Relationship between prostatic alpha(1)-adrenoceptor binding and reduction in intraurethral pressure following continuous infusion of KMD-3213 in rats

The relationship between alpha(1)-adrenoceptor binding in rat tissues and pharmacodynamic effects of continuous infusion of KMD-3213 was examined. In vivo specific binding of [(3)H]KMD-3213 after continuous intravenous infusion of the ligand (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min for 60 or 90 min) differed largely among the tissues examined. Specific binding of [(3)H]KMD-3213 in aorta, heart, lung, and kidney was not different in terms of infusion time in the case of continuous infusion for 10, 70 and 100 min, whereas the binding in prostate, vas deferens, and submaxillary gland by 70- and/or 100-min infusion was significantly greater than that by the 10-min infusion. A similar extent of specific binding in the prostate was observed by the infusion (100 min) of a three-fold higher dose of [(3)H]KMD- 3213. Continuous intravenous infusion of KMD-3213 (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min) for 70 or 100 min significantly reduced the phenylephrine-induced increase in the mean blood pressure and that in the intraurethral pressure of anesthetized rats. Extent and time course of the KMD-3213 effect reduction in the phenylephrine-induced increase in intraurethral pressure were closely associated with those in prostatic [(3)H]KMD-3213 binding after continuous infusion of the corresponding dosage of the radioligand. The reduction in the phenylephrine-induced increase by the infusion of a three-fold higher dose of KMD-3213 was significantly greater in the case of the intraurethral pressure than in that of the mean blood pressure, thereby suggesting a greater selectivity for the alpha(1)-adrenoceptor in the lower urinary tract than for that in the vascular tissue. In conclusion, the present study has shown that specific binding of [(3)H]KMD-3213 in the rat prostate after the continuous intravenous infusion of the radioligand may be closely associated with the pharmacological effect of this drug on the lower urinary tract.     

一种新的α1A肾上腺素受体选择性拮抗剂—Sertindole

本工作分别在稳定表达α_1A,α_1B和α_1D肾上腺素受体(adrenoceptor,AR)的人胚胎肾脏细胞( human embryonic kidney 293,HEK 293)和大鼠离体血管上,用放射配体结合实验和离体血管收缩功能实验方法以确定sertindole对α₁-AR亚型的选择性拮抗作用。结果显示sertindole与克隆α_1A-AR的亲和性分别是与克隆α_1B-AR和克隆α_1D-AR的69倍和132倍。Sertindole拮抗去甲肾上腺素引起的主动脉和肾动脉收缩反应的pA₂值分别与其对α_1D和α_1A亚型的pKI值相符。分别稳定表达3种亚型受体的HEK293细胞膜标本经与sertindole预温育30min后,受体与¹²⁵IBE2254结合的B_max值显著降低,KD值无显著变化;而在 sertindole 存在条件下,α₁-AR3种亚型与¹²⁵IBE2254 结合的KD值显著增大,但B_max值无显著改变。上述结果表明sertindole为不可逆性竞争性α₁-AR拮抗剂,并有α_1A亚型选择性。     

Influence of endogenous bradykinin on acute blood pressure response to vasopressors in normotensive rats assessed with a bradykinin antagonist

The present study was designed to assess in conscious normotensive rats the influence of various pressor agents on the acute blood pressure response to a bradykinin antagonist (B4162). This antagonist was used at a dose (400 micrograms i.v.) which had been previously shown to block the blood pressure lowering effect of exogenous bradykinin for several minutes. In control rats, the bradykinin antagonist had no effect on blood pressure. However, in rats pretreated with nonpressor doses of angiotensin II or methoxamine or with pressor doses of vasopressin or methoxamine, the same antagonist significantly increased blood pressure by 10 +/- 2.2, 12 +/- 2.7, 9 +/- 1.7, and 16 +/- 3.4 mm Hg, respectively. It therefore appears that circulating bradykinin is not directly involved in blood pressure regulation of conscious normotensive rats. Endogenous bradykinin may however play an important role in blood pressure control by attenuating the pressor effect of angiotensin II, vasopressin, and alpha-adrenoceptor stimulation.     

Selective and sustained occupancy of prostatic alpha1-adrenoceptors by oral administration of KMD-3213 and its plasma concentration in rats

This study examined the ex-vivo occupancy by KMD-3213 of alpha1-adrenoceptors in the prostate and other tissues of rats in terms of tissue selectivity and duration of occupancy in relation to plasma concentration. Oral administration of KMD-3213 (0.2-20.2 micromol kg(-1), 0.5 h) dose-dependently decreased [3H]prazosin binding sites (Bmax) in the prostate (42-74%) and submaxillary gland (54-88%) compared with the control value. In contrast, there was only a slight change in the Bmax values in the spleen and cerebral cortex of KMD-3213-treated rats. The alpha1-adrenoceptor occupancy in the prostate and submaxillary gland was increased, with plasma free concentration of KMD-3213 at 0.5 h after oral administration of KMD-3213 (0.6-20.2 micromol kg(-1)). The receptor occupancy in these tissues was much greater than that in the spleen, heart or cerebral cortex. After oral administration of KMD-3213 (6.1 micromol kg(-1)), the alpha1-adrenoceptor occupancy in the prostate and submaxillary gland occurred rapidly, in parallel with the rise in the plasma concentration of the drug, and it lasted for at least 24 h, despite a remarkable decrease in the plasma concentration. It is concluded that KMD-3213 may produce fairly selective and sustained occupancy of alpha1-adrenoceptors in the prostate, a target organ for treatment of bladder outlet obstruction in patients with benign prostatic hyperplasia.     

Alpha-1 adrenoceptor up-regulation induced by prazosin but not KMD-3213 or reserpine in rats

1. We have investigated the effects of chronic administration of prazosin (a subtype-nonspecific alpha-1 AR antagonist), KMD-3213 (an alpha-1A AR subtype-specific antagonist) and reserpine (a catecholamine depletor) on the density of alpha-1 AR subtypes in various rat tissues (liver, kidney, submaxillary gland, heart and spleen). 2. Administration of prazosin (2 mg kg(-1) day(-1), i.p.) for 2 weeks did not affect K(D) values for [(3)H]-prazosin or [(3)H]-KMD-3213 of alpha-1 ARs in five rat tissues tested. However, it caused 52% up-regulation of alpha-1B AR in the spleen, and 84% and 107% up-regulation of alpha-1A- and alpha-1B ARs, respectively, in the heart. Although major subtypes of alpha-1 AR are alpha-1A AR in the submaxillary gland, alpha-1B AR in the liver, and alpha-1A and alpha-1B ARs in the kidney, these tissues showed no up-regulation. The mRNA levels of alpha-1 AR subtypes were not affected by prazosin administration in any tissue tested. 3. Neither administration of KMD-3213 (2 mg kg(-1) day(-1), i.p.) nor reserpine (0.5 - 1 mg kg(-1) day(-1), i.p.) for 2 weeks caused any change in either the binding affinity for [(3)H]-prazosin or [(3)H]-KMD-3213 or the density of the alpha-1 AR subtypes in the five rat tissues. 4. Neither prazosin nor KMD-3213 treatment reduced the noradrenaline content in the five rat tissues, in contrast to reserpine treatment, which markedly reduced it. 5. The findings of the present study demonstrated that up-regulation of alpha-1 AR is selectively caused by prazosin treatment in some tissues but neither by KMD-3213 treatment nor by chemical denervation with reserpine. These results suggest that up-regulation of alpha-1 ARs is not caused by a simple blockade of sympathetic tone.     

Effects of alpha1-adrenoceptor antagonists on agonist and tilt-induced changes in blood pressure: relationships to uroselectivity.

We evaluated the uroselectivity of a series of alpha1-adrenoceptor antagonists by comparing their potency against phenylephrine-induced increases in urethral perfusion pressure and diastolic blood pressure in the anesthetized rabbit and pithed rat. In the rabbit, Rec 15/2739 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl -4H-1-benzopyran-8-carboxamide) as well as analogs with a chlorine substituent on the methoxyphenyl ring (Rec 15/2869) or this substituent combined with the replacement of the phenyl substituent on the pyran ring by cyclohexyl (Rec 15/3011) were 2-6-fold more potent against the urethral vs. vascular response to phenylephrine. Rec 15/2841 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-cyc lohexy-4H-1-benzopyran-8-carboxamide) was only 1.5-fold more potent against the urethral response. SL 89.0591 and tamsulosin also showed selectivity for the urethral response (2-2.5-fold), while the quinazolines produced equipotent blockade of urethral and vascular responses (selectivity ratio = 0.9-1.1). The urethral selectivities of Rec 15/2739 and its derivatives were confirmed by evaluation of the response to tilt in sedated, hypovolemic rabbits. Phenylephrine challenge assays did not show any of the antagonists, with the exception of terazosin at 300 microg kg(-1), to be uroselective in the rat (selectivity ratios = 0.2-1.5); potentiation of tilt-induced hypotension in the anesthetized rat showed substantial differences from the rabbit, with Rec 15/2739, but not Rec 15/3011 and Rec 15/2841 showing orthostatic effects equivalent to that observed for prazosin. Hence, Rec 15/2739 was uroselective in the rabbit, but not in the rat, while two of its close structural analogs were highly uroselective in both species. An assay for orthostatic activity in the conscious rat yielded different results, showing prazosin and terazosin, but not Rec 15/2739, to cause a reversal of the pressor response to tilt. Hence, the apparent uroselectivity of an alpha1-adrenoceptor antagonist is both species- and assay-dependent.     

Cardiovascular effects of the selective alphalA-adrenoceptor antagonist silodosin (KMD-3213), a drug for the treatment of voiding dysfunction

The aim of this study was to assess the cardiovascular effects of silodosin (CAS 160970-54-7, (-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyllamino)propyll-2,3-dihy-dro-1H-indole-7-carboxamide, KMD-3213), a potent selective alpha1A-adrenoceptor (AR) antagonist used for the treatment of dysuria. In conscious dogs, orally administered silodosin, at doses (0.2, 2 and 20 mg/kg) considerably higher than the pharmacologically effective dose, decreased blood pressure. These doses, however, had no effects on heart rate or on the electrocardiogram (PR interval, QRS interval, QT interval or QTc). In addition, the cardiac effects of silodosin were evaluated in an in vitro electrophysiological study. Silodosin inhibited the human ether-a-go-go-related gene (HERG) tail current, leaving a residual tail current of 45 % control at 10 micromol/L. However, the concentration that inhibited the HERG tail current was considerably higher than its affinity for alphal-ARs. These results suggest that while the alpha1B-AR subtype is mainly involved in the regulation of blood pressure, the alphalA-AR subtype is not. There seems to exist no evidence of a correlation between the function of alphal-AR and ECG changes reflecting inhibition of the HERG current. The cardiovascular profile of silodosin suggests therefore that it is a safe and well-tolerated drug.     

Silodosin, a novel selective alpha 1A-adrenoceptor selective antagonist for the treatment of benign prostatic hyperplasia

Silodosin is a novel selective alpha(1A)-adrenoceptor (AR) antagonist generated by Kissei Pharmaceutical Co. Ltd. This drug selectively binds to alpha(1A)-AR, which is widely distributed in the prostate, urethra and bladder trigone, involved in their contraction, located at the lower urinary tract. This high selectivity for alpha(1A)-AR contributes to inhibition of sympathetic nerve stimulation and relaxation of smooth muscle tone of the lower urinary tract tissues, resulting in suppression of increase in intraurethral pressure. Clinical data suggested that silodosin showed significant improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia, as well as in quality of life. The improvements were observed in both voiding and storage symptoms. In addition, the clinical effects occurred in the early treatment phase, and were observed not only in mild cases, but also in cases with severe symptoms. Long-term study revealed that the efficacy and safety was sustained for 1 year. Although silodosin showed relatively high incidence rate of abnormal ejaculation, the adverse events associated with lowering of blood pressure were low. This article reviews preclinical and clinical data of silodosin, and introduces the usefulness of the drug for treatment of benign prostatic hyperplasia patients.     

Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: I. Effects on blood pressure, heart rate and pressor responsiveness in normotensive subjects.

1. Abanoquil (UK 52,046) is a novel, quinoline-derivative, alpha 1-adrenoceptor antagonist which, on the basis of animal studies, possesses antiarrhythmic activity at doses which have little or no effect on blood pressure. 2. In two placebo-controlled, double-blind, crossover studies the alpha 1-adrenoceptor antagonist activity (phenylephrine pressor responses) and the effects on blood pressure and heart rate (in the presence and absence of concomitant beta-adrenoceptor blockade) have been investigated in healthy, normotensive subjects following the intravenous administration (i.v.) of abanoquil. 3. In the first study, abanoquil at a dose of 0.4 micrograms kg-1 i.v. (as a bolus or by increments) produced significant alpha 1-adrenoceptor antagonism (with rightward shifts of more than two-fold in the phenylephrine pressor dose-response curves) but no significant effects on supine or erect blood pressure and heart rate. 4. In the second study, a dose of 0.5 micrograms kg-1 i.v. had no significant effect on supine or erect blood pressure but pre-treatment with atenolol promoted a small fall in erect blood pressure without causing significant orthostatic hypotension. 5. In conclusion, significant alpha 1-adrenoceptor antagonism without marked reflex tachycardia or profound postural hypotension suggest that abanoquil has a different haemodynamic profile from that of 'classical' peripheral alpha 1-adrenoceptor antagonists.     

The effects of SB 216469, an antagonist which discriminates between the alpha 1A-adrenoceptor and the human prostatic alpha 1-adrenoceptor.

1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the alpha 1A-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha 1B-adrenoceptors of the rat spleen and liver (7.7-8.2). 3. At cloned rat alpha 1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha 1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha 1a-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha 1b-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha 1d-adrenoceptor (8.7-9.2). 4. At functional alpha 1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the alpha 1A-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the alpha 1B-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha 1D-adrenoceptors of the rat aorta (8.8). 5. Several recent studies have concluded that the alpha 1-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha 1A-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic alpha 1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha 1a-adrenoceptors (human, rat, bovine) or the native alpha 1A-adrenoceptors in radioligand binding and functional studies in the rat. 6. Our results with SB 216469, therefore, suggest that the alpha 1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha 1a-adrenoceptor or native alpha 1A-adrenoceptor. Since it has previously been shown that the receptor is not the alpha 1B- or alpha 1D-adrenoceptor, the functional alpha 1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the alpha 1-adrenoceptors currently defined by pharmacological means.     

Hypotensive effects of carvacrol on the blood pressure of normotensive rats

Carvacrol is the major compound of essential oils of many plants, ethnomedically used for centuries but there were no detailed investigations on its action on the cardiovascular system. The aim of our study was to investigate the role of carvacrol on the cardiovascular functions of anesthetized rats and in vitro of isolated rat aorta. Carvacrol (100 microg/kg, I. P.) decreased heart rate, mean arterial pressure and systolic and diastolic blood pressures of the anesthetized rats whereas there were no effects at 1, 10 and 20 microg/kg. Carvacrol was observed to exhibit hypotension and to inhibit N((omega))-nitro- L-arginine methyl ester ( L-NAME)-induced hypertension. The lack of inhibitory action of carvacrol (10 (-4) M) on the CaCl (2)- and phenylephrine-induced contractions of isolated rat aorta showed that neither adrenergic receptors nor voltage-dependent vascular L-type calcium channels were involved. But, based on previous investigations, the involvement of cardiac L-type calcium channel blocking actions are suggested for the hypotensive actions of carvacrol was assumed.     

Differential response to chloroethylclonidine in blood vessels of normotensive and spontaneously hypertensive rats: role of alpha 1D- and alpha 1A-adrenoceptors in contraction

The effects of chloroethylclonidine on alpha(1)-adrenoceptor-mediated contraction in endothelium-denuded caudal arteries and aorta from normotensive Wistar and Wistar Kyoto (WKY), and from spontaneously hypertensive (SHR) rats were evaluated. Chloroethylclonidine elicited concentration-dependent contractions. Maximal contraction was similar in caudal arteries among strains ( approximately 40% of noradrenaline effect). However, chloroethylclonidine elicited a higher contraction in aorta from SHR than from normotensive rats. In Wistar aorta chloroethylclonidine produced the smallest contractile response. In SHR aorta, BMY 7378 and 5-methylurapidil blocked chloroethylclonidine-elicited contraction, while (+)-cyclazocine did not inhibit it; while in caudal arteries, 5-methylurapidil blocked chloroethylclonidine action; the other antagonists had no effect. In chloroethylclonidine-treated aorta noradrenaline elicited biphasic contraction-response curves, indicating a high affinity (pD(2), 8.5 - 7.5) chloroethylclonidine-sensitive component and a low affinity (pD(2), 6.3 - 5.2) chloroethylclonidine-insensitive component. The high affinity component was blocked by chloroethylclonidine; while in caudal arteries noradrenaline elicited monophasic contraction-response curves with pD(2) values (6.5 - 5.7) similar to the low affinity component in aorta. Chloroethylclonidine inhibition of noradrenaline response was greater in aorta than in caudal arteries. Chloroethylclonidine increased the EC(50) values of noradrenaline approximately 1000 fold in aorta and approximately 10 fold in caudal arteries. In SHR aorta BMY 7378 protected alpha(1D)-adrenoceptors and in caudal arteries 5-methylurapidil protected alpha(1A)-adrenoceptors from chloroethylclonidine alkylation, allowing noradrenaline to elicit contraction. These results show marked strain-dependent differences in the ability of chloroethylclonidine to contract aorta; moreover, chloroethylclonidine stimulates alpha(1D)-adrenoceptors in aorta and alpha(1A)-adrenoceptors in caudal arteries. The higher contraction observed in aorta from SHR and WKY suggests an augmented number of alpha(1D)-adrenoceptors in these strains.     

Tissue distribution of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist, in pigmented rats.

After a single oral administration of 1 mg/kg of 14C-NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), the radioactivity distribution in tissues of male pigmented rats was studied and compared with that in male albino rats. One eye of each pigmented rat was divided into melanin-containing structures (uvea, pigmented epithelium and sclera) and others without melanin (cornea and lens), and the radioactivity concentration in each ocular tissue was measured. In all the pigmented rat body tissues tested, maximum radioactivity concentrations (Cmax) were reached within 4 h after administration. At 1 h, the kidney showed the highest concentration (11 times the plasma concentration), followed by the urethra, liver, urinary bladder and lung. Concentrations in the other tissues were similar to or less than the plasma concentration. The radioactivity concentrations in most tissues decreased rapidly, being less than 10% of the Cmax 24 h after administration. These characteristics of the 14C-NS-49 tissue distribution in the pigmented and albino rats did not differ. In the eye, however, the radioactivity concentration decreased more slowly in the pigmented than in the albino rats. Most of the radioactivity in the eyes of the pigmented rats was present in melanin-containing structures indicating that NS-49 binds to ocular melanin. The radioactivity concentration in the melanin-containing structures reached a maximum 4 h after administration, then decreased as did that for the whole eye with a t1/2, beta of 66.8 h.     

Effect of single oral administration of YM598, a novel selective endothelin ETA receptor antagonist, on blood pressure in normotensive and hypertensive rats

We investigated the effect of YM598, a selective endothelin ETA receptor antagonist, on blood pressure (BP) in normotensive rats (NTR), spontaneously hypertensive rats (SHR) and Dahl salt-sensitive hypertensive rats (Dahl-SS). We also examined the concomitant effect of YM598 with the L-type Ca2+ channel antagonist nifedipine on BP. Single oral administration of YM598 did not affect BP in NTR and SHR. In Dahl-SS, in contrast, YM598 slightly, but not significantly, reduced BP. Concomitant administration of YM598 with nifedipine at doses inducing slight hypotension on respective single administrations resulted in a stronger hypotensive effect than single administration of either compound alone. However, the magnitude of the concomitant hypotensive effect demonstrated only a simple additive effect of the two compounds. These results indicate that YM598 did cause slight hypotensive effects in some types of hypertension. These results also indicate the possibility of additive, but not synergic, hypotensive effects on concomitant administration of ET receptor antagonist and an L-type Ca2+ channel antagonist.     

The alpha1A-adrenoceptor gene is required for the alpha1L-adrenoceptor-mediated response in isolated preparations of the mouse prostate

Background and purpose:This study investigated whether deletion of the alpha(1A)-adrenoceptor gene influences contractile responses of mouse prostate to noradrenaline. Responses of mouse prostate to noradrenaline are known to be mediated by alpha(1L)-adrenoceptors, which are thought to be a functional phenotype of alpha(1A)-adrenoceptor.Experimental approach:Prostate tissues from alpha(1A)-adrenoceptor knockout mice which were homozygous (alpha(1A)-/-) and heterozygous (alpha(1A)+/-) for the disrupted alpha(1A)-adrenoceptor gene, as well as wild-type (alpha(1A)+/+) littermates were mounted in glass-isolated organ baths. Electrical field stimulation of nerves and exogenous application of noradrenaline were used to investigate the effects of alpha(1A)-adrenoceptor disruption on prostate contractility.Key results:Frequency-response curves to electrical field stimulation (0.5 ms pulse duration, 60 V, 0.1-20 Hz) yielded frequency-dependent contractions. At frequencies of 10 and 20 Hz, prostates from alpha(1A)-/- mice elicited an approximately 30% decreased response compared with prostates from alpha(1A)+/+ mice. Prazosin (0.3 muM) attenuated responses to electrical field stimulation in prostates from alpha(1A)+/+ and alpha(1A)+/- mice but not from alpha(1A)-/- mice. Increasing concentrations of exogenously administered noradrenaline (10 nM-1 mM) produced mean concentration-response curves in prostates from alpha(1A)+/+ and alpha(1A)+/- mice, which were not different. Maximum responses to noradrenaline were decreased by approximately 80% in prostates from alpha(1A)-/- mice compared with alpha(1A)+/+ mice. Prazosin attenuated responses to noradrenaline in all genotypes.Conclusions and implications:alpha(1L)-Adrenoceptor-mediated responses in mouse prostate are abolished in alpha(1A)-/- mice, demonstrating that the alpha(1A)-adrenoceptor gene is essential to the manifestation of the prostatic alpha(1L)-adrenoceptor phenotype. This implies that alpha(1L)-adrenoceptors are indeed a functional phenotype of alpha(1A)-adrenoceptor.British Journal of Pharmacology (2008) 155, 103-109; doi:10.1038/bjp.2008.245; published online 16 June 2008.     

Effects of phentolamine,dihydroergocristine and isoxsuprine on the blood pressure and heart rate in normotensive,hypotensive and hypertensive rats

Summary Phentolamine, dihydroergocristine and isoxsuprine were compared for their effects on the blood pressure in anaesthetized normotensive rats, in rats made hypotensive by ganglionic blockade or by pithing and in rats with noradrenaline-induced hypertension. Their ability to inhibit pressor responses elicited by electrical stimulation of the posterior hypothalamus and of the sympathetic outflow from the spinal cord was also investigated.All three drugs appeared very potent in inhibiting noradrenaline-induced hypertension and caused a dose-dependent fall in blood pressure in normotensive rats, which however was less pronounced with dihydroergocristine than with phentolamine and isoxsuprine. In hypotensive rats, dihydroergocristine caused a rise in blood pressure.At higher doses than those required to block noradrenaline-induced hypertension, the three drugs inhibited pressor responses elicited by electrical stimulation and were equally active on peripherally- and centrally-evoked responses.Simultaneous recording of heart rate and blood pressure, both in anaesthetized and in pithed rats, indicated a reflex origin for phentolamine-induced tachycardia and a direct cardiac stimulation for isoxsuprine. Reflex changes of heart rate were not observed with dihydroergocristine.     

Haemodynamic effects of dicentrine, a novel alpha 1-adrenoceptor antagonist: comparison with prazosin in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. The haemodynamic effects of dicentrine, an aporphine derivative isolated from the plant Lindera megaphylla, were investigated and compared with prazosin in rats. 2. In anaesthetized normotensive Wistar-Kyoto (WKY) rats, i.v. administration of dicentrine (0.1, 0.5, 1.0 mg kg-1) and prazosin (0.01, 0.05, 0.1 mg kg-1) induced a dose-related reduction of mean arterial pressure (MAP) which reached a maximal effect 5-10 min after injection and persisted for 2 h. 3. In anaesthetized WKY rats, a higher dose of dicentrine (1.0 mg kg-1, i.v.) did not cause any significant changes in heart rate (HR), cardiac output (CO) and stroke volume (SV) but markedly increased tail blood flow. In contrast, a higher dose of prazosin (0.1 mg kg-1, i.v.) produced a decrease in HR which paralleled the time course of the hypotensive response. 4. The hypotensive activity of dicentrine was completely abolished by alpha-adrenoceptor blockade. Both dicentrine and prazosin significantly attenuated pressor responses to noradrenaline but failed, even at maximal hypotensive doses, to impair the pressor effects of angiotensin II or vasopressin. These observations suggest that dicentrine appears to exert its hypotensive action through alpha 1-adrenoceptor blockade. 5. In conscious normotensive and spontaneously hypertensive (SH) rats, dicentrine (0.5-2.0 mg kg-1, i.v.) and prazosin (0.05-0.2 mg kg-1, i.v.) also evoked dose-related decreases in MAP which were of greater magnitude in SH rats. Oral administration of dicentrine (5 and 8 mg kg-1) to conscious SH rats caused a hypotensive effect which persisted for over 15 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist

L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(?3-[4-(2-pyridin yl)-1-piperidinyl]propyl?amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.