Arterial Flow Baseline

Peak

(ml./min.) 32 ± 25.5 163 ± 38.2 24 ± 17 122 ± 31.1

Values± S.D. * The animals were given 1 to 10 mg. nicotine intravenously. At the sampling

time, the mean blood level was 1. 7 µg./ml. In both animals, the erection response was blocked within 23 to 30 minutes of the injection. t The peak pressure was only transient, could not be maintained.

TABLE 6. Mean intracorporeal pressure response to saline infusion without and with neurostimulation before and after nicotine in 2 dogs*

Erection Response

(ng./ml.)

64 ± 39.6

No

Baseline

Corporeal Pressure Baseline

Peak

(cm. H20) Before nicotine Without stimulation With stimulation After nicotine Without stimulation With stimulation

No Yes

10 ± 2.8 12 ± 5.7

87 ± 111.7 226 ± 2.8t

No No; not maintained

15 ± 7.1 14 ± 8.5

35 96

Values± S.D.

Values± S.D.

* Saline was infused at 0.9 or 1.9 ml./min.; aorta occluded. The 2 dogs smoked 1 and 6 cigarettes respectively before erectile failure was noted. In both dogs the venous restriction response was blocked within 15 to 36 minutes after smoke exposure. t P <0.05 when compared with peak achieved before smoke exposure. :j: Peak plasma levels were measured 5 minutes after completing smoking.

first five minutes after smoking was completed, whereas the erection response was abolished 15 to 30 minutes after smoking when the systemic blood levels for nicotine and cotinine had already diminished. Nicotine injection study. In two additional dogs the effect of intravenous nicotine bitartrate administration on the penile arterial and venous systems during erection was studied. The same phenomenon as in the "smoking" dogs was observed; the effect was greater on the venous system than on arterial flow. When 200 µg. to one mg_ of nicotine was given (equal to a blood level of 215 ng./ml.), the venous outflow restriction to neurostimulation was removed, whereas one to 10 mg. (=1.7 mg./ ml.) was required to block the arterial response (tables 5 and 6). DISCUSSION

Our previous hemodynamic studies in simian and canine models clearly demonstrated that penile erection is the result of increased arterial flow, decreased venous flow, and sinusoidal relaxation. 12• 13 Our anatomical and pharmacologic studies showed that the smooth muscles of the arterial and sinusoidal spaces play a key role in erection and detumescence. In the flaccid state, the cavernous muscles and the helicine arteries are contracted and allow minimal arterial flow and free venous drainage. Sexual stimulation results in relaxation of cavernous and arterial smooth muscles with increased compliance of sinusoidal spaces; the drop in resistance to the internal pudendal artery allows maximal flow into the sinusoidal spaces. Distension of these spaces against the relatively inelastic tunica albuginea results in compression of the venules and emissary veins, effectively reducing venous flow during erection. Our present study demonstrates that the erection response to neurostimulation is affected by cigarette smoking. Smoking has a greater effect on the venous mechanism, which is primarily controlled by cavernous smooth muscle, than on the arterial smooth muscles. We have postulated that the arteriolar

* Saline was infused at 1.9 ml./min. (aorta occluded). The intravenous nicotine dosage was increased from 0.2 to 1 mg. until the venous restriction response was blocked (within 10 to 16 minutes post-injection), at which time the blood level was 0.215 µg./ml. t The value ran off the scale.

smooth muscles and the cavernous muscles may be controlled by different neurotransmitters. Further studies are needed to investigate the exact mechanism of cigarette smoking on the blocking or release of neurotransmitters. Interestingly, the effect on erection did not occur during the first five minutes, when the serum nicotine level was at its peak, but after 15 to 30 minutes, when the nicotine level was diminishing. We postulate that, in the flaccid state, the corpora cavernosa receive a minimal amount of arterial flow; for the erectile response to be affected, both neurostimulation and the passage of time may be required for enough nicotine to accumulate in the penile tissue. Unfortunately, because of the small size of the corpora, we were unable to obtain penile blood for measurement of nicotine levels in the flaccid state. Because the systemic blood pressure and the blood gases did not change after cigarette smoke exposure, the erectile failure cannot be explained by a systemic vascular effect. Although the response to smoke exposure was reproduced by intravenous administration of nicotine bitartrate, the blood levels of nicotine were much higher after the latter. Thus, it is possible that some other component in the cigarette smoke may also contribute to its effect on penile erection. The concentrations of nicotine measured in our dogs after smoke exposure were similar to those found in human smokers (25 ng./ml.). 16 We could not correlate the onset of erectile failure with a specific blood level of nicotine since the blood concentrations of nicotine differed remarkably among the dogs at the point at which the erection response disappeared. This difference may be due to differences in inhalation efficiency, body weight, and other individual factors. In summary, our studies demonstrate that: 1. Cigarette smoking causes temporary impotence by blocking the venous occlusion mechanism and slightly decreasing the arterial flow to the penis, probably due to contraction or non-relaxation of the smooth-muscle tissue of the corpora cavernosa during erection. 2. These hemodynamic changes can be reproduced by intra-

EFFECT OF CIGARETTE SMOKE ON PENILE ERECTION

venous nicotine, but ,.,~,"~"~'-' other factors in the smoke contribute as well. 3. The nicotine levels in the animals after cigarette smoke exposure correspond to the concentrations found in human smokers. One may speculate as to whether nicotine works directly on the corporeal smooth-muscle, acts via synaptic inhibition on pre- or post-ganglionic sites, or acts by means of sympathetic nervous stimulation mediated by the central nervous system or the adrenal medulla. 3 · 4 • 8 Indeed, we had observed in other animal experiments that the injection ofnorepinephrine clearly caused detumescence (data not shown). It is likely that the erection-blocking effect of nicotine is related to a catecholamine effect on the corporeal or vascular smooth-muscle tone, since recent findings clearly show that the blood levels of circulating catecholamines increase with smoking or nicotine administration.4·6·8·17 However, regional differences in the action of nicotine8 make it difficult to generalize about influences on erectile mechanisms. The impotence-causing effect of cigarette smoking and nicotine is most likely multiply mediated by direct smooth-muscle and neurogenic actions. Further studies are needed to settle this question. Our in vivo studies provide evidence for a potentially important role of cigarette smoking in erectile failure. Most smoking patients who develop erectile failure do so after years of smoking, in their forties and fifties. Most likely this reflects accelerated development of vascular disease. Perhaps diminished vascular reserve and the direct pharmacologic effects of cigarette smoking act in concert to produce impotence. From our findings we conclude: cigarette smoking can block the penile erection response by inhibiting smooth-muscle relaxation of the erectile tissue, which leads to a failure in venous occlusion and diminished arterial flow during erection. Evaluation of smoking history is recommended before any impotence work-up is initiated. Patients should be encouraged and helped to quit smoking and the benefit of correction of the habit should be evaluated before any invasive treatment is undertaken. REFERENCES

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