Effects of some α-adrenoceptor agonists and antagonists on the guinea-pig ileum

Summary The purpose of the present study was to further characterize the -adrenoceptors located on parasympathetic fibres. Segments of guinea-pig ileum were stimulated by transmural electrical pulses, and the ensuing contractions, which are due to the release of acetylcholine from postganglionic parasympathetic fibres, were monitored. Clonidine and tramazoline, which are thought to act preferentially on presynaptic -adrenoceptors, reduced the contractions, whereas phenylephrine and methoxamine, postsynaptic -adrenoceptor agonists, were ineffective. Contractions induced by acetylcholine were not changed by clonidine but were abolished by atropine. Yohimbine, piperoxan, phentolamine and thymoxamine reversed or prevented the inhibitory effect of clonidine. Prazosin and AR-C239 did not antagonize this effect. The inhibitory effect of tramazoline was antagonized by piperoxan but not by AR-C239 or by prazosin. Naloxone did not alter the action of clonidine, and piperoxan did not change the inhibitory effect of morphine.In conclusion, these experiments suggest the presence on cholinergic postganglionic fibres of both opiate receptors and -adrenoceptors. The latter appear to resemble more closely ₁-adrenoceptors than ₁-adrenoceptors.     

Age and region-dependent contraction to α-adrenoceptor agonists in rat and guinea-pig isolated trachea

1. The influence of age and of region on α-adrenoceptor-mediated contraction to (−)-adrenaline and (−)-noradrenaline was examined in rat (4–136 weeks) and guinea-pig (2–156 weeks) isolated tracheal ring preparations with particular emphasis on the early (up to 12 weeks) maturation phase.
2. In rat tracheal rings, significant regional variation was observed with respect to maximal (−)-adrenaline-induced contraction, such that the greatest activity was seen in ring preparations from the laryngeal end of the trachea. Tracheal rings from the carinal end responded very poorly or were unresponsive to (−)-adrenaline, depending on animal age. These regional differences were seen across the age range. The potencies of (−)-adrenaline and (−)-noradrenaline remained unchanged with respect to animal age, but the maximum contractile tension that developed in response to these agonists increased with increasing animal age in all regions of the trachea.
3. In guinea-pig isolated tracheal tissue, maximum contractile responses (E_max) to (−)-adrenaline and (−)-noradrenaline remained unchanged with increasing animal age. In addition, there was no evidence for a region-dependence in the responsiveness of tracheal tissue to α-adrenoceptor-mediated contraction in this species.
4. In both guinea-pig and rat isolated tracheal tissue, α-adrenoceptor-mediated contraction appeared to involve the activation of α₁-adrenoceptors.

     

Subclassification of presynaptic α2-adrenoceptors: α2D-autoreceptors and α2D-adrenoceptors modulating release of acetylcholine in guinea-pig ileum

The study was designed to classify in terms of _2A, _2B, _2C and _2D the presynaptic ₂-autoreceptors, as well as the ₂-receptors modulating the release of acetylcholine, in the myenteric plexus-longitudinal muscle (MPLM) preparation of the guinea-pig ileum. A set of antagonists was chosen that was able to discriminate between the four subtypes. Small pieces of the MPLM preparation were preincubated with ³H-noradrenaline or ³H-choline and then superfused and stimulated electrically.The stimulation periods used (3H-noradrenaline: 3 trains of 20 pulses, 50 Hz, train interval 60 s; ³H-choline: single trains of 30 pulses, 0.2 Hz) did not lead to ₂-autoinhibition or inhibition of ³H-acetylcholine release by endogenous noradrenaline. The ₂-selective agonist 5-bromo6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced the evoked overflow of tritium in both ³H-noradrenaline and ³H-choline experiments. Most (³H-noradrenaline) or all (³H-choline) of the 10 antagonists shifted the concentration-inhibition curves of UK 14,304 to the right. pK_d values of the antagonists were calculated from the shifts. pK_d values from ³H-noradrenaline experiments correlated with pK_d values from ³H-choline experiments (r = 0.981).It is concluded that ₂-autoreceptors and ₂-heteroreceptors modulating the release of acetylcholine in the MPLM preparation are of the same subtype. Comparison with antagonist affinities for prototypic native ₂ binding sites, binding sites in cells transfected with ₂ subtype genes, and previously classified presynaptic ₂-adrenoceptors — all taken from the literature — indicates that both are _2D. The results are consonant with the hypothesis that at least the majority of ₂-autoreceptors belong to the _2A/D branch of the ₂-adrenoceptor tree, across mammalian or at least across rodent and lagomorph species. The same may hold true for ₂-adrenoceptors on non-noradrenergic neurones.     

Increase by α-adrenolytic drugs of acetylcholine release evoked by field stimulation of the guinea-pig ileum

Summary The release of acetylcholine evoked by field stimulation of the guinea-pig ileum (3 Hz) is increased by yohimbine and tolazoline but not affected by phentolamine. It is proposed that yohimbine and tolazoline by blocking -adrenoceptors of the cholinergic nerves abolish the inhibition caused by endogenous noradrenaline, and thus facilitate the output of acetylcholine.     

Binding ofβ-adrenoceptor blocking drugs to human serum albumin,to α1-acid glycoprotein and to human serum

Summary The binding of 8 -adrenergic blocking drugs to human serum albumin, to ₁-acid glycoprotein and to serum from normal volunteers and from patients with rheumatoid arthritis was studied. Protein binding was determined in vitro using equilibrium dialysis of labelled drug at 25° C. Oxprenolol and propranolol were highly bound to serum, alprenolol, pindolol and timolol to a lesser degree, and atenolol, metoprolol and sotalol were negligibly bound. For the five compounds which were appreciably bound, the mean binding was significantly higher in serum from patients with rheumatoid arthritis than in serum from normal volunteers. For those drugs, binding to ₁-acid glycoprotein was higher than to human serum albumin, and binding to a mixture of both proteins approached that to serum from healthy volunteers. For each of these drugs there was a strong correlation between the serum ₁-glycoprotein concentration and the percentage binding.     

Binding of perazine to α1-acid glycoprotein

Summary The high-affinity binding of perazine to human serum-protein (non-albumin binding) was previously investigated by gel-chromatography. The immunoelectrophoretic identification of the binding agent as ₁-acid glycoprotein is described here. It was demonstrated by equilibrium dialysis that the average free fraction of³H-perazine added to 22 sera from patients before neuroleptic treatment was 3.67±0.42%, and that there was a significant correlation between the ₁-acid glycoprotein content and the free fraction in these serum samples. This result is in accordance with what others have found for impramine. It is suggested that the nature of this binding should be studied in more detail, since specific binding to ₁-acid glycoprotein may be related to the receptor binding of perazine and possibly other drugs.A preliminary summary of the present findings appeared in Naunyn-Schmiedebergs Arch Pharmacol 307 (Suppl) R 70 (1979)     

Modulation of κ-opioid receptor mediated tolerance in the guinea-pig ileum by chronic co-administration of dihydropyridines

The influence of the L-type Ca²⁺ channel modulators nimodipine (a Ca²⁺ blocker) and BAY K 8644 (a Ca²⁺ activator) on the expression of tolerance to the inhibitory effects of - and µ-opioid agonists in the guinea-pig ileum from guinea-pigs rendered tolerant to the -opioid receptor agonist U-50,488H was investigated. Tolerance to U-50,488H was induced by its administration (15 mg/kg twice a day) for 4 days. Control groups received saline at the same time schedule. Chronic infusion of guinea-pigs with nimodipine (2 /l/h for 7 days) or BAY K 8644 (0.5 /l/h for 7 days), did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) preparation from naive guinea-pigs. The Ca²⁺ antagonist nimodipine increases the potency of U-50,488H (selective agonist) to reduce the amplitude of neurogenic contractions of the MPLM strip in naïve animals, whereas the Ca²⁺ activator BAY K 8644 induced the opposite effect. However, the effect of DAMGO (selective µ agonist) was not modified in guinea-pigs infused with nimodipine or BAY K 8644. Tolerance to the inhibitory effects of both U-50,488H and DAMGO was observed following administration of U-50,488H for 4 days and was revealed as a rightward shift of the concentration-response curves for the two agonists. Chronic infusion of guinea-pigs with nimodipine concurrently with chronic U-50,488H, markedly attenuated the expression of selective tolerance to U-50,488H as well as the cross-tolerance between U-50,488H and DAMGO. By the contrary, the magnitude of tolerance to U-50,488H and to DAMGO was enhanced by concomitant infusion of BAY K 8644. The results suggest that, in the GPI, -opioid receptor may be functionally linked to the dihydropyridine-sensitive Ca²⁺ channel: The blockade of the channel increased whereas its activation reduced the potency of U-50,488H. In chronic experiments, nimodipine prevented the expression of tolerance to U-50,488H and the cross-tolerance between U-50,488H and DAMGO, whereas BAY K 8644 produced the opposite effect. These results suggest that, in the GPI, selective tolerance to -agonist as well as cross-tolerance between - and µ-opioid agonists would involve activation of L-type Ca²⁺ channels, which could indicate that intracellular Ca²⁺ may be the final common pathway through which myenteric neurons adapt to the chronic opioid exposure.     

Multiple effects of putative α-adrenoceptor agonists on the electrical and mechanical activity of guinea-pig papillary muscle

Summary The effects of the putative -adrenoceptor agonists phenylephrine, methoxamine and clonidine on force of contraction and on calcium-dependent action potentials were studied in guinea-pig papillary muscles.Phenylephrine increased the force of contraction by stimulating -adrenoceptors as well as -adrenoceptors. It increased the amplitude and duration of slow action potentials, but this effect was exclusively due to stimulation of -adrenoceptors. The positive inotropic effect mediated by -adrenoceptors can presumably not be explained by an increase in calcium influx during the action potential via the slow inward current.Methoxamine had no effect on the force of contraction at 10^–5 and 10^–4 mol/l, but at 10^–4 mol/l it slightly decreased amplitude and duration of slow action potentials.Clonidine produced a large increase in force of contraction and in amplitude and duration of slow action potentials. These effects were due to stimulation of H₂-histamine receptors.It is concluded that in guinea-pig papillary muscle the tested putative -adrenoceptor agonists do not share a common -adrenoceptor effect, but produce prominent effects which are mediated through either -adrenoceptors (phenylcphrine), or H₂-histamine-receptors (clonidine) or are non-specific (methoxamine) in nature.     

Pharmacological characterization of the β-adrenoceptor that mediates the relaxant response to noradrenaline in guinea-pig tracheal smooth muscle

Pharmacological characteristics of beta-adrenoceptors (beta-ARs) mediating noradrenaline-induced relaxation were investigated in guinea-pig tracheal smooth muscle. The inhibitory effects of several types of beta-AR antagonists on noradrenaline-induced relaxation against histamine contraction were scrutinized with Schild plot analysis. The concentration-response curve for noradrenaline obtained in the absence of phentolamine and uptake inhibitors was competitively antagonized by all of the beta-AR antagonists used in this study (propranolol, bupranolol, atenolol, butoxamine and ICI-118,551). However, their pA2 values were markedly less than the expected values for beta1-AR and beta2-AR. On the other hand, pA2 values of ICI-118,551 (6.85) determined in the presence of phentolamine suggested a contribution of a beta1 -AR rather than beta2 -AR. In the presence of phentolamine and uptake inhibitors (desipramine and deoxycorticosterone), the Schild plot for atenolol was a better fit, with two distinct straight lines. The pA2 values of atenolol provided by the regression were: approximately 7.0, which corresponds to the expected beta1-AR value, and approximately 6.5, which was 3 times less than the expected value for beta1 -AR, and thus the possible presence of two classes of beta1 -AR (beta1(Low) and beta1(High)) was suggested. This view was also supported by Schild plot analysis for propranolol, which fit two straight lines each with a slope of 1.0. The present findings indicate that beta1 -ARs contributing to noradrenaline-elicited relaxation in guinea-pig tracheal smooth muscle exhibit diverse pharmacological characteristics and may be subdivided into at least two classes with distinct affinities for atenolol. Under physiological conditions, beta1(Low) rather than beta1(High) seems to play a more significant role in noradrenaline-regulated airway smooth muscle tone.     

Enhancement of contractile responses to partial α-adrenoceptor agonists during warming in rat aorta

Summary We examined the effects of warming on the contractile responses to full and partial -adrenoceptor agonists in rat aorta. The contractions elicited by norepinephrine and methoxamine were not affected during warming (40°C, 42°C), whereas those induced by clonidine and St 587 were significantly enhanced. KCl-induced contractions of rat aorta were not affected by warming. The dissociation constants of clonidine and St 587 at 40°C were not different from those at 37°C. At 40°C, the receptor occupancy-contractile response curve of clonidine was a hyperbolic curve similar to that of methoxamine at 37°C, although at 37°C the curve was almost linear. The responses of St 587 at both 37°C and 40°C were related inversely hyperbolic to the receptor occupancy, but the receptor occupancy-contractile response curve was shifted to the left and upward during warming. Clonidine and St 587 elicited equal responses at lower fractional occupancies at 40°C than at 37°C. The relative efficacies of clonidine and St 587 to methoxamine were significantly augmented during warming. It is suggested that the contractile responses to partial -adrenoceptor agonists in rat aorta are enhanced during warming, and that this effect is related to the intrinsic efficacy of the agonists rather than to any function of their relative selectivity for ₁- or ₂-adrenoceptors. Such enhancement is due to augmentation of the efficacy rather than to augmentation of the affinity of the agonists. Send offprint requests to H. Kitagawa     

Down-regulation of α2-adrenoceptor subtypes

To characterize further the α₂-adrenoceptor subtypes in terms of their regulation, monolayers of cells expressing either the α_2A (CHO-A2AR cells) or α_2C (OK cells) subtype were preincubated with norepinephrine for various times and the extent of receptor down-regulation was assessed. Exposure to 30 μM norepinephrine caused a similar time course and extent of down-regulation (approximately 50%) in both cells lines. The extent of down-regulation caused by 0.3 μM norepinephrine in OK cells was similar to that with 30 μM norepinephrine in CHO-A2AR cells, although the time course was somewhat slower. Reversal of the down-regulation of the α₂-adrenoceptor caused by 30 μM norepinephrine was more rapid in the CHO-A2AR than in the OK cell. With 0.3 μM norepinephrine, reversal of down-regulation of the α₂-adrenoceptor in the OK cell was slightly faster than that of the CHO-A2AR cell with 30 μM norepinephrine. These data indicate that although norepinephrine is more potent in causing down-regulation of the α_2C (OK cells) as compared to the α_2A subtype (CHO-A2AR cells), the time courses for down-regulation and its reversal are similar for the two subtypes.     

Renal aging change of α1-adrenoceptor in wistar rats

• 1.1. The aging changes of density of the α₁-adrenoceptors in the kidney were evaluated with Wistar rats of several ages (8, 52 and 104 weeks old).
• 2.2. [³H]prazosin and [³H]YM617 (newly synthesized α₁-blocker) were used for the ligand. The B_max of [³H]prazosin was 74.0 ± 9.5 fmol/mg/protein in 8 week, 52.1 ± 7.3 fmol/mg protein in 52 week, and 31.3 ± 4.2 fmol/mg/protein in 104 week rats, and that of [³H]YM617 was 45.0 ± 6.6 fmol/mg/protein in 8 week, 32.4 ± 5.7 fmol/mg/protein in 52 week, and 19.3 ± 5.5 fmol/mg/protein in 104 week rats.
• 3.3. The B_max of both ligands for 104 week rats was significantly decreased compared to 8 week rats, however, 52 week rats showed no decrease of B_max for both ligands.
• 4.4. The K_d values showed no difference in these three age groups for both ligands.
• 5.5. Autoradiographic study supported the result above mentioned. Furthermore, the binding sites of α₁-adrenoceptors were mainly in the cortex (vascular wall and peritubular area) and that α₁-adrenoceptors were chiefly chlorethylclonidine dihydrochloride (CEC) insensitive.

     

Subclassification of presynaptic α2-adrenoceptors: α2D-autoreceptors in guinea-pig atria and brain

The study was devised to classify, by means of antagonist and agonist affinities, the presynaptic ₂-autoreceptors in guinea-pig heart atria and brain cortex in terms of _2A, _2B, _2C and _2D. A set of antagonists and agonists was chosen that was able to discriminate between the four subtypes. Small pieces of the atria and slices of the brain cortex were preincubated with ³H-noradrenaline and then superfused and stimulated electrically.In one series of experiments (atria only), tissue pieces were stimulated by relatively long pulse trains (1 min) leading to marked ₂-autoinhibition. All 10 antagonists increased the evoked overflow of tritium. pEC_30% values (concentrations causing 30% increase) were interpolated from concentration-response curves. In a second series of experiments (atria and brain slices), tissue pieces were stimulated by brief pulse trains (0.4 s or 40 ms) that led to little (atria) or no (brain slices) ₂-autoinhibition, and antagonist effects against the ₂-selective agonist 5-bromo-6(2-imidazolin-2-ylamino)-quinoxaline UK 14,304 were examined. All 10 (atria) or 8 (brain) antagonists shifted the concentration-inhibition curve of UK 14,304 to the right. pK_d values of the antagonists were calculated from the shifts. In a third series of experiments (brain slices only), also with brief pulse trains (40 ms), pK_a values (negative logarithms of dissociation constants of agonist-₂-adrenoceptor complexes) were determined by comparison of concentration-inhibition curves of UK 14,304, guanoxabenz and oxymetazoline in normal tissue and in tissue in which a fraction of the receptors had been blocked by phenoxybenzamine. pEC_30% values in atria correlated with pK_d values (r = 0.942). pK_d values in atria correlated with pK_d values in the brain cortex (r = 0.970).It is concluded that the ₂-autoreceptors in atria and the brain cortex are the same. Comparison with antagonist affinities for prototypic native ₂ binding sites, binding sites in cells transfected with ₂ subtype genes, and previously classified presynaptic ₂-adrenoceptors — all taken from the literature - indicates that both autoreceptors are _2D. In atria, this identification is reached with either of the two independent estimates of autoreceptor affinity, pEC_30% and pK_d, and in the brain cortex it is supported by the agonist pK_a values. The results are compatible with the hypothesis that at least the majority of ₂-autoreceptors belong to the _2AD branch of the ₂-adrenoceptor tree.     

Pharmacokinetics of amosulalol,an α, β-adrenoceptor blocker,in rats,dogs and monkeys

1. The pharmacokinetics of an α,β-adrenoceptor blocker, amosulalol hydrochloride, were studied after i.v. and oral administration to rats, dogs and monkeys.

2. After an i.v. dose (1 mg/kg), the plasma concentration-time curve fitted a two-compartment open model with terminal half-lives of 2-5 h in rats, 21 h in dogs and 1-8 h in monkeys. The order of plasma clearances for amosulalol was: rats > dogs > monkeys.

3. After oral administration, the maximum plasma concentration was obtained at 0-5-1 h in rats (10-100mg/kg) and dogs (3-30mg/kg), and at l-7-2-7h in monkeys (3-10 mg/kg). A linear relationship between the area under the plasma concentration-time curve and dose administered was obtained for all three species. The systemic availabilities of the drug in rats, dogs and monkeys were 22-31%, 51-59% and 57-66%, respectively.

4. After repeated oral administration (10 mg/kg) to dogs for 15 days, the pharmaco-kinetic parameters did not differ significantly from those on the first day.     

Pupillary dilation as an index of central nervous system α2-adrenoceptor activation

In recent years there has been increasing evidence that some antihypertensive drugs like clonidine and α-methyldopa (after conversion in the brain to α-methylnorepinephrine) may decrease sympathetic tone by stimulating central nervous system (CNS) α₂-adrenoceptors. These same drugs also produce pupillary dilation in cats and rats. In this review, evidence is presented supporting the hypothesis that clonidinelike drugs act either directly or indirectly on CNS postsynaptic α₂-adrenoceptors to cause pupillary dilation by reduction of parasympathetic neural tone to the iris. It is further suggested that the underlying physiologic mechanism for this mydriatic action is activation of an ascending pathway that provides tonic inhibitory input by releasing norepinephrine on neurons in the Edinger-Westphal complex. Yohimbine-sensitive pupillary dilation in these species may provide a simple and effective model for quantitatively accessing CNS α₂-adrenoceptor activity.     

Potency of N6-modified N-alkyl adenosine-5′-uronamides at presynaptic adenosine receptors in guinea-pig ileum

Summary The ability of a series of N⁶-modified N-alkyl-5-uronamides to cause presynaptic inhibition of transmitter release was examined in isolated guinea-pig ileum stimulated at 0.2 Hz. These analogs inhibited the twitch responses to nerve stimulation, the majority being full agonists with their inhibitory effects being antagonised by theophylline. These analogs had no significant effects on responses of ileum to carbachol. N-ethyl 5-uronamide substitution resulted in an up to four-fold reduction in activity of N⁶-substituted adenosine analogs, while stereoselectivity of the N⁶-substituted analogs continued to be present. 5-Uronamide substitutions to N⁶-(3-pentyl)-adenosine resulted in a marked loss of activity when there were large alkyl groups at the amide or with amides of secondary amines. It was concluded that adenosine analogs interact with both the N6 and C-5 regions of the adenosine receptor in this tissue, with the interaction being less than additive.Abbreviations CHA N⁶-cyclohexyladenosine - HNBMPR 6[(2-hydroxy-5–nitro)benzylthiol-inosine - NECA N-ethyladenosine-5-uronamide - NCPCA N-cyclopropyl-adenosine-5-uronamide - R-PIA N⁶-R-(1-phenyl-2-propyl)adenosine - S-PIA N⁶-S-(1-phenyl-2-propyl)adenosine Supported by grants from the Medical Research Council of New Zealand and the Auckland Medical Research Foundation (to D. M. Paton) and the Suncoast Chapter, Florida AHA Affiliate, Nelson Research and Development Inc. and the NIH (HL-26611) (to RAO) Send offprint requests to D. M. Paton at the above address     

Binding characteristics of (+)-, (±)- and (-)-[125Iodo] cyanopindolol to guinea-pig left ventricle membranes

Summary [¹²⁵Iodo]cyanopindolol [(±)-ICYP], a potent and selective ligand for -adrenoceptors, exhibited complex biphasic dissociation kinetics. Consequently, in receptor binding studies, the pure (+)- and (-)-enantiomers of ICYP were synthesised and their equilibrium and kinetic binding characteristics were investigated on a membrane preparation of guinea pig left ventricle containing almost only ₁-adrenoceptors.All three ligands, i. e. (+)-, (-)- and (±)-ICYP, bind to -adrenoceptors as assessed by competition experiments with different -blocking agents; irrespective of the ligand used, the same dissociation constant was found for the competitor. In a first series of saturation binding experiments performed in a low concentration range of free ligand (0–250 pM), ICYP showed the following dissociation constants: K _D=93, 9 and 23 pM, and number of binding sites: B _max=40,128 and 124 fmoles/mg protein for (+)-, (-)-, and (±)-ICYP, respectively. Asexpected, (±)-ICYP showed the same B _max as (-)-ICYP, whereas its K _D was approximately two times higher than that of (-)-ICYP. Surprisingly, the B _max of (+)-ICYP represented only 30% of the B _max of (-)-ICYP. All three ligands bound apparently to a single class of binding sites.In dissociation experiments, the enantiomers of ICYP showed biphasic dissociation curves as observed for the racemic ligand. (+)-, (-)- and (±)-ICYP showed a rapidly dissociating (k _-1=0.488, 0.047 and 0.049 min^–1) and a slowly dissociating component (k _-2=0.0205, 0.0033 and 0.0025 min^–1). The ratio slow dissociating/fast dissociating component represented respectively for (+)-, (-)- and (±)-ICYP 40/60, 90/10 and 90/10. For all three ligands, the association rate constants were of the same order of magnitude (ca. 10⁹ M^–1 min^–1), typical for a diffusion controlled reaction.In contrast to equilibrium binding studies, the existence of multiple receptor affinity sites was evident from the biphasic dissociation behaviour observed especially with the nonracemic ligands (+)-ICYP and (-)-ICYP.Simulation of theoretical saturation curves performed with the ratios of high versus low affinity sites and the K _D-values suggested by kinetic analysis, indicated that the delineation into two affinity states might be visible in saturation experiments, under certain conditions.Therefore, equilibrium binding studies were repeated with an increased number of ligand concentrations covering a large concentration range of 0–800 pM. Simultaneous analysis of saturation curves from the same experiment using three different ligands, provided more accurate estimates of the ratio of high and low affinity sites, as well as the affinity constants of the ligand for each receptor affinity state, in good agreement with the results from kinetic analysis.The contribution of the (+)enantiomer in the binding of the racemic ligand under low receptor concentrations could be neglected since dissociation characteristics of (±)- and (-)-ICYP were identical. A model that explains the biphasic dissociation of (±)-ICYP by differential binding of both enantiomers could be rejected. Kinetic and equilibrium binding characteristics of the three radioligands were not influenced by the guanylnucleotide Gpp(NH)p (10^–4 M).The antagonist ICYP binds to -adrenoceptors in a high and low affinity state which are probably interconvertible.Abbreviations CYP cyanopinodolol - ICYP [¹²⁵Iodo]cyanopindolol - HYP (±)-hydroxybenzylpindolol - IHYP (±)-[¹²⁵Iodo]hydroxybenzylpindolol - ³H-DHA (-)-[³H]dihydroalprenolol - ³H-HBI (±)-[³H]-hydroxybenzylisoproterenol - ISA intrinsic sympathomimetic activity; Gpp(NH)p, guanyl-5yl-imidodiphosphate - FM 24 1-(2-exobicyclo[2,2,1]hept-2yl-phenoxy)-3-[(1-methylethyl)amino]-2-propranolol Part of this work has been presented at the Spring Meeting of the German Pharmacological Society, Mainz, March 10–13, 1981     

The use of α-adrenoceptor antagonists in lower urinary tract disease

α-adrenoceptor antagonists have traditionally been used in the treatment of hypertension but in recent years they have become increasingly common in the treatment of benign prostatic enlargement (BPE), where they reduce the ‘dynamic’ component of bladder outlet obstruction and appear to have additional actions to reduce irritative symptoms of the disease. Prazosin (Hypovase^®, Alza), doxazosin (Cardura^®, Pfizer), indoramin (Doralese^®, Wyeth-Ayerst Pharmaceuticals Inc.) and terazosin (Hytrin^®, Abbott Laboratories) are currently available in the UK for BPE but these agents have cardiovascular actions in a significant number of patients, inducing effects which must be considered adverse unless the patient also requires treatment for mild-to-moderate hypertension. The uroselective α-adrenoceptor antagonists tamsulosin (Flomax^®, Yamanouchi Pharmaceutical Co. Ltd.) and alfuzosin (Xatral^®, Sanofi-Synthelabo) have recently been introduced. These agents exert their selectivity via different mechanisms; selective tissue distribution for alfuzosin and α-adrenoceptor subtype selectivity for tamsulosin. The incidence of cardiovascular side effects for both drugs is similar to placebo. Several lines of evidence suggest that the α-adrenoceptor antagonists may relieve lower urinary tract (LUT) symptoms by other mechanisms additional to those which account for the reduction in bladder outlet obstruction. If correct, these agents may be of use in the treatment of other bladder conditions.