Age-related change of the role of alpha1L-adrenoceptor in canine urethral smooth muscle.

To examine age-related alteration of the role of alpha1L-adrenoceptor in the urethra, young non-parous and aged parous female dogs were used. In a functional study, we evaluated phenylephrine-induced contraction and antagonistic effects of JTH-601, a newly synthesized alpha1-adrenoceptor antagonist, and prazosin; in a localization survey using autoradiographic technique, we investigated specific [3H]JTH-601 and [3H]tamsulosin binding. Concentration-response curves were obtained for phenylephrine (pD2 = 5.0-5.3). JTH-601 and prazosin antagonized this contraction with pA2 values of 8.2-8.3 and 8.0-8.1, respectively. Specific binding of both [3H]JTH-601 and [3H]tamsulosin were observed in the bladder neck and proximal section of urethra. There were no significant differences of the pD2, pA2, and radio ligand binding between young non-parous and aged parous dogs.     

Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs

We examined the effect of JTH-601 (3-?N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl?-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system.     

Alpha(1L)-, but not alpha(1H)-, adrenoceptor antagonist prevents allergic bronchoconstriction in guinea pigs in vivo

alpha-Adrenoceptors have been classified into alpha(1)- and alpha(2)-adrenoceptors. Recently, the alpha(1)-adrenoceptors were divided into two subtypes: alpha(1L) with low affinity and alpha(1H) with high affinity for prazosin. Little is known concerning the role of each subtype of alpha(1)-adrenoceptor in asthma. We investigated the effects of specific antagonists of alpha(1)- and alpha(2)-, alpha(1H)-, alpha(1L)-, and alpha(2)-adrenoceptors, namely moxisylyte, prazosin, 3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy) ethyl]-N-methylaminomethyl]-4-methoxy-2, 5, 6-trimethylphenol hemifumarate (JTH-601), and yohimbine, respectively, on antigen-induced airway reactions in guinea pigs. Fifteen minutes after intravenous administration of moxisylyte (0.01, 0.1 or 1 mg/kg), prazosin (0.01, 0.1, 1 or 10 mg/kg), JTH-601 (1, 3, 6 or 10 mg/kg) or yohimbine (0.1 or 1 mg/kg), passively sensitized and artificially ventilated animals received an aerosolized antigen challenge. Bronchial responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)) in non-sensitized animals. JTH-601 and moxisylyte, but not prazosin or yohimbine, dose dependently inhibited antigen-induced bronchoconstriction. None of the tested drugs altered PC(200). JTH-601 significantly reduced leukotriene C(4) levels in bronchoalveolar lavage fluid obtained 5 min after antigen challenge, but prazosin did not. These results indicate that prevention of antigen-induced bronchoconstriction by blockade of alpha-adrenoceptors is due to the inhibition of mediator release via alpha(1L)-adrenoceptor antagonism.     

Ex vivo and in vivo alpha1-adrenoceptor binding characteristics of a novel alpha1L-adrenoceptor antagonist, JTH-601, in rat tissues.

In vitro, ex vivo and in vivo alpha1-adrenoceptor binding of JTH-601 (3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminometh yl]-4-methoxy-2,5,6-trimethyl-phenol hemifumarate), a novel alpha1L-adrenoceptor antagonist, in rat tissues was investigated. JTH-601 competed in a concentration-dependent manner with [3H]prazosin for binding sites in the prostate, submaxillary gland and spleen of rats in vitro, and the inhibitory effect was not largely different among these tissues, as shown by the Ki values of 2-3 nM. At 0.25, 0.5 and 3 h after oral administration of JTH-601 (6.5 micromol/kg) in rats, there was a significant (57, 64 and 28%, respectively) increase in the apparent dissociation constant (Kd) for prostatic [3H]prazosin binding, compared to the control value. The administration of a higher dose (21.8 micromol/kg) of this agent produced greater (67-99%) increases in Kd values for prostatic [3H]prazosin binding at 0.5-12 h later. Similar significant increases in Kd values, as with the prostate, were seen in the submaxillary gland and heart 0.25-12 h after the oral administration of JTH-601 (6.5 and 21.8 micromol/kg), but significant increases in the spleen and cerebral cortex were seen only at 0.25-3 h and 0.5 h, respectively. At 10 min of i.v. injection of [3H]JTH-601 in rats, in vivo specific binding was observed in the prostate, cerebral cortex, submaxillary gland, spleen and heart but not in the aorta. The binding in the prostate, submaxillary gland and heart, but not in the cerebral cortex and spleen, lasted until 120 min. It is concluded that JTH-601 may exert a considerably sustained blockade of alpha1-adrenoceptors in the prostate of rats. This finding may be important in characterizing the therapeutic effect of JTH-601 for bladder outlet obstruction in patients with benign prostatic hyperplasia.     

Effect of JTH-601, a putative alpha(1L)-adrenoceptor antagonist, on guinea pig nasal mucosa vasculature

The existence of alpha(1)-adrenoceptors with low affinity for prazosin, an alpha(1L) subtype, has been proposed in addition to alpha(1)-adrenoceptor subtypes with high affinity for prazosin, i.e. the alpha(1H) group: alpha(1A), alpha(1B) and alpha(1D) subtypes. In the present study, we investigated the effect of JTH-601 (3-(N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminomethyl)-4-methoxy-2,5,6-trimethylphenol hemifumarate), a putative alpha(1L)-adrenoceptor antagonist, on the isolated guinea pig nasal mucosa vasculature. JTH-601 (0.01-0.03 microM) competitively antagonized the noradrenaline-induced contraction of the tissue in a concentration-dependent manner. The pA(2) value for JTH-601 was 8.14 +/- 0.04 (means +/- SEM, n = 6). The data suggests that the alpha(1L)-subtype is involved in the noradrenaline-induced contraction of the guinea pig nasal mucosa vasculature.     

Disposition and alpha(1)-adrenoceptor binding characteristics of JTH-601 and its metabolites in rat tissues.

The present study was performed to characterize the disposition and alpha(1)-adrenoceptor binding of JTH-601, a novel alpha(1L)-adrenoceptor antagonist, and its metabolites (beta-D-glucopyranosyl uronic acid, JTH-601-G1; hydrogen sulfate, JTH-601-S1) in the rat prostate and other tissues. JTH-601, JTH-601-G1, and JTH-601-S1 inhibited competitively specific [(3)H]tamsulosin binding in the prostate, submaxillary gland, and spleen of rats in vitro, and the inhibitory effect of JTH-601 was 2. 5 to 6.4 times more potent than that of its metabolites. JTH-601 and its metabolites inhibited dose dependently in vivo specific [(3)H]tamsulosin binding in the particulate fraction of the prostate, aorta, submaxillary gland, and spleen of rats. Compared with that of JTH-601, the in vivo inhibitory effect of JTH-601-G1 was 1.9 to 2. 9 times more potent, and the effect of JTH-601-S1 was 1.3 to 3.2 times less potent. Based on the ratios of ID(50) values, JTH-601 and JTH-601-G1 appeared to be 4.0 to 6.9 times more selective than prazosin as far as the alpha(1)-adrenoceptors in the prostate and submaxillary gland versus the spleen or aorta were concerned. The total radioactivity in rat tissues after i.v. injection of [(3)H]JTH-601-G1 was considerably lower than that of [(3)H]JTH-601. The plasma concentration of [(3)H]JTH-601-G1 at 10 min after i.v. injection in rats was 3 times higher than that of [(3)H]JTH-601, and conversely, the concentration in the prostate was 3 times lower. Although in vivo [(3)H]JTH-601-G1 binding at 10 min was significantly lower than that of [(3)H]JTH-601 in most rat tissues, there was comparable binding between these radioligands in the prostate and vas deferens. Specific binding of [(3)H]JTH-601, at 60 min after i.v. injection compared with that at 10 min, was considerably reduced in rat tissues except the prostate and vas deferens, both of which showed relatively sustained binding. In conclusion, the present study has shown that JTH-601 and its metabolites bind to alpha(1)-adrenoceptors in rat tissues in vivo and that JTH-601-G1 retains the prostatic alpha(1)-adrenoceptor subtype selectivity of its parent compound.     

Effects of KMD-3213, a uroselective alpha 1A-adrenoceptor antagonist,on the tilt-induced blood pressure response in normotensive rats

KMD-3213 ((-)-1-(3-hydroxypropyl)-5-((2R)-2-[[2-([2-[(2,2,2-trifluoroethyl)oxy]phenyl]oxy)ethyl]amino]propyl)-2,3-dihydro-1H-indole-7-carboxamide), an alpha(1A)-adrenoceptor antagonist with potency similar to that of tamsulosin, is under development for the treatment of bladder outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we investigated the effects of KMD-3213 on the tilt-induced blood pressure response in anesthetized normotensive rats. Male normotensive Sprague-Dawley rats were placed in the supine position on a board under cocktail anesthetization (alpha-chloralose, urethane and sodium pentobarbital). The arterial blood pressure was measured from the carotid artery. The animals were given consistent 45 degrees head-up tilt from the horizontal position, following the transient decrease in the blood pressure, and then recovery of the blood pressure to the normal level. Significant orthostatic hypotension was seen with intravenous administration of both prazosin and tamsulosin at doses over 3 micro g/kg, and these drugs completely blocked the tilt-induced blood pressure responses at 30 micro g/kg. On the other hand, these responses were still retained when KMD-3213 was administered intravenously at a dose up to 75 micro g/kg of KMD-3213. Moreover, KMD-3213 showed the highest uroselectivity of the test drugs. These results indicate that KMD-3213 is not likely to induce orthostatic hypotension and would be a useful compound for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia.     

Distribution of alpha1L-adrenoceptors in canine prostate: characterization by quantitative autoradiography

Our aim was to determine the distribution of alpha1L-adrenoceptors in canine prostate by an autoradiographic technique using [3H]JTH-601 (an alpha1L-adrenoceptor antagonist) and [3H]JTH-601-G1 (an active metabolite of JTH-601). Prostates were removed from three male beagle dogs. Several slices of the specimens were incubated with 5 nM of [3H]JTH-601, [3H]JTH-601-G1 and [3H]tamsulosin (an alpha1A-adrenoceptor antagonist). For macroscopic autoradiography, visualization was performed using an imaging plate and image-analyser. To examine microscopic localization of binding sites, preparations were exposed, developed and fixed. Specific binding of [3H]JTH-601 and [3H]JTH-601-G1 was observed diffusely throughout the entire interstitium on macroscopic autoradiography. Specific binding of [3H]tamsulosin was also recognized although the binding was weaker than that of [3H]JTH-601. On microscopic autoradiograms, the grains of each ligand were mainly distributed on smooth muscle. These results indicate morphologically that specific binding sites of JTH-601 and JTH-601-G1 exist in canine prostate, suggesting the distribution of alpha1L-adrenoceptors in this tissue, in addition to alpha1A-adrenoceptors.     

In vivo experiments for the evaluation of alpha 1-adrenoceptor antagonistic effects of SGB-1534 on canine urethra

The alpha 1-adrenoceptor blocking effects of SGB-1534 on the urethral smooth muscle were compared in in vivo lower urinary tract preparations of anesthetized dogs, with the effects of other alpha 1-adrenoceptor antagonists, prazosin and bunazosin. Hypogastric nerve stimulation and selective administration of phenylephrine to the urethra and bladder through the cannulated right external iliac artery (i.a.) elicited reproducible frequency- and dose-dependent increases in intra-urethral pressure. Intra-bladder pressure was increased by the nerve stimulation but not by i.a. phenylephrine. SGB-1534, prazosin or bunazosin (0.1-10 micrograms/kg i.v.) dose dependently suppressed the urethral contraction evoked by the nerve stimulation and i.a. phenylephrine but did not influence the bladder contraction elicited by nerve stimulation. The alpha 1-adrenoceptor blocking potency of SGB-1534 was approximately 2.3 and 8.1 times greater than that of prazosin and bunazosin, respectively. The results indicate that alpha 1-adrenoceptors may mediate mainly the urethral contraction induced by hypogastric nerve stimulation and i.a. phenylephrine, and that SGB-1534 was more potent alpha 1-adrenoceptor blocking activity than prazosin and bunazosin in the canine urethra.     

Effects of α1-adrenoceptor antagonists on phenylephrine-induced salivary secretion and intraurethral pressure elevation in anesthetized rats

α(1)-Adrenoceptor antagonists are widely used for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Activation of α(1)-adrenoceptors is reported to induce salivary secretion in rats and humans. However, the effects of α(1)-adrenoceptor antagonists on salivary secretion remain unknown. Here, we investigated the effects of the α(1)-adrenoceptor antagonists prazosin, silodosin, tamsulosin and urapidil on phenylephrine-induced salivary secretion and compared the results with the effects on phenylephrine-induced intraurethral pressure (IUP) elevation in anesthetized rats. All antagonists inhibited phenylephrine-induced salivary secretion and IUP elevation in a dose-dependent fashion. Comparison of DR(10) values (the dose required to shift the dose-response curve 10-fold to the right) in both tissues showed that the inhibitory effect of silodosin was significantly more potent in the salivary gland than in the urethra (18-fold), but tamsulosin (2.3-fold), prazosin (1.7-fold) and urapidil (1.1-fold) did not show comparable tissue selectivity. These results suggest that α(1)-adrenoceptor antagonists inhibit not only urethral contraction but also salivary secretion, and that high tissue selectivity for the salivary gland over the urethra as shown by silodosin may contribute to the incidence of dry mouth.     

Heterogeneous effect of leucotriene CysLT1 receptor antagonists on antigen-induced motor and inflammatory responses in guinea-pig airways

1. The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2. In sensitized animals, ovalbumin (0.3 mg kg(-1), i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01-1 micromol kg(-1), i.v.), whereas montelukast (0.01-1 micromol kg(-1), i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3. Ovalbumin (1 mg kg(-1), i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10-30 micromol kg(-1), i.v.), whereas the effect of montelukast (0.1-30 micromol kg(-1), i.v.) was marginal (15-30% inhibition). Neither MEN91507 nor montelukast (30 micromol kg(-1), i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 micromol kg(-1), i.v.) in sensitized animals. 4. It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors.     

Relationship between the functional effect of tamsulosin and its concentration in lower urinary tract tissues in dogs

We investigated the relationship between the pharmacological effect of tamsulosin and its concentrations in plasma and several lower urinary tract (LUT) and arterial tissues in conscious male dogs. Oral administration of tamsulosin (30 and 100 microg/kg) inhibited phenylephrine-induced intraurethral pressure (IUP) elevation. Inhibition peaked at 1, 2 h after dosing and lasted up to 6--8 h. Basal mean blood pressure did not significantly change throughout the observation period. Plasma concentration reached maximum within 0.5 h after dosing, whereas that in LUT tissues (prostate, urethra and bladder) reached maximum at 1, 2 h, and prostatic and urethral concentrations remained higher than those in plasma and arterial tissues at almost all observation points. Prostatic concentrations of tamsulosin at individual time points were 2.2- to 18.0-fold higher than plasma and 3.7- to 12.3-fold higher than mesenteric artery concentrations. Urethral concentrations of tamsulosin were also higher than those in both plasma and mesenteric artery. The prostatic and urethral concentrations of tamsulosin correlated well with its effect on IUP response [r2 = 0.98 (p<0.01) and r2 = 0.99 (p<0.01), respectively]. Our data demonstrate that tamsulosin is selectively retained in LUT tissues compared with plasma and arterial tissues and that its sustained effect on IUP response appears to be related to the prostatic and urethral retention of tamsulosin.     

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ET A receptor antagonist, on the lower urinary tract

We investigated the contractile response of the lower urinary tract to endothelin-1 in vitro (rabbits) and in vivo (dogs). We also assessed the effects of a selective endothelin ET_A receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2, 2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on endothelin-1-induced contractile responses. In the in vitro study, endothelin-1 induced contractile responses in isolated rabbit bladder base, urethra, and prostate tissues. YM598 (10^− 7–10^− 5 M) antagonized these endothelin-1-induced contractile responses without affecting the maximal responses. In the in vivo study, endothelin-1 induced the elevation of non-prostatic urethral pressure as well as prostatic urethral pressure even in the presence of tamsulosin (10 μg/kg, i.v.) in anesthetized male dogs. YM598 (0.1–3 mg/kg, i.v.) inhibited these endothelin-1-induced contractile responses in a dose-dependent fashion. These results suggest that endothelin ET_A receptors play an important role in the lower urinary tract contraction, and that the selective endothelin ET_A receptor antagonist YM598 has ameliorating effects on various urinary dysfunctions, including benign prostatic hyperplasia.     

In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.

It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.     

Intrinsic pressor activity of midaglizole, an alpha-2 adrenoceptor antagonist, in pithed rats

Midaglizole (3 and 30 mg/kg, i.v.) increased blood pressure in pithed rats. The pressor response was not inhibited by intravenous prazosin (0.3 mg/kg), yohimbine (1 mg/kg), ketanserin (1 mg/kg) or diphenhydramine (5 mg/kg). Diltiazem (1 mg/kg) antagonized the hypertension. Idazoxan (10 mg/kg) also increased blood pressure, and the pressor response was inhibited by prazosin, but not by yohimbine. These results suggest that the vascular effect of midaglizole is due to a mechanism different from that of idazoxan.     

Pharmacological properties of naftopidil, a drug for treatment of the bladder outlet obstruction for patients with benign prostatic hyperplasia

Naftopidil, a phenylpiperazine derivative, is a novel alpha 1-adrenoceptor antagonist and is new drug for the bladder outlet obstruction in patients with benign prostatic hyperplasia (BPH). Naftopidil competitively inhibited specific [3H]prazosin binding in prostatic membranes of humans, and its Ki value was 11.6 nM. Using cloned human alpha 1-adrenoceptor subtypes (alpha 1a, alpha 1b and alpha 1d), naftopidil was selective for the alpha 1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha 1a- and alpha 1b-adrenoceptor subtypes, respectively. In anesthetized dogs, naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure. The selectivity of naftopidil for prostatic pressure was more potent than those of tamsulosin and prazosin. In conscious rabbits, the effect of naftopidil on the blood pressure reactions following the tilting was less potent than those of tamsulosin and prazosin. In clinical studies, naftopidil has been demonstrated to be effective in the treatment of bladder outlet obstruction in patients with BPH. In Japan, naftopidil has been already approved for clinical use as a drug for BPH.     

Pharmacological characteristics of inhibitory action of the selective alpha1-antagonist JTH-601 on the positive inotropic effect mediated by alpha1-adrenoceptors in isolated rabbit papillary muscle

Influence of JTH-601 [N-(3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl)-N-methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hemifumarate], a selective alpha1-adrenoceptor antagonist, on alpha1-mediated positive inotropic effect (PIE) was studied in isolated rabbit papillary muscle (1 Hz at 37 degrees C). JTH-601 (0.1-10 microM) shifted the concentration-response curve (CRC) for PIE of phenylephrine mediated by alpha1-adrenoceptor (with timolol at 1 microM) to the right and downward. In the presence of 100 nM WB 4101, an alpha1A antagonist, the shift to the right disappeared and JTH-601 (1-3 microM) shifted CRC for phenylephrine downward. The antagonistic action of JTH-601 was unchanged by 100 nM (+)-niguldipine, another alpha1A antagonist. Following pretreatment with 10 microM chloroethylclonidine, an alpha1B antagonist, the shift of CRC for phenylephrine to the right disappeared and JTH-601 (3-10 microM) shifted CRC downward. Antagonistic action of JTH-601 (3 microM) was unaltered by 100 nM BMY 7378, an alpha1D antagonist. JTH-601 (10 microM) had no effect on beta-mediated PIE of isoproterenol. These results indicate that JTH-601 exerts an inhibitory action on alpha1-mediated PIE through antagonism of alpha1A- and/or alpha1B-adrenoceptors in rabbit ventricular myocardium. As an alpha1 antagonist, JTH-601 is much less potent in rabbit ventricular muscle than in smooth muscle.     

Pharmacological mechanisms in the cardiovascular effects of methamphetamine in conscious squirrel monkeys.

The effects of methamphetamine were studied on cardiovascular function in conscious squirrel monkeys. Methamphetamine (0.1-3.0 mg/kg, IV) produced a dose-dependent increase in blood pressure. Its effects on heart rate were more complex, with lower doses (0.1-0.3 mg/kg) producing increases in heart rate and higher doses (1.0-3.0 mg/kg) producing decreases. To determine the pharmacological mechanisms involved in methamphetamine's effects, a number of drugs were tested as pretreatments to an injection of 0.2 mg/kg methamphetamine. This dose produced the maximal heart rate increase. The alpha 1-antagonist prazosin completely antagonized the effects of methamphetamine on blood pressure, while the nonselective beta-antagonist propranolol and beta 1-selective antagonist atenolol completely antagonized the tachycardiac effect of methamphetamine. The dopaminergic antagonists SCH 23390 and haloperidol antagonized some of the cardiovascular effects of methamphetamine. These results indicate that the pressor and tachycardiac effects of methamphetamine are mediated via alpha 1- and beta 1-adrenoceptor mechanisms, respectively. Dopaminergic mechanisms are also involved in methamphetamine's cardiovascular effects.     

Effect of moxisylyte on the lower urinary tracts (2). Effect on the urethra in anesthetized dogs]

Effect of moxisylyte on the lower urinary tracts was studied with the urethral pressure profile (UPP) and balloon method in anesthetized female dogs. In the UPP, moxisylyte produced relaxation in both the proximal and distal urethras. The relaxation effects of prazosin and bunazosin on the distal urethra was weaker than on the proximal urethra. In the balloon method, moxisylyte, prazosin, bunazosin and phentolamine caused a decrease in urethral pressure dose-dependently. The ID25 values of moxisylyte, prazosin, bunazosin and phentolamine were 23.4, 0.43, 0.76 and 33.1 micrograms/kg, respectively. In the balloon method, moxisylyte noncompetitively antagonized phenylephrine induced contraction of the urethra at high doses, whereas prazosin, bunazosin, phentolamine and yohimbine competitively antagonized phenylephrine induced contraction of the urethra. These results suggest that moxisylyte relaxes both the proximal and distal urethras due to alpha 1-adrenoceptor antagonistic and direct urethral smooth muscle relaxant actions. Therefore, moxisylyte is useful for the therapeutic treatment of micturitional disorder.     

In vivo and in vitro pharmacological studies of a new hypotensive compound (QF0301B) in rat: comparison with prazosin,a known alpha1-adrenoceptor antagonist

In this work, we studied the in vivo and in vitro pharmacological effects of the novel compound QF0301B (2-[2-(N-4-o-methoxyphenyl-N-1-piperazinyl)ethyl]-1-tetralone) and compared with those of prazosin. In anaesthetized normotensive rats, both QF0301B and prazosin (0.1-0.2 mg/kg iv) caused a pronounced and prolonged fall in mean arterial blood pressure accompanied by bradycardia. Neither QF0301B nor prazosin (0.2 mg/kg iv) significantly modified the cardiovascular effects of either 5-hydroxytryptamine (serotonin, 5-HT, 75 microg/kg iv) or the selective alpha(2)-adrenoceptor agonist B-HT 920 (0.2 mg/kg iv), but both markedly inhibited the hypertensive effect of noradrenaline (5 microg/kg iv), a nonselective alpha-adrenergic receptor agonist. In isolated rubbed rat aorta rings, QF0301B and prazosin showed marked alpha(1)-adrenoceptor blocking activity, with pA(2) values of 9.00+/-0.12 and 9.75+/-0.14, respectively. In addition, QF0301B reversed and competitively antagonized the inhibitory action produced by clonidine in electrically stimulated rat vas deferens and inhibited the force and rate of contraction in rat isolated atria (pA(2)=5.91+/-0.43), competitively antagonized the contractile effect of 5-HT in rat aorta (pA(2)=6.75+/-0.06) and in rat stomach fundus (pA(2)=7.13+/-0.48) and the contractions induced by histamine in isolated guinea pig longitudinal ileal muscle (pA(2)=7.40+/-0.40). QF0301B showed noncompetitive low action in 5-HT(3), muscarinic and nicotinic receptors, or as Ca(2+) antagonist. These results indicate that a alpha(1)-adrenoceptor blocking lead has been obtained with a new chemical structure and interesting pharmacological properties, which only alpha(1)-adrenoceptor blocking activity seems to be responsible for its cardiovascular effects.