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Pharmacological Characteristics of Smooth Muscle in Benign Prostatic Hyperplasia and Normal Prostatic Tissue
0022-534 7/87 /1381-0158$02.00/0 Vol. 138, July
THE JOURNAL OF UROLOGY
Copyright© 1987 by The Williams & Wilkins Co.
Printed in U.S.A.
PHARMACOLOGICAL CHARACTERISTICS OF SMOOTH MUSCLE IN BENIGN PROSTATIC HYPERPLASIA AND NORMAL PROSTATIC TISSUE SHINICHIRO KITADA* AND JOICHI KUMAZAWA From the Department of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
ABSTRACT
Strips of prostatic hyperplastic adenoma and normal prostate were studied by observing the mechanical response to application of certain drugs. The sensitivity of BPH tissue to potassium chloride, phenylephrine and prostaglandins was about double that of normal prostate. The small hyperplastic adenoma showed a higher sensitivity to phenylephrine than the large. However, sensitivity to phenylephrine was almost the same among the various histological types of BPH. (J. Ural., 138: 158-160, 1987) Recently, a large amount of pharmacological work on human prostatic or posterior urethral smooth muscle has been performed.1-4 It has been well established in these studies that alpha-adrenoceptors are present in smooth muscle in benign prostatic hyperplasia. 5 •6 However, as no comprehensive pharmacological study has ever been made of the smooth muscle of benign prostatic hyperplasia and of normal prostate in particular, the present study will address the pharmacological activity of the smooth muscle of the human prostate.
separated into three groups, small (below 19 gm.), medium (20 to 49 gm.) and large (over 50 gm.). The sensitivity of respective groups to certain drugs were examined. RESULTS
In eighty per cent of both benign prostatic hyperplasia and normal prostate specimens, spontaneous contractions appeared after thirty minutes. These had an amplitude representing approximately 0.1 gram tension and a frequency of one to two times per minute. Cumulative administration of 10 mM KCl MATERIALS AND METHODS produced gradual contractions and the maximum contracture Specimens of benign prostatic hyperplasia were obtained was induced by 100 mM KCl (fig. 1). Figure 2 shows the curve from thirty men, aged 62 to 81 years, who underwent suprapubic of dose response to KCl for benign prostatic hyperplasia and prostatectomy (16 men) or transurethral prostatectomy (14 normal prostate respectively. The wet weights of strips of men). In transurethral prostatectomy we used the first cutting benign prostatic hyperplasia were 55.4 ± 7.8 mg., and those of fragments, which were over six mm. in diameter, for this study. normal prostate were 54.8 ± 7.9 mg., being almost the same. Prostatic weights were 13 to 80 gm. with a mean weight of 41.6 However, the contractile response of benign prostatic hyperplagm. in cases of BPH, five to eight gm. with a mean weight of sia to KCl was about double that seen in normal prostate. 6.9 gm. in cases of normal prostate. Specimens of normal Phenylephrine in doses of over 5 X 10- 7 gm./ml., produced prostate were obtained from twelve men, aged 57 to 72 years, contractions which were abolished following treatment with who underwent cystourethrectomy due to malignancy of the phentolamine or prazosin. Pretreatment with prazosin also bladder without prior radiation. Normal prostatic tissue was abolished the response to phenylephrine (fig. 3). The relative resected from the outer glands of the prostate and proved to be response to phenylephrine 10-6 gm./ml. was 33.3 per cent of normal in appearance both macroscopically and microscopi- the 100 mM KCl-induced contracture for benign prostatic cally. hyperplasia and 33.9 per cent for normal prostate (fig. 4). As Immediately following removal, the specimens were placed the contractile response of benign prostatic hyperplasia to KCl in Krebs solution and transported to the laboratory. Strips was about double that seen in the case of normal prostate, the parallel to the urethra and approximately two mm. wide and actual response of benign prostatic hyperplasia to phenylephtwo cm. long were cut and mounted in a 50 ml. muscle chamber, rine was also about double that of normal prostate. The recontaining Krebs solution at 37C, through which was bubbled sponses to phenylephrine of the different histological types of a mixture containing 95 per cent oxygen and 5 per cent carbon benign prostatic hyperplasia were almost the same; however, dioxide. the small hyperplastic adenoma showed a significantly higher Isometric tension was recorded by means of force transducers sensitivity to phenylephrine than the large (p <0.01) (fig. 5). (TB612T Nihonkoden) connected to a polygraph (RM25 NiAdministration of prostaglandin F2 a (PGF 2a) (5 X 10- 7 gm./ honkoden). The strips were subjected to a one-gram resting ml.) produced a contractile response, the strength of which was tension and a stable tension level was obtained before the 13.5 per cent of a 100 mM KCl-induced contracture for benign experiment started. At first, potassium chloride (KCl) was prostatic hyperplasia and 12.2 per cent of that for normal administrated up to 100 mM in each sample. Thereafter phen- prostate (fig. 4). ylephrine, prostaglandin F 2a and prostaglandin E2 were used. Both phentolamine and atropine produced no effects on the Following isometric experiments, isolated strips were fixed PGF 2 a-induced contractions. As seen in the case ofphenylephin 10 percent neutral formalin. These strips were stained with rine, the contractile responses of the different histological types hematoxylin and eosin, and were analyzed microscopically. of benign prostatic hyperplasia to the PGF 2a were almost the Histological types of benign prostatic hyperplasia were classi- same. Sensitivity to PGF 2a was, however, rather independent fied into three groups, fibromuscular, mixed and glandular. For of the size of the adenoma. This is in contrast to that seen the purpose of mixing pharmacological comparisons among when phenylephrine was administered. various prostatic sizes, prostatic adenoma weights were also Low concentrations (lo-s to 10-7 gm./ml.) of PGF 2a produced some slight relaxation and inhibited spontaneously generated Accepted for publication September 30, 1986. contractions. High concentrations (10- 6 gm,/ml.), however, *Requests for reprints: Dept. of Urology, Faculty of Medicine, Kyushu University, Maidashi 3 Chome 1-1, Fukuoka, Japan. produced a slight contraction, the strength of which was 6.2 158
159
SMOOTH MUSCLE IN BPH AND NORMAL PROSTATE 7001M I
51),,,M
~0,,11
a
M1t1II I
b
hyperplastic nodule
I
normal prostate
I
50
FIG. 1. Effect of cumulatively applied various concentrations of [K] o recorded from strip excised from prostatic hyperplastic nodule. Maximum contracture was induced by 100 mM [K]o. wash: washed out with normal Krebs solution.
40
~
•-•
phenylephrine
e-41
•-•
PGF,a
• - • PGFa:1
A-.4.
PGE 2
• - • PGE2
phenylephrine
30
a
1.0
"
~
hyperplastic nodule (Mean ± SE)
..-.
20
o----o normal prostate• 10
10"'
-+--+
0.5
10
20
40
30
50
60
70
90
80
10·' Concentration (g/ml)
-10
100
50
40
;; rn··g1,,1
'I
• - • fibromuscular
a-•
medium size
• - • mixed
J..-4
larges12e
A-.,t,,
glandular
30
1o·'g/.,\
l~~UwJJ,.lh _'.'
. _ . small size
a a
~h•ntol.,olne
~h,nylepl,dn~
b
a
FIG. 2. Relationship between [K]o concentration and contraction. Developed tension was measured at point when maximum was reached. Amplitude of contraction was indicated by value actually recorded. Individual points indicate mean ± S.E. (e----e hyperplastic nodule n = 6, 0----0 normal prostate n = 6).
I.
6
FIG. 4. A, effects ofphenylephrine, PGF2• and PGE2on mechanical properties of hyperplastic nodule. Individual points indicate mean ± S.E. (e----e phenylephrine, n = 30, .__.. PGF2., n = 30, .&--.& PGE2, n = 30. B, effects of phenylephrine, PGF2• and PGE2 on mechanical properties of normal prostate. Individual points indicate the mean ± S.E. (e----e phenylephrine, n = 12, .__.. PGF2., n = 12, .&--.& PGE2, n = 12). Amplitude of isometric tension evoked by 100 mM [K]o was registered as relative tension of 100%.
K - concentration (mM)
~
sx1 o·• 1o·
Concentration (g/ml)
1:
1 ,
•
•
•
~
20
:'!,.~-.-
10
pl,onyleohdne \O"'g/"1
Phenylephrine - concentration (g/ml)
FIG. 3. Effects of phentolamine or prazosin (a orb, respectively) on mechanical response evoked by phenylephrine. In c, prazosin was treated before application of phenylephrine. Concentrations of drugs were inserted in figure. per cent of the 100 mM KCl induced contraction in benign prostatic hyperplasia and 7.5 per cent of that in normal prostate (fig. 4). Sensitivity to PGF2, similarly to that to PGF2m was independent from both the size and the histological type of the adenoma. DISCUSSION
Smooth muscle is present in the surrounding glands in prostatic tissue and it mainly acts to contract the prostatic acini. In benign prostatic hyperplasia (BPH), smooth muscle is also present to various degrees in its stroma. It has been established by many investigators that alpha-adrenoceptors are present in the smooth muscle in BPH. 5 •6 However, pharmacological studies of smooth muscle in normal prostatic tissue are very few. In this study, the pharmacological activities of the smooth muscle in BPH were compared with those of normal prostatic tissue. Our results demonstrated that activation induced by KCl in BPH was about double that seen in the normal prostate. A
FIG. 5. A, effects of phenylephrine on mechanical properties of preparations selected from three different sizes. e----e small size (n = 13), .__.. medium size (n = 11), .&--.& large size (n = 6). B, effects of phenylephrine on mechanical properties of preparations selected from three different histological types. e----e fibromuscular type (n = 14), .__.. mixed type (n = 8), .&--.& glandular type (n = 8). Individual points indicate mean ± S.E. Amplitude of isometric tension evoked by 100 mM [K]o was registered as relative tension of 100%. recent morphological study by Rohr et al.7 showed that BPH tissues contained a larger amount of smooth muscle than normal prostate. If BPH tissue is more densely packed with smooth muscle cell than normal prostate, the higher sensitivity to KCl in BPH tissue shown in this study may be expected. However, it will be unsafe to conclude from our study that BPH tissue contains morphologically a larger amount of smooth muscle than normal tissue. KCl-induced activation is a method of depolarization different from that occurring in the action potential. Increasing the external potassium concentration results in a sustained depolarization of the membrane without action potential. 8 During application of solutions with high potassium concentrations, an increased influx of 45 Ca++ has been detected and total tissue calcium has been described to be increased. 9 This stimulation of the calcium influx induced by potassium depolarization can be assumed to depend on the opening of voltage operated
160
KITADA AND KUMAZAWA
channels through which external calcium can flow into the cell. There were considerable differences in potassium-induced activation between BPH and normal prostate in this study. Qualitative differences of smooth muscle cell membrane in which voltage operated calcium channels exist, or quantitative differences of tissue calcium restored between BPH and normal prostate may be present. This study showed that the relative response to phenylephrine was 33.3 per cent of the maximum KCl-induced contraction, the response to PGF2 a was 13.5 per cent and the response to PGE 2 was minimal in BPH. Caine et al. 5 have already detected the contractile response to alpha-adrenergic agents in smooth muscle of BPH. Further, Shapiro et al. 6 have shown that those responses are abolished by an administration of an alpha 1-blocker such as prazosin, as in our study. They concluded that alpha-adrenoceptors were present in smooth muscle cells in BPH and speculated that acute urinary retention in patients with BPH might be due to the contracture of smooth muscle. In the past, however, there has been very little work on the effect of PGF2a on the smooth muscle of BPH. In this study contractile response to PGF2., in prostatic adenoma was less than half of that to phenylephrine. Effects of PGF2., are less intense than those of alpha-stimulants. However, we must mind PGF2., effects on prostatic adenoma, which may cause an increase in the posterior urethral resistance, using PGF2., in patients with BPH. It is also of interest to note that small hyperplastic adenomas showed a higher sensitivity to phenylephrine than large adenomas in the relative tension of the maximum potassiuminduced contraction. In this study, samples from smaller prostates were obtained by the transurethral method and those from larger prostates were obtained by open surgery. The possibility cannot be excluded that these different operative methods may influence this experiment. To prevent alteration by electrocautery, we used the first cutting fragments, which were over six mm. in diameter, for specimens. Strips used in this experiment, therefore, were at least microscopically intact. As our results showed that sensitivities to phenylephrine were almost the same among the three histological types, we cannot explain why the small adenomas have a higher sensitivity to alpha-adrenergic agents than the large, from a morphological viewpoint. We suspect that this result should be discussed as a
pharmacological problem. While no direct evidence has yet been made available, the possibility cannot be denied that alpha-adrenoceptors which are distributed on smooth muscle cell membrane may relatively decrease in number with the increase of smooth muscle cells of the prostatic adenoma. This speculation should be confirmed by other methods, such as specific radioligand receptor binding assay. However, so little is known with certainty of the properties of the agonist-receptor interaction in BPH that at present no substantial proposal can be made, aside from the observation that the smaller adenomas had a stronger activity to alpha-stimulants than the large. REFERENCES
1. Raz, S. and Caine, M.: Adrenergic receptors in the female canine
urethra. Invest. Urol., 9: 319, 1972. 2. Gosling, J. A. and Dixon, J. S.: The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra. Brit. J. Urol., 47: 549, 1975. 3. Gosling, J. A., Dixon, J. S. and Lendon, R.: The autonomic innervation of the human male and female bladder neck and proximal urethra. J. Urol., 118: 302, 1977. 4. Finkbeiner, A. E., Bissada, N. K. and Welch, L.: Uropharmacology: VIII. Sympathomimetic agents. Urology, 11: 536, 1978. 5. Cain, M., Raz, S. and Ziegler, M.: Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Brit. J. Urol., 47: 193, 1975. 6. Shapiro, A., Mazouz, B. and Caine, M.: The alpha-adrenergic blocking effect of prazosin on human prostate. Urol. Res., 9: 17, 1980. 7. Rohr, H. P. and Bartsch, G.: Human benign prostatic hyperplasia; a stromal disease? New perspectives by quantitative morphology. Urology, 16: 625, 1980. 8. Golenhofen, K., Hermstein, N. and Lammel, E.: Membrane potential and contraction of vascular smooth muscle (portal vein) during application of noradrenaline and high potassium and selective inhibitory effects of iproveratril (verapamil). Microvasc. Res., 5: 73, 1973. 9. Casteels, R. and Droogmans, G.: Membrane potential and excitation-contraction coupling in smooth muscle. Fed. Proc., 41: 2879, 1982. 10. Breemen, C. van, Farinas, B. R., Gerba, P. and McNaughton, E. D.: Excitation-contraction coupling in rabbit aorta studied by the lanthanum method for measuring cellular calcium influx. Circ. Res., 30: 44, 1972.
THE JOURNAL OF UROLOGY
Copyright© 1987 by The Williams & Wilkins Co.
Printed in U.S.A.
PHARMACOLOGICAL CHARACTERISTICS OF SMOOTH MUSCLE IN BENIGN PROSTATIC HYPERPLASIA AND NORMAL PROSTATIC TISSUE SHINICHIRO KITADA* AND JOICHI KUMAZAWA From the Department of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
ABSTRACT
Strips of prostatic hyperplastic adenoma and normal prostate were studied by observing the mechanical response to application of certain drugs. The sensitivity of BPH tissue to potassium chloride, phenylephrine and prostaglandins was about double that of normal prostate. The small hyperplastic adenoma showed a higher sensitivity to phenylephrine than the large. However, sensitivity to phenylephrine was almost the same among the various histological types of BPH. (J. Ural., 138: 158-160, 1987) Recently, a large amount of pharmacological work on human prostatic or posterior urethral smooth muscle has been performed.1-4 It has been well established in these studies that alpha-adrenoceptors are present in smooth muscle in benign prostatic hyperplasia. 5 •6 However, as no comprehensive pharmacological study has ever been made of the smooth muscle of benign prostatic hyperplasia and of normal prostate in particular, the present study will address the pharmacological activity of the smooth muscle of the human prostate.
separated into three groups, small (below 19 gm.), medium (20 to 49 gm.) and large (over 50 gm.). The sensitivity of respective groups to certain drugs were examined. RESULTS
In eighty per cent of both benign prostatic hyperplasia and normal prostate specimens, spontaneous contractions appeared after thirty minutes. These had an amplitude representing approximately 0.1 gram tension and a frequency of one to two times per minute. Cumulative administration of 10 mM KCl MATERIALS AND METHODS produced gradual contractions and the maximum contracture Specimens of benign prostatic hyperplasia were obtained was induced by 100 mM KCl (fig. 1). Figure 2 shows the curve from thirty men, aged 62 to 81 years, who underwent suprapubic of dose response to KCl for benign prostatic hyperplasia and prostatectomy (16 men) or transurethral prostatectomy (14 normal prostate respectively. The wet weights of strips of men). In transurethral prostatectomy we used the first cutting benign prostatic hyperplasia were 55.4 ± 7.8 mg., and those of fragments, which were over six mm. in diameter, for this study. normal prostate were 54.8 ± 7.9 mg., being almost the same. Prostatic weights were 13 to 80 gm. with a mean weight of 41.6 However, the contractile response of benign prostatic hyperplagm. in cases of BPH, five to eight gm. with a mean weight of sia to KCl was about double that seen in normal prostate. 6.9 gm. in cases of normal prostate. Specimens of normal Phenylephrine in doses of over 5 X 10- 7 gm./ml., produced prostate were obtained from twelve men, aged 57 to 72 years, contractions which were abolished following treatment with who underwent cystourethrectomy due to malignancy of the phentolamine or prazosin. Pretreatment with prazosin also bladder without prior radiation. Normal prostatic tissue was abolished the response to phenylephrine (fig. 3). The relative resected from the outer glands of the prostate and proved to be response to phenylephrine 10-6 gm./ml. was 33.3 per cent of normal in appearance both macroscopically and microscopi- the 100 mM KCl-induced contracture for benign prostatic cally. hyperplasia and 33.9 per cent for normal prostate (fig. 4). As Immediately following removal, the specimens were placed the contractile response of benign prostatic hyperplasia to KCl in Krebs solution and transported to the laboratory. Strips was about double that seen in the case of normal prostate, the parallel to the urethra and approximately two mm. wide and actual response of benign prostatic hyperplasia to phenylephtwo cm. long were cut and mounted in a 50 ml. muscle chamber, rine was also about double that of normal prostate. The recontaining Krebs solution at 37C, through which was bubbled sponses to phenylephrine of the different histological types of a mixture containing 95 per cent oxygen and 5 per cent carbon benign prostatic hyperplasia were almost the same; however, dioxide. the small hyperplastic adenoma showed a significantly higher Isometric tension was recorded by means of force transducers sensitivity to phenylephrine than the large (p <0.01) (fig. 5). (TB612T Nihonkoden) connected to a polygraph (RM25 NiAdministration of prostaglandin F2 a (PGF 2a) (5 X 10- 7 gm./ honkoden). The strips were subjected to a one-gram resting ml.) produced a contractile response, the strength of which was tension and a stable tension level was obtained before the 13.5 per cent of a 100 mM KCl-induced contracture for benign experiment started. At first, potassium chloride (KCl) was prostatic hyperplasia and 12.2 per cent of that for normal administrated up to 100 mM in each sample. Thereafter phen- prostate (fig. 4). ylephrine, prostaglandin F 2a and prostaglandin E2 were used. Both phentolamine and atropine produced no effects on the Following isometric experiments, isolated strips were fixed PGF 2 a-induced contractions. As seen in the case ofphenylephin 10 percent neutral formalin. These strips were stained with rine, the contractile responses of the different histological types hematoxylin and eosin, and were analyzed microscopically. of benign prostatic hyperplasia to the PGF 2a were almost the Histological types of benign prostatic hyperplasia were classi- same. Sensitivity to PGF 2a was, however, rather independent fied into three groups, fibromuscular, mixed and glandular. For of the size of the adenoma. This is in contrast to that seen the purpose of mixing pharmacological comparisons among when phenylephrine was administered. various prostatic sizes, prostatic adenoma weights were also Low concentrations (lo-s to 10-7 gm./ml.) of PGF 2a produced some slight relaxation and inhibited spontaneously generated Accepted for publication September 30, 1986. contractions. High concentrations (10- 6 gm,/ml.), however, *Requests for reprints: Dept. of Urology, Faculty of Medicine, Kyushu University, Maidashi 3 Chome 1-1, Fukuoka, Japan. produced a slight contraction, the strength of which was 6.2 158
159
SMOOTH MUSCLE IN BPH AND NORMAL PROSTATE 7001M I
51),,,M
~0,,11
a
M1t1II I
b
hyperplastic nodule
I
normal prostate
I
50
FIG. 1. Effect of cumulatively applied various concentrations of [K] o recorded from strip excised from prostatic hyperplastic nodule. Maximum contracture was induced by 100 mM [K]o. wash: washed out with normal Krebs solution.
40
~
•-•
phenylephrine
e-41
•-•
PGF,a
• - • PGFa:1
A-.4.
PGE 2
• - • PGE2
phenylephrine
30
a
1.0
"
~
hyperplastic nodule (Mean ± SE)
..-.
20
o----o normal prostate• 10
10"'
-+--+
0.5
10
20
40
30
50
60
70
90
80
10·' Concentration (g/ml)
-10
100
50
40
;; rn··g1,,1
'I
• - • fibromuscular
a-•
medium size
• - • mixed
J..-4
larges12e
A-.,t,,
glandular
30
1o·'g/.,\
l~~UwJJ,.lh _'.'
. _ . small size
a a
~h•ntol.,olne
~h,nylepl,dn~
b
a
FIG. 2. Relationship between [K]o concentration and contraction. Developed tension was measured at point when maximum was reached. Amplitude of contraction was indicated by value actually recorded. Individual points indicate mean ± S.E. (e----e hyperplastic nodule n = 6, 0----0 normal prostate n = 6).
I.
6
FIG. 4. A, effects ofphenylephrine, PGF2• and PGE2on mechanical properties of hyperplastic nodule. Individual points indicate mean ± S.E. (e----e phenylephrine, n = 30, .__.. PGF2., n = 30, .&--.& PGE2, n = 30. B, effects of phenylephrine, PGF2• and PGE2 on mechanical properties of normal prostate. Individual points indicate the mean ± S.E. (e----e phenylephrine, n = 12, .__.. PGF2., n = 12, .&--.& PGE2, n = 12). Amplitude of isometric tension evoked by 100 mM [K]o was registered as relative tension of 100%.
K - concentration (mM)
~
sx1 o·• 1o·
Concentration (g/ml)
1:
1 ,
•
•
•
~
20
:'!,.~-.-
10
pl,onyleohdne \O"'g/"1
Phenylephrine - concentration (g/ml)
FIG. 3. Effects of phentolamine or prazosin (a orb, respectively) on mechanical response evoked by phenylephrine. In c, prazosin was treated before application of phenylephrine. Concentrations of drugs were inserted in figure. per cent of the 100 mM KCl induced contraction in benign prostatic hyperplasia and 7.5 per cent of that in normal prostate (fig. 4). Sensitivity to PGF2, similarly to that to PGF2m was independent from both the size and the histological type of the adenoma. DISCUSSION
Smooth muscle is present in the surrounding glands in prostatic tissue and it mainly acts to contract the prostatic acini. In benign prostatic hyperplasia (BPH), smooth muscle is also present to various degrees in its stroma. It has been established by many investigators that alpha-adrenoceptors are present in the smooth muscle in BPH. 5 •6 However, pharmacological studies of smooth muscle in normal prostatic tissue are very few. In this study, the pharmacological activities of the smooth muscle in BPH were compared with those of normal prostatic tissue. Our results demonstrated that activation induced by KCl in BPH was about double that seen in the normal prostate. A
FIG. 5. A, effects of phenylephrine on mechanical properties of preparations selected from three different sizes. e----e small size (n = 13), .__.. medium size (n = 11), .&--.& large size (n = 6). B, effects of phenylephrine on mechanical properties of preparations selected from three different histological types. e----e fibromuscular type (n = 14), .__.. mixed type (n = 8), .&--.& glandular type (n = 8). Individual points indicate mean ± S.E. Amplitude of isometric tension evoked by 100 mM [K]o was registered as relative tension of 100%. recent morphological study by Rohr et al.7 showed that BPH tissues contained a larger amount of smooth muscle than normal prostate. If BPH tissue is more densely packed with smooth muscle cell than normal prostate, the higher sensitivity to KCl in BPH tissue shown in this study may be expected. However, it will be unsafe to conclude from our study that BPH tissue contains morphologically a larger amount of smooth muscle than normal tissue. KCl-induced activation is a method of depolarization different from that occurring in the action potential. Increasing the external potassium concentration results in a sustained depolarization of the membrane without action potential. 8 During application of solutions with high potassium concentrations, an increased influx of 45 Ca++ has been detected and total tissue calcium has been described to be increased. 9 This stimulation of the calcium influx induced by potassium depolarization can be assumed to depend on the opening of voltage operated
160
KITADA AND KUMAZAWA
channels through which external calcium can flow into the cell. There were considerable differences in potassium-induced activation between BPH and normal prostate in this study. Qualitative differences of smooth muscle cell membrane in which voltage operated calcium channels exist, or quantitative differences of tissue calcium restored between BPH and normal prostate may be present. This study showed that the relative response to phenylephrine was 33.3 per cent of the maximum KCl-induced contraction, the response to PGF2 a was 13.5 per cent and the response to PGE 2 was minimal in BPH. Caine et al. 5 have already detected the contractile response to alpha-adrenergic agents in smooth muscle of BPH. Further, Shapiro et al. 6 have shown that those responses are abolished by an administration of an alpha 1-blocker such as prazosin, as in our study. They concluded that alpha-adrenoceptors were present in smooth muscle cells in BPH and speculated that acute urinary retention in patients with BPH might be due to the contracture of smooth muscle. In the past, however, there has been very little work on the effect of PGF2a on the smooth muscle of BPH. In this study contractile response to PGF2., in prostatic adenoma was less than half of that to phenylephrine. Effects of PGF2., are less intense than those of alpha-stimulants. However, we must mind PGF2., effects on prostatic adenoma, which may cause an increase in the posterior urethral resistance, using PGF2., in patients with BPH. It is also of interest to note that small hyperplastic adenomas showed a higher sensitivity to phenylephrine than large adenomas in the relative tension of the maximum potassiuminduced contraction. In this study, samples from smaller prostates were obtained by the transurethral method and those from larger prostates were obtained by open surgery. The possibility cannot be excluded that these different operative methods may influence this experiment. To prevent alteration by electrocautery, we used the first cutting fragments, which were over six mm. in diameter, for specimens. Strips used in this experiment, therefore, were at least microscopically intact. As our results showed that sensitivities to phenylephrine were almost the same among the three histological types, we cannot explain why the small adenomas have a higher sensitivity to alpha-adrenergic agents than the large, from a morphological viewpoint. We suspect that this result should be discussed as a
pharmacological problem. While no direct evidence has yet been made available, the possibility cannot be denied that alpha-adrenoceptors which are distributed on smooth muscle cell membrane may relatively decrease in number with the increase of smooth muscle cells of the prostatic adenoma. This speculation should be confirmed by other methods, such as specific radioligand receptor binding assay. However, so little is known with certainty of the properties of the agonist-receptor interaction in BPH that at present no substantial proposal can be made, aside from the observation that the smaller adenomas had a stronger activity to alpha-stimulants than the large. REFERENCES
1. Raz, S. and Caine, M.: Adrenergic receptors in the female canine
urethra. Invest. Urol., 9: 319, 1972. 2. Gosling, J. A. and Dixon, J. S.: The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra. Brit. J. Urol., 47: 549, 1975. 3. Gosling, J. A., Dixon, J. S. and Lendon, R.: The autonomic innervation of the human male and female bladder neck and proximal urethra. J. Urol., 118: 302, 1977. 4. Finkbeiner, A. E., Bissada, N. K. and Welch, L.: Uropharmacology: VIII. Sympathomimetic agents. Urology, 11: 536, 1978. 5. Cain, M., Raz, S. and Ziegler, M.: Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Brit. J. Urol., 47: 193, 1975. 6. Shapiro, A., Mazouz, B. and Caine, M.: The alpha-adrenergic blocking effect of prazosin on human prostate. Urol. Res., 9: 17, 1980. 7. Rohr, H. P. and Bartsch, G.: Human benign prostatic hyperplasia; a stromal disease? New perspectives by quantitative morphology. Urology, 16: 625, 1980. 8. Golenhofen, K., Hermstein, N. and Lammel, E.: Membrane potential and contraction of vascular smooth muscle (portal vein) during application of noradrenaline and high potassium and selective inhibitory effects of iproveratril (verapamil). Microvasc. Res., 5: 73, 1973. 9. Casteels, R. and Droogmans, G.: Membrane potential and excitation-contraction coupling in smooth muscle. Fed. Proc., 41: 2879, 1982. 10. Breemen, C. van, Farinas, B. R., Gerba, P. and McNaughton, E. D.: Excitation-contraction coupling in rabbit aorta studied by the lanthanum method for measuring cellular calcium influx. Circ. Res., 30: 44, 1972.