Selectivity and specificity for alpha 1-adrenoceptor blocking activity of R(-)- and S(+)-YM-12617 orally administered to pithed, spontaneously hypertensive rats

The selectivity and specificity for alpha 1-adrenoceptor blocking activity of the optical isomers of YM-12617 have been examined in pithed, spontaneously hypertensive rats. R(-)-YM-12617 and prazosin (1 mg kg-1 p.o.) produced 360- and 88-fold rightward shifts, respectively, of the dose-response curve of control to phenylephrine, whereas S(+)-YM-12617 (1 mg kg-1 p.o.) failed to cause a shift. Based on dose ratio, R(-)-YM-12617 was 320 times more potent as an alpha 1-adrenoceptor antagonist than S(+)-YM-12617. This potency ratio corresponded to that formed in an in-vitro study. Both R(-)- and S(+)-YM-12617 hardly affected the UK-14304, angiotensin II, vasopressin and isoprenaline dose-response curves. These results suggest that R(-)-YM-12617 exerted selective alpha 1-adrenoceptor blocking activity and its activity was specific for alpha 1-adrenoceptors.     

A difference in mode of antagonism between optical isomers of a potent selective alpha 1-adrenoceptor blocker (YM-12617) and norepinephrine in isolated rabbit iris dilator and aorta

Optical isomers of YM-12617, a potent and selective alpha 1-adrenoceptor blocker, were tested on the rabbit iris dilator and aorta. The order of potency was R(-)-isomer greater than racemate greater than S(+)-isomer. The R(-)-isomer and racemate behaved as an essentially irreversible antagonist to norepinephrine in the iris dilator where the efficacy of norepinephrine was small, although the S(+)-isomer was a competitive antagonist. These drugs behaved as a competitive antagonist of norepinephrine in the aorta where the efficacy of norepinephrine was large.     

Assessment of alpha-adrenergic receptor subtypes in isolated rat aortic segments

The postsynaptic alpha-adrenoceptors in the isolated rat aorta have been characterized according to the sensitivity of the tissue to selective alpha 1- and alpha 2-adrenoceptor agonists and antagonists. The potency (-log EC50) order of the non-selective alpha-agonist norepinephrine and relatively selective agonists was as follows: norepinephrine (alpha 1 = alpha 2; 7.30); clonidine (alpha 2 greater than alpha 1; 7.01); phenylephrine (alpha 1 greater than alpha 2; 6.99), SK & F 89748--A (alpha 1 greater than alpha 2; 6.65); BHT-920 (alpha 2 much greater than alpha 1; 5.56) and M-7 (alpha 2 greater than alpha 1; 4.66). The isolated rat aorta was 12-200-fold more sensitive to the alpha 1-adrenoceptor agonists phenylephrine and SK & F 89748-A, than to the alpha 2-agonists, BHT-920 and M-7. Prazosin is 245-1259-fold more potent than rauwolscine as an antagonist of contractions induced by various alpha 1- and alpha 2-agonists in the rat aorta. These data indicate that constriction of the smooth muscle of the rat aorta to alpha-adrenergic agonists is mediated through alpha 1- but not alpha 2-adrenoceptors.     

Studies on YM-12617: A selective and potent antagonist of postsynaptic α1-adrenoceptors

YM-12617, 5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2 -methoxybenzenesulfonamide HCl is a structurally new type of extremely potent alpha 1-adrenoceptor antagonist. Its alpha-adrenoceptor blocking properties have been compared with those of prazosin, phentolamine and yohimbine using both pharmacological and 3H-ligand binding techniques in vitro and in vivo. In the isolated rabbit aorta, a tissue known to contain mainly alpha 1-adrenoceptors at postjunctional sites, YM-12617 competitively antagonized noradrenaline-induced contraction with a pA2 value of 10.11. Although YM-12617 was also a competitive antagonist toward clonidine at prejunctional alpha 2-adrenoceptors in the isolated rat vas deferens, its affinity for these receptors (pA2 = 6.41) was 5,000 times lower than that displayed for the postjunctional alpha 1-adrenoceptors in the isolated rabbit aorta. YM-12617 displaced both 3H-WB 4101 and 3H-clonidine binding to rat brain membranes; however, the affinity of YM-12617 for alpha 1-adrenoceptors (pKi = 9.64) was 3800 times higher than that for alpha 2-adrenoceptors (pKi = 6.06). Based on pA2 values obtained in the isolated tissues and pKi values in the binding assays, YM-12617 was 2-18, 36-117 and 1,740-5,750 times more potent than prazosin, phentolamine and yohimbine in antagonizing alpha 1-adrenoceptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that the population of postjunctional-adrenoceptors mediating contraction of smooth muscle in the rabbit isolated ear vein is predominantly alpha 2.

1. Noradrenaline (NA), phenylephrine and UK-14304 elicited concentration-dependent contractions of the rabbit isolated ear vein of similar maximal magnitude. The rank order of potency, UK-14304 greater than noradrenaline greater than phenylephrine, is consistent with that of an effect mediated through an alpha 2-subtype. 2. The potent and highly selective alpha 1-adrenoceptor antagonists prazosin and YM-12617, at concentrations as high as 1 microM, produced less than a 4 fold rightward displacement of the NA concentration-response curve. 3. The selective alpha 2-adrenoceptor antagonists rauwolscine, Wy-26703 and CH-38083 antagonized responses to noradrenaline in a competitive manner. For all three antagonists, the pA2 values were consistent with an effect at alpha 2-adrenoceptors. However, 0.1 microM YM-12617 increased the potency of rauwolscine 2 fold indicating the presence of a small population of postjunctional alpha 1-adrenoceptors. 4. The relative antagonist potency of the yohimbine diastereoisomers rauwolscine and corynanthine against noradrenaline (rauwolscine 30 fold greater than corynanthine) is also consistent with an effect at alpha 2-adrenoceptors. 5. Contractions elicited by noradrenaline in the rabbit isolated ear vein appear to be mediated predominantly by postjunctional alpha 2-adrenoceptors.     

Pharmacological analysis of postjunctional alpha-adrenoceptors mediating contractions to (-)-noradrenaline in the rabbit isolated lateral saphenous vein can be explained by interacting responses to simultaneous activation of alpha 1- and alpha 2-adrenoceptors.

1. The pharmacological characteristics of the alpha-adrenoceptor population in the rabbit isolated saphenous vein has been examined with (-)-noradrenaline (NA), as principal agonist, and a number of antagonists with selectivity for either alpha 1- or alpha 2-adrenoceptors. 2. The rank order of potency of various agonists is consistent with a population of alpha 2-adrenoceptors; UK-14304 greater than (-)-noradrenaline = (-)-adrenaline greater than B-HT 920 = cirazoline greater than phenylephrine greater than amidephrine, but the rank order of pA2 values for the antagonists against (-)-noradrenaline: BDF-6143 greater than rauwolscine = prazosin greater than CH-38083 = YM-12617 greater than Wy-26703 = phentolamine greater than corynanthine, is indicative of a mixed population of alpha 1- and alpha 2-adrenoceptors or, alternatively, a new subtype with characteristics of both the alpha 1- and alpha 2-subtypes. 3. Further evidence for two discrete populations of alpha-adrenoceptors is provided by, (a) the potent but non-competitive effect of prazosin against (-)-noradrenaline, (b) the presence of a component of the contractions elicited by NA and phenylephrine which is resistant to the selective alpha 2-adrenoceptor antagonists rauwolscine and CH-38083: these responses were inhibited by the selective alpha 1-adrenoceptor antagonists prazosin and YM-12617, but not by the selective alpha 2-adrenoceptor antagonist BDF-6143 and, (c) the relative potency of the yohimbine diastereoisomers rauwolscine and corynanthine against NA, phenylephrine and UK-14304. 4. In spite of the overwhelming evidence for a population of postjunctional alpha 2-adrenoceptors, prazosin was similarly effective against all agonists and failed to discriminate between those with putative selectivity for alpha 1- and alpha 2-adrenoceptors. This suggests an interaction of the effects of agonists at the two alpha-adrenoceptor subtypes. 5. An attempt has been made to reconcile a number of paradoxical observations with regard to the identification of postjunctional alpha 2-adrenoceptors in vitro, and it is suggested that in many of the isolated blood vessels presently available for examination both subtypes reside on the same smooth muscle cell. The pharmacological consequences of multiple subtypes of receptors mediating the same response is considered.     

Effect of diltiazem upon contractile responses to phenylephrine, cirazoline, Sgd 101/75, St 587 and B-HT 920 in rabbit aorta and dog saphenous vein preparations

Diltiazem (10 microM) did not significantly affect concentration-response curves to the full, relatively selective alpha 1-adrenoceptor agonists phenylephrine and cirazoline in rabbit aorta and dog saphenous vein preparations. The effects of these 2 agonists remained resistant to diltiazem even in tissues pretreated with phenoxybenzamine (0.03 or 0.1 microM, 20 min) to reduce the alpha-adrenoceptor reserve. Sgd 101/75 and St 587 were partial agonists in both vascular preparations. The concentration-response curves to these relatively selective alpha 1-adrenoceptor agonists were also unaffected, or only slightly attenuated, by diltiazem. B-HT 920 at low concentrations preferentially stimulated the dog saphenous vein preparation and only at high concentrations elicited small contractions of the rabbit aorta. The responses to B-HT 920 were mediated by alpha 2-adrenoceptors in the vein and by alpha 1-adrenoceptors in the aorta yet concentration-response curves to this agonist were significantly attenuated by diltiazem in both tissues. The results indicate that the resistance of certain alpha-adrenoceptor-mediated responses in vascular preparations to calcium entry blockers need not be associated with the presence of a significant receptor reserve and that calcium dependency of a response may be determined by the agonist.     

Comparison of haemodynamic effects of alpha-sympathomimetic drugs

Dose-response curves for nine α-sympathomimetic drugs were determined in pithed rats. The order of potency was: norepinephrine 1, phenylephrine 0.1, oxymetazoline 0.1, clonidine 0.029, LD 2855 0.028, naphazoline 0.087, tramazoline 0.030, tetryzoline 0.01, Bayer 1470 0.0003. Pretreatment with reserpine (10 mg/kg 24 hr before) did not change the dose-response curves; phentolamine (2 mg/kg) shifted the dose-response curve to the right but did dose-response curve to the right and reduced the maximal response suggesting non-competetive antagonism. Cocaine (5 mg/kg) and imipramine (2 mg/kg) reduced the hypertension produced by clonidine but increased slightly hypertension following naphazoline.     

Alpha 1-adrenoceptors: the ability of various agonists and antagonists to discriminate between two distinct [3H]prazosin binding sites

Recently, it has been demonstrated that two distinct alpha 1-adrenoceptor binding sites showing high and low affinity for WB-4101 (2-(2,6-dimethoxyphenoxy)ethyl-aminomethyl-1,4-benzodioxane) and 5-methyl-urapidil can be distinguished. In the present study we examined the ability of several agonists and antagonists to discriminate between these alpha 1-adrenoceptor binding sites. [3H]Prazosin binding to membranes of rat liver, heart, cerebral cortex and hippocampus was inhibited monophasically by butanserine, I-BE 2254 (2-(3-(4-hydroxy-3-iodophenyl)ethylaminomethyl)tetralone-hydrochloride), prazosin, rauwolscine and verapamil. In contrast, competition curves of adrenaline, oxymetazoline, amidephrine and YM-12617 (5-[2-[[2-(o-ethoxy-phenoxy)ethyl]-amino]propyl]-2- methoxybenzenesulfonamide HCl) were best described by a model of two binding sites. Chloroethylclonidine (CEC), a compound shown to irreversibly eliminate binding sites with low affinity for WB-4101, increased the proportion of high affinity binding sites for oxymetazoline and amidephrine, whereas the binding data for prazosin and adrenaline remained unchanged. These results indicate that amidephrine, oxymetazoline and YM-12617, but not the other drugs tested discriminate between different alpha 1-adrenoceptor recognition sites labelled by [3H]prazosin.     

Sensitivity of alpha-adrenoceptor agonists to the calcium channel activator, Bay K 8644, in canine saphenous vein

The purpose of the present study was to determine if the calcium channel activator, Bay K 8644, enhances the vasoconstrictor actions of selective alpha 1- and alpha 2-adrenoceptor agonists in canine saphenous vein. Phenylephrine (PE) and St 587 were used as fully and partially selective alpha 1-adrenoceptor agonists, B-HT 920 and B-HT 958 were used as fully and partially selective alpha 2-adrenoceptor agonists. Bay K 8644 (10(-8) M) markedly potentiated B-HT-958-mediated vasoconstrictor responses with a leftward shift and an increase in the maximum response of the logarithmic dose-response curve. Bay K 8644 produced less potentiation of responses to B-HT 920 and had minimal effects on responses to St 587 and PE. The intrinsic activities of the alpha-adrenoceptor agonists, as compared to the maximum response obtained by norepinephrine, in decreasing order, were PE greater than St 587 greater than B-HT 920 greater than B-HT 958, whereas the susceptibility of alpha-adrenoceptor agonists to potentiation by Bay K 8644 in decreasing order were B-HT 958 greater than B-HT 920 greater than St 587 greater than PE. These results suggest that Bay K 8644 preferentially improves the receptor-response coupling of alpha-adrenoceptor agonists with low intrinsic activity (alpha 2-agonists) versus agonists with high intrinsic activity (alpha-agonists) in canine saphenous vein.     

INVESTIGATIONS INTO THE NATURE OF α2-ADRENOCEPTORS IN RAT TAIL ARTERIES

In rat isolated perfused tail arteries, dose-response curves were established for the vasopressor effects of phenylephrine (alpha 1-adrenoceptor agonist), clonidine (alpha 1- and alpha 2-adrenoceptor agonist), clonidine in the presence of 10(-7) mol/l prazosin (alpha 2-agonist), and BHT-920 (alpha 2-agonist). The ED50 values were: phenylephrine 1.85 X 10(-10) mol; clonidine 6.3 X 10(-10) mol; clonidine + prazosin 3.2 X 10(-6) mol; BHT-920 6.1 X 10(-6) mol. The arterial reactivity to BHT-920 was stable only after 4-5 h of perfusion. Responses to BHT-920 were not antagonized by yohimbine (alpha 2-adrenoceptor antagonist) but were antagonized by low concentrations of prazosin (alpha 1-adrenoceptor antagonist). These data constitute conflicting evidence regarding the existence of alpha 2-adrenoceptors in rat tail arteries. The data are consistent with the proposal that there are two recognition sites on alpha 1-adrenoceptors; phenylephrine and BHT-920 may stimulate different sites on alpha 1-adrenoceptors.     

Further characterization of the myocardial alpha-adrenoceptors mediating positive inotropic effects in the rabbit myocardium

[3H]Prazosin bound with high affinity to the membrane fraction derived from the rabbit ventricular myocardium. Oxymetazoline displaced [3H]prazosin from its binding site, did not elicit a positive inotropic effect but antagonized the positive inotropic effect of phenylephrine mediated by alpha-adrenoceptors in the presence of a beta-antagonist. Naphazoline was more potent in displacing [3H]prazosin and behaved as a weak partial agonist. YM-12617 (5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2- methoxybenzenesulfonamide HCl), a potent selective alpha 1-antagonist, displaced [3H]prazosin and antagonized the alpha-mediated positive inotropic effect with equal potency. Thus, a good correlation was found between the potency of alpha-antagonists to displace [3H]prazosin and their ability to antagonize the alpha-mediated positive inotropic effect. On the other hand, there was no significant correlation between the Ki and the pD2 value of the alpha-agonists (norepinephrine, epinephrine, phenylephrine and naphazoline), indicating that there is a non-linear relationship between agonist binding to myocardial alpha 1-adrenoceptors and subsequent functional changes. Myocardial alpha 1-adrenoceptors showed some pharmacological characteristics which appear to be different from those in smooth muscle tissues.     

Involvement of alpha 1-adrenergic receptors in stimulation of phosphatidylinositol metabolism by catecholamines in mouse thyroids

The effects of alpha-adrenergic agonists and thyroid stimulating hormone on the incorporation of radioactive phosphate into phosphatidylinositol were investigated in mouse thyroids in vitro. The incorporation of 32P orthophosphate into phosphatidylinositol was stimulated by thyroid stimulating hormone, norepinephrine (a mixed alpha 1- and alpha 2-adrenergic agonist), methoxamine and phenylephrine (alpha 1-agonists) and slightly by clonidine and oxymetazoline (alpha 2-agonists) but not by isoproterenol (beta-agonist). Prazosin (alpha 1-antagonist) inhibited the stimulation by norepinephrine of 32P incorporation into phosphatidylinositol, but yohimbine (alpha 2-antagonist) was less effective. Although norepinephrine inhibits the thyroid stimulating hormone-induced release by activating alpha-, especially alpha 1-adrenoceptors in mouse thyroids [M. L. Maayan et al., Metabolism 26, 473 (1977); M. L. Maayan et al., Endocrinology 101, 284 (1977); T. Muraki et al., Endocrinology 110, 51 (1982)] alpha 1-agonists did not decrease the stimulation of turnover elicited by thyroid stimulating hormone and did not have additive action with it. These results suggest that (1) the stimulation of phosphatidylinositol turnover of mouse thyroids elicited by adrenergic agonists is mediated by activation of alpha 1-adrenoceptors and (2) the inhibitory effect of norepinephrine on the thyroid stimulating hormone-induced release of thyroxine is not mediated by norepinephrine-inhibition of phosphatidylinositol-turnover stimulated by thyroid stimulating hormone.     

Sympathetic innervation and alpha-adrenoceptor profile of blood vessels in the posterior region of the rabbit knee joint.

1. Experiments were performed to determine the nature of adrenoceptors mediating neurally-induced vasoconstriction of blood vessels in the posterior region of the rabbit knee joint capsule. 2. Electrical stimulation of the posterior articular nerve resulted in frequency-dependent vasoconstriction which was maximal at 10 Hz. This response was mediated predominantly by alpha 2-adrenoceptors as it was only slightly reduced by prazosin administration and was not only abolished but converted into a dilator response by the alpha 2-adrenoceptor antagonist rauwolscine. Further experiments with another specific alpha 1-adrenoceptor antagonist YM-12617 showed that the frequency-response curve in the presence of this antagonist did not differ significantly from control. 3. Neurally-induced vasoconstriction did not appear to have a purinergic component as it was unaffected by the P2x-purinoceptor desensitiser alpha, beta methylene ATP. 4. The rank-order of potency of alpha-adrenoceptor agonists given as a bolus by close intra-arterial injection was: adrenaline = UK-14304 > clonidine > phenylephrine, suggesting that the vasoconstrictor effects were mediated predominantly by postjunctional alpha 2-adrenoceptors. 5. The alpha 2-adrenoceptor antagonist rauwolscine converted the constrictor response to close intra-arterial injection of adrenaline into a dilator response. The vasoconstrictor responses to UK-14304, clonidine and phenylephrine were substantially inhibited by rauwolscine. The alpha 1-adrenoceptor antagonist prazosin failed to inhibit the vasoconstrictor responses to adrenaline, clonidine and UK-14304 and resulted in enhancement of their constrictor effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro characterization of alpha-adrenergic receptor in rabbit detrusor muscle

In the isolated detrusor smooth muscle of the rabbit urinary bladder, acetylcholine, prostaglandin (PG) F2 alpha, histamine and methoxamine produced dose-dependent contractions. The order of efficacy was acetylcholine greater than PGF2 alpha greater than histamine greater than methoxamine. Acetylcholine and oxotremorine increased tension remarkably in the rabbit detrusor muscle; and McN-A-343 also developed tension, but with weaker sensitivity and efficacy. The contractile response to acetylcholine was competitively antagonized by atropine (pA2 9.24) and pirenzepine (pA2 6.96), respectively. Histamine and 2-pyridylethylamine caused dose-dependent contractions. On the other hand, dimaprit caused no response in this tissue. Mepyramine (pA2 8.80) competitively antagonized the contraction induced by histamine, whereas cimetidine failed to antagonize the contraction even at a high concentration of 10(-5) M. Norepinephrine, phenylephrine and methoxamine have greater efficacies in the ability to contract than clonidine. R(-)- and S(+)-YM-12617 and YM-12617 (pA2 10.4, 8.31 and 9.75, respectively) and prazosin (pA2 8.13), phentolamine (pA2 7.55) and yohimbine (pA2 6.44) competitively antagonized the contraction elicited by methoxamine. These results suggest that the contraction of rabbit detrusor muscle can be mediated by alpha 1-adrenergic receptors as well as M2-muscarinic and H1-histaminergic receptors and suggest that the contractile force mediated by alpha 1-adrenergic receptor agonist is smaller than those stimulated by the other receptor agonists.     

Alpha-adrenoceptor reserve in the canine cephalic vein

In the canine cephalic vein, the pD2 for the selective alpha 1-agonist, phenylephrine, was 6.08 +/- 0.08 (n = 14) and that for the selective alpha 2-agonist, UK-14,304, was 8.32 +/- 0.06 (n = 10). The pA2 values for the antagonism exerted by the selective alpha 1-antagonist, prazosin, against phenylephrine and UK-14,304 were 7.74 +/- 0.05 (n = 14) and 6.28 +/- 0.03 (n = 8), respectively, while those for the antagonism exerted by the selective alpha 2-antagonist, yohimbine, against phenylephrine and UK-14,304 were 7.40 +/- 0.02 (n = 14) and 8.93 +/- 0.05 (n = 14), respectively. Furthermore, the concentration-response curve for UK-14,304 was typically biphasic, the first phase being antagonized by yohimbine and the second phase by prazosin and phenoxybenzamine. These results show that there are postsynaptic alpha 1- and alpha 2-adrenoceptors in the canine cephalic vein. In such a preparation, only one concentration of phenoxybenzamine (1 nM) shifted the concentration-response curves for noradrenaline, adrenaline and isoprenaline to the right without reducing the maximum. However, at the concentrations tested, phenoxybenzamine did not shift the concentration-response curve for phenylephrine to the right without depressing its maximum. It is concluded that: (1) the canine cephalic vein is a suitable preparation to study postsynaptic alpha 1- and alpha 2-adrenoceptors; (2) according to the original definition of 'spare receptors', there is no alpha 1-adrenoceptor reserve in canine cephalic vein; (3) UK-14,304 is a partial agonist at alpha 1-adrenoceptors.     

Effects of isoproterenol pretreatment on phosphatidylinositol turnover in rat parotid gland

The effects of isoproterenol pretreatment on phosphatidylinositol turnover in rat parotid slices were studied to elucidate the relationship between beta- and alpha 1-adrenoceptors. 32P-Labeling of phosphatidylinositol in parotid slices was increased by an alpha 1- and alpha 2-agonist (epinephrine and norepinephrine) and alpha 1-agonists (methoxamine and phenylephrine), but not by an alpha 2-agonist (clonidine) and a beta-agonist (isoproterenol). Prazosin inhibited the increase in phosphatidylinositol turnover elicited by epinephrine, but propranolol did not. These results indicate that the stimulation of phosphatidylinositol turnover elicited by adrenergic agonists is mediated by activation of alpha 1-adrenoceptors in the parotid glands. Isoproterenol pretreatment of the parotid slices caused a significant increase in 32P-labeling of phosphatidylinositol and a decrease in that of phosphatidic acid. The epinephrine- or phenylephrine-induced increase in 32P-labeling of phosphatidylinositol were further enhanced by the isoproterenol pretreatment of the slices. In the isoproterenol-treated membranes of the parotid glands, [3H]prazosin binding to alpha 1-receptors increased, but [3H]dihydroalprenolol binding to beta-receptors did not. These findings indicate that the acceleration of phosphatidylinositol turnover induced by the isoproterenol pretreatment may be associated with an increase in alpha 1-adrenoceptor binding sites which might have appeared as a result of the isoproterenol pretreatment of the parotid slices.     

Different subtypes of alpha 1A-adrenoceptor mediating contraction of rat epididymal vas deferens, rat hepatic portal vein and human prostate distinguished by the antagonist RS 17053.

1. The alpha 1-adrenoceptor subtype mediating contraction of the rat hepatic portal vein to phenylephrine was characterized by use of competitive antagonists previously shown to have selectivity between the expressed alpha 1-subtype clones. Prazosin competitively antagonized the phenylephrine contractions with a pA2 value of 9.2, as did WB 4101 (pA2 9.4), 5-methyl urapidil (pA2 8.6), indoramin (pA2 8.4) and BMY 7378 (pA2 6.5). 2. The pA2 values on the rat portal vein correlated highly with their previously published pA2 values for the alpha 1A-adrenoceptors mediating contraction of the rat epididymal vas deferens and human prostate and poorly with those for the alpha 1B- and alpha 1D-adrenoceptors mediating contraction of the rat spleen and aorta, respectively. The antagonist pA2 values on the rat portal vein correlated highly with their previously published pK1 values for the expressed alpha 1a-clone and poorly with those for the expressed alpha 1b- and alpha 1d-clones. Therefore the results show that contraction of the rat portal vein to phenylephrine is mediated by alpha 1A-adrenoceptors. 3. The novel alpha 1-adrenoceptor antagonist RS 17053 had a relatively high affinity for the alpha 1A-adrenoceptors mediating contraction of the rat epididymal vas deferens (pA2 9.5) compared with the alpha 1B-adrenoceptors in the rat spleen (pA2 7.2) or the alpha 1D-adrenoceptors in the rat aorta (pKB 7.1), in agreement with its selectivity for the expressed alpha 1a-clone. However, RS 17053 had over 100 fold lower affinity for the alpha 1A-adrenoceptors mediating contraction of the rat portal vein (pKB 7.1) and human prostate (pKB 7.1) compared with its affinity for the alpha 1A-adrenoceptors in the rat epididymal vas deferens or the expressed alpha 1a-clone. 4. The difference in affinity of RS 17053 between the rat epididymal vas deferens and rat portal vein cannot be explained by a species difference in the receptor. Therefore RS 17053 may distinguish between subtypes of the alpha 1A-adrenoceptor in the rat portal vein and human prostate compared with those in the rat epididymal vas deferens or the expressed alpha 1a-clone.     

Protective action of YM-12617, an alpha 1-adrenoceptor antagonist, on the hypoxic and reoxygenated myocardium

The present study was designed to determine whether the 1-form of YM-12617, which was developed recently as an alpha 1-adrenoceptor blocker, is capable of protecting the myocardium from hypoxia-induced disturbances of cardiac function and metabolism. Isolated rabbit hearts were perfused for 25 min under hypoxic conditions in the absence or the presence of 28 microM YM-12617, followed by 45 min with oxygenated perfusion medium, and functional and metabolic changes of the heart were examined. Hypoxia induced several pathophysiological changes. Upon subsequent reoxygenation, there was less than 10% recovery of the contractile force and an approximately 40% recovery of the myocardial high-energy phosphates. Treatment with YM-12617 during the hypoxic periods resulted in approximately 90% recovery of the cardiac contractile function upon subsequent reoxygenation. Treatment with YM-12617 restored the myocardial high-energy phosphates, such as ATP and creatine phosphate, to approximately 90 and 80% of the initial value, respectively, during the subsequent reoxygenation. These results suggest that YM-12617 is capable of protecting the myocardium from hypoxia-induced disturbances of cardiac function and metabolism.     

Effects of aging on postsynaptic alpha 1-adrenoceptor mechanisms in rat aorta.

1. Effects of aging on alpha 1-adrenoceptor and S2-serotonin receptor mechanisms in rat aorta were studied. 2. In rat aorta, the potency (pD2 value) of norepinephrine or phenylephrine increased with age from 3 to 10 weeks, but decreased thereafter with age from 10 to 80 weeks. The affinity (pKA value) of norepinephrine or phenylephrine and of prazosin (pA2 value) did not alter with aging. 3. In rat vas deferens, the efficacy of norepinephrine and the maximum binding sites of [3H]prazosin increased with age from 3 to 18 weeks, but decreased thereafter with age from 18 to 60 weeks. The affinity (pKA value) of norepinephrine and the dissociation constant (KD value) of prazosin did not alter with aging. 4. In rat aorta, the potency (pD2 value) and affinity (pKA value) of serotonin, and affinity (pA2 value) of ketanserin did not alter with aging. 5. There is no significant difference between slopes of regression lines between a cytosolic free Ca2+ level [( Ca2+]i) and tension in the presence of phenylephrine in aorta strips from 10- and 60-week-old rats. 6. These results suggest that changes in alpha 1-adrenoceptor mechanisms with aging are due to changes in receptor density or receptor reserve, but not to changes in affinity of drugs to alpha 1-adrenoceptor or sensitivity of contractile system to Ca2+ mediated through alpha 1-adrenoceptor, and that S2-serotonin receptor mechanisms in rat aorta do not alter with aging.