Guinea Pig Prostate Research Articles

K+ channel modulation of slow wave activity in the guinea‐pig prostate

The aim of this study was to investigate the role of different K(+) channel populations and the inhibitory effect of various exogenously applied K(+) channel openers in the regulation of slow wave activity in the guinea-pig prostate. Recordings of membrane potential were made using intracellular microelectrodes. Tetraethylammonium (TEA 300 micro M and 1 mM), iberiotoxin (150 nM) and 4-aminopyridine (4-AP 1 mM) increased the frequency of slow wave discharge. Apamin (1-200 nM) and glibenclamide (1 micro M) had no effect on slow wave activity. Lemakalim (1 micro M) and PCO-400 (1 micro M) abolished the slow waves, as did sodium nitroprusside (SNP 10 micro M) and calcitonin gene-related peptide (CGRP 100 nM). The inhibitory effect of these agents was independent of a significant change in membrane potential. In the presence of 4-AP (1 mM), TEA (1 mM) or glibenclamide (1 micro M) the inhibitory actions of SNP (10 micro M) were attenuated. The inhibitory actions of CGRP (100 nM) were also reversed by glibenclamide (1 micro M). In contrast, isoprenaline (1 micro M) did not alter the frequency of slow wave discharge. These results demonstrate that BK(Ca) and 4-AP-sensitive K(+) channels regulate the frequency of prostatic slow wave discharge. SNP and CGRP abolish slow waves in a hyperpolarisation-independent manner, partially via opening of K(ATP) channels. BK(Ca) and 4-AP-sensitive K(+) channels also play an important role in the SNP-induced inhibition of slow wave activity. The lack of membrane hyperpolarisation associated with the SNP- and CGRP-induced inhibition implies that the channels involved in this action are not predominantly located on the smooth muscle cells.

Effects of muscarinic agonists in the guinea‐pig prostate

1. The contractile response to transmural stimulation of the guinea-pig prostate is largely due to activation of noradrenergic neurons but there is a small contribution from cholinergic neurons. Carbachol and acetylcholine have been reported to act via muscarinic M(1) cholinoceptors to facilitate contractions produced by neuronal stimulation of the tissue. This action of cholinomimetics was further investigated in isolated ventral lobes of the prostate. 2. Oxotremorine-M, bethanecol, pilocarpine, xanomeline and McN-A-343 produced facilitation of the response to transmural stimulation of the prostate. When carbachol was applied as the first agonist, the facilitatory response to the latter four agonists above was absent or reduced, compared with the effect observed when the other agonist was applied first, indicating that the effect of these agonists is readily desensitized. Only oxotremorine-M was unaffected by prior exposure of the tissue to carbachol. When applied first, pilocarpine and xanomeline produced a smaller degree of facilitation than carbachol indicating they were partial agonists for the effect. The facilitation produced by McN-A-343, when applied as the first agonist, was variable. In some preparations the facilitation was less than that of carbachol but in others it exceeded that produced by a subsequent application of carbachol. 3. The release of endogenous choline from the prostate was measured at rest and during transmural stimulation using a chemiluminescent technique. A statistically significant negative correlation existed between pmol mg(-1) of endogenous choline released during transmural stimulation and the mass of the ventral lobe of the prostate. As the guinea-pig prostate is known to undergo postpubertal stromal hypertrophy the finding suggests that endogenous choline release from the prostate is largely from epithelial, rather than stromal tissue. 4. The possible involvement of facilitatory M(1) autoreceptors on cholinergic neurons in the effect of cholinomimetics was investigated. Tissue was incubated with (3)H-choline to label neuronal stores of acetylcholine and the subsequent release of (3)H-choline from the tissue was measured. Carbachol per se increased the release of (3)H-choline. 5. Transmural stimulation usually increased the release of (3)H-choline but in c. 30% of preparations there was a decrease. In the presence of carbachol there was a significant increase in the release of (3)H-choline during transmural stimulation of prostate lobes. However, there was no correlation between the two effects of carbachol; facilitating contractions produced by transmural stimulation and enhancing (3)H-choline release during transmural stimulation. The finding provides no evidence that facilitatory M(1) autoreceptors on cholinergic neurons play a major role in the facilitation of contractions.

Changes in steroid receptors and proteoglycan expression in the guinea pig prostate stroma during puberty and hormone manipulation

Proteoglycans are structural and informational molecules important during embryogenesis and organ maturation. Maturation of the prostate is influenced by androgens and estrogens, but changes in the relative spatiotemporal expression of steroid receptors and proteoglycans during hormonal change are unexplored. Guinea pig prostate was used to define hormone-induced changes in the expression of androgen (AR) and estrogen (ER(alpha)) receptors, chondroitin sulfate (CS) glycosaminoglycan and core proteins of versican and syndecan-1. Tissue locations of AR, ER(alpha), CS and the proteoglycans versican and syndecan-1 were determined by immunohistochemistry. Cellular content of ER(alpha) and syndecan-1 was assessed visually. Versican, CS56 epitope, and AR were quantified by image analysis. AR expression within prostate epithelial and stromal cell nuclei decreased following castration and increased following treatment of castrate animals with dihydrotestosterone (DHT). ER(alpha) expression was restricted to prostate stromal cell nuclei and decreased during puberty, and following treatment of castrate animals with DHT. Versican was present in periacinar stroma immediately peripheral to basal epithelial cells, fibromuscular stromal tissue bands surrounding acinar units, and loose fibrovascular connective tissue interspersed between individual acini. Versican and native CS expression decreased (>10-fold) in periacinar stroma during puberty and following administration of DHT to castrated animals. Expression of syndecan-1 was restricted to fibromuscular cells of prostate stroma, and remained constant during puberty and hormone manipulation. ER(alpha), versican core protein and CS side chain epitopes are negatively regulated in prostate stromal tissue by DHT, whilst AR levels are positively regulated.

The effect of histamine on field-stimulated contractions of the guinea-pig prostate

The aim of this study was to investigate the effect of histamine on field-stimulated contractions of the guinea-pig prostate using isolated preparations in organ bath experiments. The histamine receptor subtype involved in potentiating the twitch responses was characterised, and the presence of any post-synaptic effects was determined. In addition, the effects of histamine on nerve-stimulated contractions of the ventral and dorsal prostate as well as the coagulating gland were compared in preliminary experiments. Histamine (300 microM) approximately doubled the magnitude of the twitch contractions in the ventral and dorsal lobes of the prostate (nerve stimulation parameters were 10 Hz for 2 s every 50 s, 0.5 ms duration at supramaximal voltage). In the coagulating glands, histamine increased the contractions more than fourfold. Further experiments were performed only on the ventral glands. The H(1) receptor antagonist, mepyramine, exhibited an apparent competitive antagonism against the histamine-induced potentiations of the twitch responses (apparent pK(B) value = 9.21+/-0.17 (n=5). The H(2) receptor antagonist, ranitidine, produced a small, significant shift to the right, as did the time control. The H(3) receptor antagonist, thioperamide, had no significant effect on the concentration-response curve. The effects of histamine (10 microM) on exogenously applied acetylcholine (Ach), noradrenaline (NA) and adenosine 5'-triphosphate (ATP) were determined. In each case, the contractile responses were significantly potentiated: ATP (5.8-fold P<0.0001, n=8), NA (1.6-fold P<0.05, n=10) and Ach (2.1-fold P<0.0007, n=10). This is the first study that has shown the effects of histamine on field-stimulated contractions in the prostate of any species. It is concluded that histamine, acting on H(1) receptors, elicits a considerable potentiation of the nerve-stimulated twitch contractions in the guinea-pig prostate. One mechanism whereby histamine exerts its potentiating effect is a post-synaptic enhancement of the response to ATP in particular, but also to NA and Ach. It is suggested that H(1)-receptor and purinoceptor antagonists may have a role to play in the treatment of benign prostatic hyperplasia (BPH).

Characterization of Spontaneous Depolarizations in Smooth Muscle Cells of the Guinea Pig Prostate

Characterization of Spontaneous Depolarizations in Smooth Muscle Cells of the Guinea Pig Prostate

Characterization of Spontaneous Depolarizations in Smooth Muscle Cells of the Guinea Pig Prostate

We characterized the electrical events recorded in small segments of the dorsal lobe of the prostate of immature male guinea pigs and examined some mechanisms underlying their generation. Membrane potential recordings were made in the stroma of the guinea pig prostate using conventional single microelectrode techniques. Three distinct, spontaneously occurring electrical events were recorded in guinea pig prostate, namely slow waves, consisting of a depolarizing transient 14 mV in amplitude with 1 to 6 nifedipine sensitive spikes superimposed, pacemaker potentials, consisting of a larger depolarization 40 mV in amplitude, and STDs 1 to 10 mV in amplitude. Only spikes on slow waves were inhibited by nifedipine. The depolarizing transient of slow waves, pacemaker potentials and STDs were abolished by cyclopiazonic acid, a blocker of the SERCA pump, and the mitochondrial uncoupler cyanide m-chlorophenyl hydrazone as well as upon exposure to Ca(2+)-free saline or the Cl(-) channel blockers niflumic acid and anthracene-9-carboxylic acid (Sigma Chemical Co., St. Louis, Missouri). Examination of the stochastic properties of STDs revealed that they were not well modeled by Poisson statistics, but rather they occurred in a clustered manner, such they may well underlie pacemaker potential generation. Guinea pig prostate shows STD and pacemaker potentials that arise from the release of Ca(2+) from intracellular stores and the activation of Ca(2+) activated Cl(-) channels. We speculate that the depolarizing transient of prostatic slow waves is the propagated response of pacemaker potentials evoked at sites electrically distant from the recording electrode.

Tissue remodeling in Guinea pig lateral prostate at different ages after estradiol treatment

Estrogen seems to have an essential role in the fibromuscular growth characteristic of benign prostatic hyperplasia (BPH). This paper describes the effects of chronic estradiol treatment on Guinea pig prostatic stroma at different ages. Tissues from experimental animals were studied by histological and histochemical procedures, morphometric-stereological analysis and transmission electron microscopy (TEM). Marked fibromuscular hypertrophy was observed after estradiol treatment in animals of pre-pubertal and adult ages. Increases in the density and thickness of the collagen and elastic fibers were observed by histochemistry. TEM revealed wide distributions of collagen fibrils and large elastic fibers adjacent to the epithelial basal lamina and between the stromal cells, establishing contacts between them. These results indicate that the Guinea pig prostate simulates the stromal modifications observed in BPH in some aged animals after estrogen treatment at different ages, making it a good model for this disease.

CHARACTERIZATION OF THE ION CHANNEL CURRENTS IN SINGLE MYOCYTES OF THE GUINEA PIG PROSTATE

We characterized membrane ionic currents underlying the action potential in single myocytes freshly isolated from the stroma of the guinea pig prostate. Whole cell and single channel currents were recorded in single stromal smooth muscle cells using standard patch clamp techniques. : A rapidly activating, nifedipine (1 microM) sensitive Ca current was recorded in CsCl (130 mM) filled myocytes at potentials positive to -50 mV This current was half maximally activated at -22 mV and half maximally inactivated at -53 mV. In KCl (130 mM) filled myocytes membrane depolarization evoked a complex set of K selective outward currents, consisting of a rapidly activating transient outward current (IKto) followed by a more slowly developing transient outward current (IP2), which decayed to a steady state current (ISS). Tetraethylammonium (1 mM), a blocker of large conductance, Ca activated K channels, substantially blocked IP2 and ISS. Initial IKto was half maximally activated at -5 mV, half maximally inactivated at -65 mV and blocked by 4-aminopyridine (IC50 0.8 mM). IP2 and ISS were decreased by ryanodine (10 microM) or cyclopiazonic acid (10 microM) and increased by caffeine (1 mM), suggesting that Ca release from internal stores participates in the activation of these large conductance, Ca activated K channel currents. We speculate that membrane currents characterized in stromal myocytes underlie the generation of simple action potentials triggered during the slow wave recorded in the intact guinea pig prostate and pharmacological manipulation of IKto and IP2 may well provide a selective avenue of modulating stromal excitability and muscle tone.

Adenosine 5′-triphosphate and noradrenaline are excitatory cotransmitters to the fibromuscular stroma of the guinea pig prostate gland

Immunohistochemical studies demonstrated abundant P2X 1-receptor immunoreactivity colocalized with α-actin within the fibromuscular stroma of the guinea pig prostate. P2X 2-, P2X 3- and P2X 4-receptor immunoreactivity was absent. αβmethylene Adenosine 5′-triphosphate (ATP) attenuated contractile responses to electrical field stimulation (50 V, 0.5 ms, 5–20 Hz) in the absence and presence of prazosin (0.3 μM). Responses to 1–2 Hz were unaffected. ARL 67156 (6- N, N-Diethyl-β-γ-dibromomethylene- d-adenosine-5-triphosphate; 100 μM) enhanced contractile responses to electrical field stimulation (50 V, 0.5 ms, 10–20 Hz). Concentration–response curves to exogenously applied ATP analogues on unstimulated preparations elicited concentration-dependent suramin (100 μM)-sensitive contractions. The rank order of potency was: αβmethylene ATP>2methylthio ATP=βγmethylene ATP>adenosine 5′-diphosphate (ADP)=ATP. Adenosine and adenosine 5′-monophosphate (AMP) did not produce contractile responses. These results demonstrate the presence of functional P2X 1-receptors within the fibromuscular stroma of the guinea pig prostate and suggest a cotransmitter role for ATP with noradrenaline during high-frequency stimulation.

Long-term testosterone stimulation induces hyperplasia in the guinea-pig prostate.

The relation between supraphysiologic circulating testosterone levels and prostatic diseases is unclear and difficult to study in men. Animal models may be advantageous. Based on a pilot study, testosterone enantate 50 mg (n=12) or 25 mg (n=12) was administered to guinea-pigs intramuscularly every 3 weeks, for either 7 or 14 months. The histopathology of the prostate was described. Epithelial hyperplasia was found in 14/21 animals receiving testosterone and in 7/12 very old animals, but no such changes were found in the sham or castrated animals. Testosterone stimulation seems to induce epithelial hyperplasia, but not cancer, in the guinea-pig prostate.

Ion-channel currents of smooth muscle cells isolated from the prostate of guinea-pig.

To characterize the voltage-activated ion-channel currents in guinea-pig prostate smooth muscle cells (GPSMCs). GPSMCs were isolated using collagenase, and used in a whole-cell patch clamp study. When GPSMCs were dialysed with a CsCl solution all the outward K+ currents were blocked and the step-like depolarization (holding voltage -70 mV) of the cell membrane evoked inward currents that were completely blocked by nifedipine (1 micromol/L). With KCl solution, step depolarizations showed outward K+ currents composed of fast, transient outward current (Ito) and outward currents that did not inactivate. Ito was resistant to a high concentration of tetraethylammonium (TEA, 5 mmol/L) but was blocked by 4-aminopyridine (5 mmol/L). The half-activation and half-inactivation voltages of Ito were 6 mV and -58 mV, respectively. With low Ca2+ buffer (0.1 mmol/L EGTA) in the solution, there were spontaneous transient outward currents (STOCs) at depolarized membrane voltages (0 mV). STOCs were blocked by TEA (1 mmol/L) or iberiotoxin (10 nmol/L) but were insensitive to apamin (100 nmol/L). This voltage-clamp study showed that GPSMCs have l-type Ca2+ channels and more than two types of K+ channels. The voltage- and time-dependent changes of these ion channels and their interactions might be important in forming action potentials and regulating contractility.

Interstitial cells in the human prostate: A new therapeutic target?

Interstitial cells have been described in different human organs, including gut and bladder. In the gut they function as pacemaker cells, generating slow wave potentials. Absence or defects in these cells result in motility disorders. In the bladder these cells express the vanilloid receptor and may contribute to the working mechanism of vanilloid therapy. Recently, slow wave potentials and interstitial cells were described in the guinea-pig prostate. In this study we describe the presence of interstitial cells in the human prostate gland. We performed immunohistochemical staining for c-kit, vanilloid receptor (VR1), cannabinoid receptor (CB1) connexin43, and neurofilament on fresh frozen tissue from 14 prostatectomy specimens. A large number of cells with a stellate aspect were noticed under the basal layer of the prostatic duct system and in between the smooth muscle cells. They were immunoreactive for c-kit, VR1, and connexin43 but not to CB1 or neurofilament. There is evidence for interstitial cells in the human prostate. Taken together their topography and immunohistochemical characterization, the discovery of slow wave potentials in guinea pig prostate and the knowledge of interstitial cells in other organs, interstitial cells are likely to be involved in normal prostate physiology.

Age-related changes in motility and in nitregic myenteric neurons in guinea pig distal colon

The histology of benign disease of the human prostate (benign prostatic hyperplasia) is heterogeneous. No other species demonstrates the same complexity, and current animal models do not appear to fully encompass the stromal and epithelial developmental changes involved in the human disease. This study describes age-related changes in the prostatic smooth muscle stroma of guinea pigs and humans, which may be pertinent to some aspects of the disease process in humans. Histologic and ultrastructural changes were examined and measured in the prostates of guinea pigs during aging (2 weeks to 31 months). Similar measurements were also made in human prostatic tissues during aging and the development of benign prostatic pathology. Morphometric analyses of prostates in guinea pigs and men demonstrated similar changes in stromal volume with age. The stromal volume proportion of the prostate in both species decreases at puberty due to the expansion of the epithelial cell compartment, and is followed by a progressive increase during adulthood until a maximum stromal content of approximately 75% of total tissue volume is reached at age 2 years in guinea pigs, and at age 70 years in men. The pathognomic feature of nodularity and the dramatic increase in gland size observed during the late stages of human benign prostatic disease did not occur in the guinea pig prostate. Ultrastructural analysis of guinea pig prostatic smooth muscle cells identified a progressive hypertrophy (approximately 10-fold) from prepuberty through to old age. Two-thirds of smooth muscle cells in the prostatic stroma of aging individuals of both species demonstrated perinuclear organelles (rough endoplasmic reticulum and free ribosomes) that were not present in younger individuals. The prominent histologic features of the guinea pig prostate during aging are increased stromal mass, significant stromal fibrosis, and occasional prostatitis. These features are frequently observed in men with clinical benign prostatic hyperplasia. The age-related increases in prostatic smooth muscle cell size and content of perinuclear organelles in the guinea pig suggest a re-activation of cellular synthetic activity. The similarity in some features of the prostatic smooth muscle stroma between aging men and guinea pigs suggests that there may be common pathophysiologic processes. We conclude that the guinea pig could be a useful model for examination of the age-related hypertrophy of the smooth muscle cell and the processes inducing reversion to a more synthetic smooth muscle cell phenotype.

Spontaneous Slow Wave and Contractile Activity of the Guinea Pig Prostate

We characterized the electrical events underlying spontaneous contractions of the stroma of the guinea pig prostate. Membrane potential of the stroma was recorded using standard electrophysiological recording techniques. The structure of the prostate was viewed using confocal or electron microscopy. In stromal cells spontaneous depolarizing membrane transients (12 mV. in amplitude) occurred at 5 minutes-1 and triggered 1 or more spikes. The membrane potential, and frequency and duration of the potential transients were not affected by the calcium channel blocker nifedipine (1 microM. for greater than 5 minutes), or blockers of neuronal propagation (tetrodotoxin), and the effects of cholinergic (atropine), adrenergic (guanethidine or prazosin) and sensory blockers (capsaicin) of neurotransmission. However, the amplitude of the superimposed spikes was significantly reduced by nifedipine. A network of c-Kit immunoreactive cells was evident in the interstitial layer between the stroma and glandular lined lumen. These prostatic interstitial cells contained many morphological features distinguishing interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract. Prostatic interstitial cells formed close appositions with each other, with neighboring smooth muscle cells and with varicose axon bundles. Movement of the contents of the peripheral prostatic acini into the minor and major prostatic ducts is likely to occur via spontaneous contractions triggered by myogenic slow wave activity in the stromal wall. By analogy with the intestine and urethra prostatic interstitial cells may well act as the pacemaker for prostatic slow waves as well as form an intercellular communication network interacting with the intrinsic nerves and stromal cells.

Spontaneous Slow Wave and Contractile Activity of the Guinea Pig Prostate

Spontaneous Slow Wave and Contractile Activity of the Guinea Pig Prostate

Neuroendocrine cells and nerves in the prostate of the guinea pig: Effects of peripheral denervation and castration

Neuroendocrine cells and nerves in the prostate of the guinea pig: Effects of peripheral denervation and castration

Neuroendocrine cells and nerves in the prostate of the guinea pig: effects of peripheral denervation and castration.

Neuroendocrine (NE) cells and nerves in the prostate gland are thought to play a central role in the regulation of growth, cellular differentiation and homeostasis of secretory activity. The objective of this experimental study was to describe the effects of peripheral denervation and castration on NE cells and nerves in the guinea pig prostate. Guinea pigs underwent sham-operation, unilateral and bilateral hypogastric nerve resection, extirpation of the right anterior major pelvic ganglion (AMPG), autotransplantation of prostatic tissue and castration. Cryostat sections of prostatic tissue were examined with immunohistochemistry by using serotonin (5-HT) and chromogranin A (CgA) and various neuropeptides. The number of 5-HT-IR NE cells was four-fold higher than CgA-IR NE cells. The innervation pattern was uniform throughout the gland with subepithelial nerves in close proximity to NE cells. Autotransplants of prostatic tissue showed total loss of nerves, but the number and morphology of 5-HT-IR NE cells were unaltered. Extirpation of the right AMPG showed significant reduction in prostate weight, decreased density of nerve terminals in the superior part of the ipsilateral prostate, whereas the number and morphological feature of 5-HT-IR NE cells remained unaffected in the entire prostate. Castration induced atrophy of the gland with a significant reduction in weight (unpaired t-test, P < 0.001), but without effect upon 5-HT-IR NE cells. The guinea pig seems to be a useful animal model for studies on the role of the NE cells in the prostate. NE cells seem to be independent of innervation and androgens. It seems that other factors influence the NE cell population to a greater extent.

Calcitonin gene-related peptide (CGRP) inhibits contractions of the prostatic stroma of the rat but not the guinea-pig

This study investigated the presence and effects of calcitonin gene-related peptide (CGRP) within the rat and guinea-pig prostate glands. Immunohistochemical studies demonstrated that CGRP immunoreactive nerve fibres are sparsely distributed throughout the prostatic fibromuscular stroma in both species. These CGRP immunopositive nerve fibres shared a similar distribution profile but were not colocalized with tyrosine hydroxylase immunopositive nerve fibres which also innervate the prostatic stroma of these species. Nerve terminals within rat and guinea-pig prostatic tissues were electrically field stimulated (60 V, 0.5 ms, 10 Hz, 20 pulses every 60 s). In guinea-pig preparations, application of human α-CGRP, rat adrenomedullin or rat amylin (0.1 nM–1 μM) had no effect on responses to field stimulation. In contrast, both rat and human α-CGRP (10 pM–300 nM), rat adrenomedullin (0.3 nM–1 μM) and rat amylin (3 nM–1 μM) concentration-dependently inhibited electrically evoked contractile responses in the rat prostate. The relative order of potency was rat α-CGRP=human α-CGRP>rat adrenomedullin>rat amylin. The inhibition by rat α-CGRP of field stimulation-induced contractions in the rat prostate was competitively antagonized by human CGRP (8–37) (1, 3 and 10 μM) with a pA 2 of 6.20±0.13. Rat α-CGRP (10 nM) attenuated contractile responses of the rat prostate to exogenously added noradrenaline (1–100 μM). Inhibitory concentration–response curves to rat α-CGRP in rat prostates were unaffected by preincubation in either glibenclamide (10–100 μM), N-nitro- l-arginine methyl ester ( l-NAME) (10 μM), bestatin (10 μM), captopril (10 μM) or phosphoramidon (3 μM). Our results indicate that CGRP-induced inhibition of electrically evoked contractions in the rat prostate occurs through activation of postjunctional CGRP 2 receptors which act independently of a K ATP channel or nitrergic mechanisms. Degradation of rat α-CGRP via peptidases does not appear to occur in the rat prostate.

Cholinergic facilitation of neurotransmission to the smooth muscle of the guinea-pig prostate gland.

1. Functional experiments have been conducted to assess the effects of acetylcholine and carbachol, and the receptors on which they act to facilitate neurotransmission to the stromal smooth muscle of the prostate gland of the guinea-pig. 2. Acetylcholine and carbachol (0.1 microM - 0.1 mM) enhanced contractions evoked by trains of electrical field stimulation (20 pulses of 0.5 ms at 10 Hz every 50 s with a dial setting of 60 V) of nerve terminals within the guinea-pig isolated prostate. In these concentrations they had negligible effects on prostatic smooth muscle tone. 3. The facilitatory effects of acetylcholine, but not those of carbachol, were further enhanced in the presence of physostigmine (10 microM). 3. The facilitatory effects of carbachol were unaffected by the neuropeptide Y Y(1) receptor antagonist BIBP 3226 ((R)-N(2)-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-arginina mide) (0.3 microM, n=3) or suramin (100 microM, n=5). Prazosin (0.1 microM, n=5) and guanethidine (10 microM, n=5) alone and in combination (n=4), reduced responses to field stimulation and produced rightward shifts of the log concentration-response curves to carbachol. 4. The rank orders of potency of subtype-preferring muscarinic receptor antagonists in inhibiting the facilitatory actions of acetylcholine and carbachol were: pirenzepine > HHSiD (hexahydrosiladifenidol) > pF-HHSiD (para-fluoro-hexahydrosiladifenidol)>/= 5 himbacine, and pirenzepine > HHSiD > himbacine>/= 5 pF-HHSiD, respectively. These profiles suggest that muscarinic receptors of the M(1)-subtype mediate the facilitatory effects of acetylcholine and carbachol on neurotransmission to the smooth muscle of the guinea-pig prostate.

α 1L-Adrenoceptors mediate noradrenaline-induced contractions of the guinea-pig prostate stroma

The α 1-adrenoceptor subtype mediating noradrenaline-induced contractions of the guinea-pig isolated prostatic smooth muscle was investigated. Noradrenaline produced concentration-dependent contractions of the tissue with a mean p D 2 value of 5.26±0.03 ( n=20). These contractions were antagonised by prazosin, 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101), N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α, α-dimethyl-1 H-indole-3-ethanamine hydrochloride (RS-17053) and ( R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]-2-methylethyl]-2-methoxybenzensulfonamide methanesulphonate hydrate (tamsulosin). Mean p A 2 or apparent p K B estimates for the antagonism of noradrenaline were 8.15±0.05 for prazosin; 8.83±0.11 for WB-4101, 7.18±0.14 for RS-17053 and 10.11±0.12 for tamsulosin. The relatively low estimates of the apparent dissociation constant for all antagonists except tamsulosin indicate that an α 1L-adrenoceptor mediates noradrenaline-induced prostatic smooth muscle contraction in the guinea-pig prostate gland.