Duration of action and effect on baroreflex function of the anti-arrhythmic alpha 1 antagonist UK-52,046.

The effects of acute and chronic oral administration of UK-52,046 (25 micrograms kg-1) on baroreflex function and its duration of action, were studied in conscious dogs. It was found that UK-52,046 had no effect on blood pressure and heart rate following acute and chronic administration. UK-52,046 shifted the phenylephrine dose response curve to the right, and the PE50 (measure of alpha 1-adrenoceptor antagonism) was increased (P less than 0.05) compared to placebo on day 1 (2, 4, 8 and 24 h) and day 8 (2, 4, 8 and 12 h). The antagonism was increased (P less than 0.05) on day 8 (0, 8 and 12 h) compared with day 1. Evaluation of the effects of UK-52,046 on baroreflex function using phenylephrine to increase blood pressure indicated no significant difference from placebo. It was concluded that at an antiarrhythmic dose, UK-52,046 has no effect on blood pressure, heart rate or baroreflex function. The pressor response curve was shifted to the right indicating a duration of action of at least 12 h on chronic oral administration.     

Dose-dependent alpha 1-adrenoceptor antagonist activity of the anti-arrhythmic drug, abanoquil (UK-52,046), without reduction in blood pressure in man.

1. The dose-dependency of the alpha 1-adrenoceptor antagonist activity of the anti-arrhythmic abanoquil (UK-52,046) was investigated in 10 healthy male subjects who received serially increasing infusions of phenylephrine before and 2, 4, 8, 12, 24 and 48 h after single oral doses of abanoquil 0.25, 0.5 and 1 mg and placebo in a double-blind randomised manner. 2. The doses of phenylephrine required to increase systolic BP by 20 mm Hg (PS20) were calculated using a quadratic fit to the individual dose-response curves. 3. Abanoquil 0.25, 0.5 and 1 mg increased the PS20 in a dose-dependent manner with effects which were maximal at 2 to 8 h and lasted for 24 to 48 h (P less than 0.05). Maximal dose ratios were: abanoquil 0.25 mg 2.0 +/- 0.9, 0.5 mg 2.4 +/- 1.3, 1 mg 3.4 +/- 1.1. 4. No change occurred in supine BP but a small increase (P less than 0.01) occurred in supine HR 8 h post-dosing (64 +/- 9, 58 +/- 6 beats min-1 for abanoquil 1 mg and placebo respectively). 5. Therefore abanoquil 0.25, 0.5 and 1 mg showed dose-dependent alpha 1-adrenoceptor antagonist activity with no effect on supine BP.     

An acute study of the electrophysiological and haemodynamic effects of intravenous UK-52,046, a novel alpha 1-adrenoceptor antagonist.

The acute electrophysiological and haemodynamic effects of UK-52,046, a novel alpha 1-adrenoceptor antagonist (0.5 microgram kg-1) were studied in 10 patients. Resting and paced conduction intervals, refractory periods, Wenckebach cycle length and sinus node recovery time were measured and compared with baseline values. Haemodynamic measurements including cardiac output were measured before and after drug administration. Changes in QRS interval (83 to 105 ms) and QRS duration during sinus rhythm (83 to 105 ms) or during constant atrial pacing (85 to 109 ms), were not significant (P greater than 0.05). Myocardial refractoriness and sinus node recovery time were not altered by the drug. Slight increases in mean heart rate (72.5 to 78.8 beats min-1), mean right atrial pressure (4.5 to 5.5 mm Hg) and mean cardiac output (5.4 l min-1 to 5.7 l min-1), were not significant (P greater than 0.05). Systolic and diastolic arterial pressure, cardiac work indices, and vascular resistance remained unchanged. These results demonstrate the safety of this drug given intravenously in a non-ischaemic setting, and warrant its further investigation as an antiarrhythmic agent in myocardial ischaemia.     

UK-52,046 (a novel alpha 1-adrenoceptor antagonist) and the role of alpha-adrenoceptor stimulation and blockade on atrioventricular conduction.

The effects of increasing intravenous (i.v.) doses of prazosin, phenylephrine, flecainide, and UK-52,046 on blood pressure (BP), heart rate (HR) and the specialized conduction system (AH and HV intervals) were investigated in anaesthetized dogs. Results indicated that UK-52,046 (1-8 micrograms/kg) had no effect on BP or HR, but reduced (p less than 0.05) BP at doses of 16 and 32 micrograms/kg; no change occurred in HR. During sinus rhythm (SR) the AH or HV intervals did not change as compared with placebo; on pacing (PA) UK-52,046 (4-16 micrograms/kg) decreased the AH interval. After prazosin BP decreased (p less than 0.05) after 20-40 micrograms/kg; HR increased after all doses (5-40 micrograms/kg). The HV interval was unaltered, but the AH interval decreased after 40 micrograms/kg during SR and PA. After phenylephrine (continuous infusion, 50 micrograms/ml/min) BP increased at 33 min and HR was decreased at 23 and 33 min. The AH interval lengthened during PA (p less than 0.05), but there was no effect on the HV interval. Administration of flecainide (0.5-2.0 mg/kg) had no effect on BP or HR but increased the HV interval during SR and PA (1 and 2 mg/kg, p less than 0.05). The results indicate that the alpha 1-adrenoceptor agonist phenylephrine and the alpha 1-adrenoceptor antagonist prazosin, on PA altered the AH (but not the HV) intervals in opposite directions in association with changes in HR and BP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Doxazosin, an alpha 1-adrenoceptor antagonist: pharmacokinetics and concentration-effect relationships in man.

The effects of single doses of doxazosin, a quinazoline derivative similar to prazosin, were studied in six normotensive volunteers. Both 1 mg (i.v.) or 2 mg (oral) doxazosin caused a fall in blood pressure which was most apparent in the erect posture at 5-6 h following drug administration. The maximum fall in blood pressure following i.v. doxazosin was from 123/81 to 106/69 mm Hg associated with a rise in heart rate from 81 to 107 beats/min. The terminal elimination half-life following oral and intravenous doxazosin was about 9 h. Pressor responsiveness to the alpha 1-adrenoceptor agonist, phenylephrine, showed no significant difference between oral and i.v. doxazosin suggesting that the route of administration did not influence alpha 1-adrenoceptor antagonism at the doses used. Using a pharmacodynamic modelling technique in individual subjects, there was a significant correlation between the change in doxazosin concentration in the effect compartment and its hypotensive effect. With the modelling technique it was possible to show a significant correlation between the pressor responsiveness to the alpha 1-adrenoceptor agonist phenylephrine and the concentration of doxazosin in the effect compartment. This is consistent with the concept that the hypotensive effect of doxazosin is mediated by alpha 1-adrenoceptor blockade.     

Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration-effect relationships in normotensive subjects.

1. This study further examines the quinoline-derivative abanoquil with particular respect to the duration of its alpha 1-adrenoceptor antagonist activity and its concentration-effect relationship following a single intravenous bolus dose of 0.5 micrograms kg-1 in young, normotensive males. 2. alpha 1-adrenoceptor antagonism (as assessed by phenylephrine pressor responses) was detectable for up to 12 h post dosing: at 12 h there was a significant 1.5-fold rightward shift (95% CI: 2.2 to 1.1) of the pressor dose-response curve for diastolic blood pressure. 3. Despite evidence of substantial alpha 1-adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate. 4. The degree of alpha 1-adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD-ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P less than 0.05) and r = 0.78 for diastolic blood pressure (P less than 0.005). 5. In conclusion, abanoquil produced significant alpha 1-adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.     

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.     

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.     

Effects of the myocardial-selective alpha 1-adrenoceptor antagonist UK-52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs.

1. Adrenaline-induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK-52046, 3.8 +/- 1.4 micrograms kg-1 (mean +/- s.e.mean), atenolol 14.6 +/- 2.1 micrograms kg-1, or a combination containing equal amounts of the two drugs of 0.36 +/- 0.1 microgram kg-1. The pressor response to adrenaline was reduced (P less than 0.01) by UK-52046 but not by atenolol or the combination of both drugs. 2. In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK-52046, 32 micrograms kg-1, increased the number of sinus beats in each 5 min period from 137 +/- 47 to 662 +/- 99 (P less than 0.01); this was associated with a significant (P less than 0.01) fall in blood pressure. Atenolol in doses of up to 800 micrograms kg-1 had no effect. 3. UK-52046, 3.7 +/- 1.4 micrograms kg-1, prevented adrenaline-induced arrhythmias 3-4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100 micrograms kg-1 produced an 84.4 +/- 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 +/- 1.1 micrograms kg-1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P less than 0.05) by UK-52046, but resting blood pressure was unaffected by the different treatments. An increase (P less than 0.01) in heart rate was associated with both UK-52046 and the combination. 4. Neither UK-52046 (doses up to 64 micrograms kg-1) nor atenolol (up to 800 micrograms kg-1) had any effect upon ouabain-induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5. In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30 min of CAL was not reduced by 4 micrograms kg-1 UK-52046 but fell (P less than 0.01 compared with placebo) after 8 micrograms kg-1 [median values with ranges for placebo, 4 micrograms kg-1 and 8 micrograms kg-1 respectively 190 (4-674), 246 (9-1204) and 12 (1-154)]. Both doses of UK-52046 were associated with significant falls in blood pressure. 6. The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7-30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK-52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29).(ABSTRACT TRUNCATED AT 400 WORDS)     

The alpha (1D)-adrenoceptor antagonist BMY 7378 is also an alpha (2C)-adrenoceptor antagonist

1 We have investigated the actions of the alpha(1D)-adrenoceptor selective antagonist BMY 7378 in comparison with yohimbine at alpha(1)- and alpha(2)-adrenoceptors. 2 In rat aorta (alpha(1D)-adrenoceptor), BMY 7378 (pA(2) of 8.67) was about 100 times more potent than yohimbine (pA(2) of 6.62) at antagonizing the contractile response to noradrenaline. 3 In human saphenous vein (alpha(2C)-adrenoceptor), BMY 7378 (pA(2) of 6.48) was approximately 10 times less potent than yohimbine (pA(2) of 7.56) at antagonizing the contractile response to noradrenaline. 4 In prostatic portions of rat vas deferens, BMY 7378 (10 mum) did not significantly affect the concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions by xylazine (an action at prejunctional alpha(2D)-adrenoceptors). 5 In ligand-binding studies, BMY 7378 showed 10-fold selectivity for alpha(2C)-adrenoceptors (pK(i) of 6.54) over other alpha(2)-adrenoceptors. 6 It is concluded that BMY 7378, in addition to alpha(1D)-adrenoceptor selectivity in terms of alpha(1)-adrenoceptors, shows selectivity for alpha(2C)-adrenoceptors in terms of alpha(2)-adrenoceptors.     

Cirazoline, an alpha 2-adrenoceptor antagonist in guinea-pig ileum

Prejunctional effects of cirazoline have been investigated in guinea pig ileum. At high concentrations cirazoline has been shown to have antimuscarinic activity, pA2 5.25 +/- 0.29. At concentrations below those producing blockade of acetylcholine, cirazoline blocks the prejunctional alpha 2-adrenoceptor activity of clonidine, pA2 6.81 +/- 0.22, and alpha-methylnoradrenaline. Results are discussed in the light of controversial evidence for the activity of cirazoline on alpha-adrenoceptors.     

Baroreceptor function in man following peripheral alpha1- and alpha2-adrenoceptor stimulation

Summary Methoxamine and α-methyl-noradrenaline were administered to six healthy male subjects on separate days as rapid bolus injections until blood pressure increased by approximately 30 mmHg; Valsalva's Manoeuvre was carried out on each occasion. Propranolol (80 mg) or placebo was administered (random order, double-blind, weekly intervals) and the observations were repeated after 2 h. Baroreceptor sensitivity (ΔR-R interval ms/mmHg systolic BP) was less (p<0.05) with α-methyl-noradrenaline than methoxamine. Propranolol abolished the differences in baroreceptor-mediated bradycardia following α-methyl-noradrenaline and methoxamine, and shifted the baroreceptor sensitivity regression lines (p<0.05) to the left. During the release phase of Valsalva's Manoeuvre baroreceptor sensitivity was increased following propranolol. The smaller baroreceptor-mediated bradycardia response observed with α-methyl-noradrenaline does not support the hypothesis that pre-synaptic α-adrenoceptors have a physiological role in the modulation of baroreceptor function in man, and may be due to α-methyl-noradrenaline having β₁-agonist activity.     

Effect of JTH-601, a novel alpha1-adrenoceptor antagonist, on the function of lower urinary tract and blood pressure.

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 novel alpha1-adrenoceptor antagonist, in vitro and in vivo. JTH-601 (10(-9)-3 x 10(-8) M) competitively antagonized phenylephrine-induced contraction in lower urinary tract tissues (prostate, urethra and bladder trigon) in a concentration-dependent manner. The mean pA2 values for JTH-601 were 8.59+/-0.14, 8.74+/-0.09 and 8.77+/-0.11 for prostate, urethra and bladder trigon, respectively. In anesthetized rabbits, intraduodenal administration of JTH-601 (0.3-3 mg/kg), prazosin (0.03-0.3 mg/kg) and tamsulosin (0.03-0.3 mg/kg) dose dependently inhibited the phenylephrine-induced increase in urethral pressure for 3 h. Although these drugs also decreased mean blood pressure, JTH-601 was less potent than prazosin or tamsulosin. In conscious rabbits, administered JTH-601 (0.01-1 mg/kg, i.v.) had a tendency to augment orthostatic hypotension, but dose dependency was not evident. Prazosin (0.01-1 mg/kg) and tamsulosin (0.001-1 mg/kg) dose dependently augmented orthostatic hypotension. These results indicate that JTH-601 antagonized alpha1-adrenoceptor-mediated contractile responses more potently than prazosin or tamsulosin in rabbit lower urinary tract both in vitro and in vivo. JTH-601 is therefore expected to be effective in the treatment of urinary outlet obstruction in benign prostatic hypertrophy.     

Effect of a new alpha 2-adrenoceptor antagonist on poststenotic coronary resistance and myocardial function

The effect of the alpha 2-adrenoceptor antagonist 4-fluoro-2-(imidazoline-2-ylamino)-isoindoline maleate (BDF 8933) on poststenotic end-diastolic distal coronary resistance and poststenotic myocardial function (sonomicrometry) was investigated under control conditions and during cardiac sympathetic nerve stimulation (CSNS = electrical stimulation of the left ventrolateral cervical cardiac nerve). In 7 vagotomized, open-chest dogs end-diastolic distal coronary resistance was determined. This variable was essentially unchanged after administration of the agent. In additional 6 dogs regional myocardial function was measured as systolic wall thickening (SWT). CSNS increased SWT of the posterior circumflex-perfused myocardium from 12.7 +/- 4.6% to 21.9 +/- 8.4% (p less than 0.05) under control conditions. With a severe stenosis on the left circumflex coronary artery, SWT was reduced to 5.4 +/- 4.0% and further decreased to 2.1 +/- 5.1% (p less than 0.05) during CSNS. After i.v. injection of 150 micrograms/kg BDF 8933, poststenotic myocardial function at rest was 4.2 +/- 4.2%, and 5.6 +/- 3.6% during CSNS. Regarding to the systemic effects BDF 8933 significantly increased peak left ventricular pressure in all 13 dogs. Thus, the new alpha 2-adrenoceptor antagonist BDF 8933 at the chosen dosage prevents sympathetically induced myocardial ischemia, but increases left ventricular afterload resistance.     

Alfuzosin, a selective alpha 1-adrenoceptor antagonist in the lower urinary tract.

1. Phenylephrine-induced contractions of rabbit isolated trigone and urethra were antagonized in a competitive manner by alfuzosin (pA2 7.44 and 7.30, respectively) and prazosin. 2. The characteristics of [3H]-prazosin binding to human prostatic adenoma tissue were evaluated. [3H]-prazosin was potently displaced by alpha 1-adrenoceptor specific agents including alfuzosin, its (+)- and (-)-enantiomers and prazosin (IC50 0.035, 0.023, 0.019 and 0.004 microM, respectively), but only weakly by alpha 2-adrenoceptor selective agents, for example, yohimbine (IC50 = 6.0 microM). 3. In the pithed rat, alfuzosin (0.03-0.3 mg kg-1, i.v.) markedly inhibited pressor responses produced by the alpha 1-selective agonist, cirazoline but inhibited only slightly responses to the alpha 2-selective agonist, UK 14,304. Alfuzosin (1 mg kg-1, i.v.) had minimal effects against responses mediated by stimulation of prejunctional alpha 2-receptors (UK 14,304-induced inhibition of sympathetic tachycardia). 4. In the anaesthetized cat, alfuzosin (0.001-1 mg kg-1, i.v.) and prazosin (0.001-0.3 mg kg-1, i.v.) produced dose-related inhibition of the increases in urethral pressure caused by stimulation of sympathetic hypogastric nerves. Prazosin was approximately 5 fold more potent than alfuzosin. When phenylephrine was employed to induce urethral and vascular alpha 1-mediated tone simultaneously, prazosin inhibited both stimuli with similar potency whereas alfusozin was 3-5 fold more potent against elevated urethral pressure. This functional uroselectivity of alfuzosin was more evident by the intraduodenal route, since doses of 0.03 and 0.1 mg kg-1 alfuzosin inhibited urethral pressure with minimal effects on arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Haemodynamic dose-response effects of UK-52,046 in ischaemic disease with or without impaired left ventricular function.

1. The haemodynamic effects of a new cardioselective postsynaptic alpha 1-adrenoceptor antagonist UK-52,046, were evaluated in 25 patients with stable coronary disease, with or without impaired left ventricular function. At rest the haemodynamic effects to two dose-response regimens were determined. In an initial eight patients 0.125, 0.125 and 0.25 micrograms kg-1 were administered peripherally at 15 min intervals; the haemodynamic measurements were determined between 10 to 15 min after each dose. In a further 17 patients, the dose regimen was doubled yielding a cumulative dose-regimen of 0.25, 0.5 and 1.0 micrograms kg-1. The exercise effects were determined by comparison of measurements during 4 min of supine sub-maximal bicycle exercise at a fixed workload before and after drug treatment. 2. At rest, the lower dose regimen of UK-52,046 significantly reduced systemic mean arterial blood pressure (-5 mm Hg; P less than 0.05) and increased cardiac index (+0.2 l min-1 m-2, P less than 0.01). The higher dose regimen of UK-52,046 reduced systemic mean arterial blood pressure (-7 mm Hg; P less than 0.01), pulmonary artery occluded pressure (PAOP) (-2 mm Hg, P less than 0.01) and vascular resistance index (-314 dyn s cm-5 m2; P less than 0.05) with an increase in heart rate (+7%, P less than 0.05) and cardiac index (+0.2 l min-1 m-2, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological prospects for alpha 2-adrenoceptor antagonist therapy.

The discovery of various alpha 2-adrenoceptor subtypes in numerous tissues and studies of alpha 2-adrenoceptor-mediated mechanisms has generated considerable interest in their physiological functions. It has also increased possibilities for the design of new pharmacological tools and for the study of the pharmacological impact of new drugs. Alpha 2-adrenoceptors are located pre- and postsynaptically both in the central noradrenergic pathways and on the autonomic nerve endings. It is difficult to dissociate alpha 2-adrenoceptor-mediated autoregulation, involving presynaptic receptors, from actions dependent on post- and extrajunctional alpha 2-adrenoceptor activation. A lot of alpha 2-adrenoceptors are subject to permanent tonic activation by the sympathetic nervous system. Max Lafontan and colleagues review the major actions of alpha 2-adrenoceptors and consider the sites of impact of alpha 2-antagonists that could initiate further research for putative applications of these drugs. Many of the possible targets for alpha 2-adrenoceptor antagonists have not yet been explored clinically.     

The selectivity of DG-5128 as an alpha 2-adrenoceptor antagonist

DG-5128 (2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate) at concentrations up to 10 microM inhibited [3H]clonidine binding more effectively than it did [3H]prazosin binding in rat cerebral cortex membranes. The mode of inhibition was homogeneous and consistent with the law of simple mass action. DG-5128 exhibited a 7.4 times higher affinity (pKi = 6.28) toward alpha 2-adrenoceptors than alpha 1-adrenoceptors. The results indicate that DG-5128 is a preferential alpha 2-antagonist.