Alpha-blocking Activity Research Articles

Carvedilol - Clinical Experience in Arrhythmias

The pharmacological profile of carvedilol incorporating beta-adrenoceptor antagonism, weak alpha-blocking activity and slight calcium channel blockade indicates its anti-arrhythmic potential, but there are little data on its efficacy in this regard. Experimental animal studies have demonstrated that the drug reduces the number of premature ventricular contractions during both short-term and prolonged myocardial ischemia. In the relatively few open studies conducted in patients with hypertension, angina pectoris or heart failure complicated by a variety of ventricular arrhythmias, carvedilol improved the arrhythmia profile and significantly decreased the number of premature ventricular contractions. Further studies are need to extend the potential clinical usefulness of carvedilol in the treatment of the sinister ventricular arrhythmias that complicate so many common cardiovascular disease syndromes.

Hemodynamic effects of amosulalol (YM-09538) in patients with essential hypertension

Amosulalol 40 to 60 mg was orally administered for approximately 3 months to 14 patients with mild to moderate essential hypertension to investigate the drug's hemodynamic effects. Eight patients who responded well to the therapy showed an increase in cardiac output and stroke volume and a decrease in total peripheral resistance and volume elasticity, but no changes in heart rate. These hemodynamic effects of amosulalol noticeably differed from those of propranolol. The important hemodynamic features of amosulalol include decreased total peripheral resistance and suppression of reflex tachycardia; these effects result from the drug's selective alpha 1-blocking and beta-blocking activity. From a hemodynamic aspect, amosulalol is preferable to a beta-blocker in the treatment of hypertension.

Effects of nipradilol, a new nitroester-containing beta-blocker, on forearm blood flow

Beta-blockers without intrinsic sympathomimetic action have been reported to produce an increase in peripheral vascular resistance. The present study was designed to determine the effects of a new beta-blocker, nipradilol (3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1-benzopyran), on forearm blood flow (FBF) in seven patients (mean age, 51.6 ± 6.7 years) with essential hypertension. After overnight fasting, FBF was determined using venous occlusion strain-gauge plethysmography before and two hours after oral administration of 6 mg nipradilol or 20 mg propranolol. Both beta-blokers produced a significant decrease in blood pressure, and heart rate also tended to decrease. As a result, the product obtained by multiplying systolic blood pressure by heart rate was reduced after both nipradilol and propranolol. Nipradilol increased FBF from 0.78 ± 0.10 ml/100 ml/min to 1.72 ± 0.28 ml/100 ml/min ( P < 0.02), while propranolol decreased FBF (from 0.99 ± 0.29 ml/100 ml/min to 0.73 ± 0.24 ml/100 ml/min, P < 0.02). Vascular resistance, calculated by dividing mean blood pressure by FBF, was reduced significantly to 46% of control levels with nipradilol, although propranolol elevated vascular resistance by 39%. These results suggest that nipradilol dilates peripheral vessels, possibly through the action of its nitroester residue or by concomitant alpha 1-blocking activity.

Chronic haemodynamic effects of carvedilol in essential hypertension at rest and during exercise.

Nineteen men (mean age 44 years) with essential hypertension, WHO stage I, were studied invasively at rest and during exercise. Blood pressure was recorded intra-arterially (brachial artery), cardiac output by dye dilution method and heart rate by electrocardiography. After initial pre-drug recordings, the patients received 25 mg carvedilol orally and central haemodynamics at rest and during exercise were recorded 1 and 2 h after tablet intake to evaluate the immediate effects of carvedilol. The results indicated a combined beta-blocking and vasodilating effect. After 6-9 months of treatment, supine haemodynamics were recorded 12-24 h after the last dose and then 1 and 2 h after an additional 25 mg dose. During chronic treatment (2 h after last dose at rest supine) mean arterial pressure was reduced by 17% (P less than 0.001) and total peripheral resistance index by 6% (NS) while heart rate and cardiac index were reduced by 12%. Exercise haemodynamics demonstrated a fall in blood pressure of 17% (P less than 0.001). Exercise stroke index increased by 5% (NS), partly compensating for the reduction in heart rate of 17%. Total peripheral resistance index was reduced by 5% (NS). It is concluded that carvedilol is an effective anti-hypertensive agent in a large proportion of patients with essential hypertension. The haemodynamic mode of action reflects an alpha 1-blocking activity, particularly in situations with low sympathetic tone. During exercise the beta 1-blocking activity (demonstrated by the reduction in heart rate) is more prominent.

Novel phenoxyalkylamine derivatives. VII. Synthesis and pharmacological activities of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives.

To find a novel alpha-blocker with high alpha-blocking selectivity against dopamine D2-receptor affinity, we performed structural modification of the alkylene chains and the substituents on two benzene rings of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives. The modification of the alkylene chain between the amino moiety in the center of the molecule and the benzene ring (ring A) was found to be the most significant. 5-[2-[[2-(5-Fluoro-2-methoxyphenoxy)ethyl]amino]propyl]-2- methoxybenzenesulfonamide (II-4), which possesses 1-methylethyl as the alkylene chain, exhibited high alpha-blocking selectivity as well as potent alpha-blocking activity.

Pharmacologic Analysis of 7-O-Ethyl-fangchinoline-Induced Vasodilation Properties in Isolated Perfused Common Carotid Arteries of Wistar Kyoto Rats and Spontaneously Hypertensive Rats.

Using the cannula insertion method, we investigated vascular effects of 7-O-ethyl-fangchinoline (TJN-220) derived from tetrandrine in isolated and perfused common carotid arteries of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). A single dose of TJN-220 caused a vasodilation in a dose-related manner in arteries preconstricted by phenylephrine. The vasodilation was not inhibited by propranolol, a potent beta-adrenoceptor antagonist. A potent alpha-antagonist bunazosin inhibited the vasoconstriction to norepinephrine while TJN-220 did not modify the norepinephrine-induced constriction, indicating TJN-220 had no alpha-blocking activity. A potent calcium entry blocker, diltiazem, markedly attenuated the KCl-induced vasoconstriction, and TJN-220 slightly but significantly attenuated the KCl-induced one in large doses. The vasodilation of TJN-220 was not abolished after removing the endothelium by an intraluminal administration of saponin, although the ACh-induced dilation was completely abolished by it. A comparison of vascular responses in WKY and SHR revealed no significant differences. From these results, it is concluded that 1) a new tetrandrine derivative, TJN-220 has relatively long-lasting vasorelaxant properties, 2) the dilatory effects might not be related to adrenergic, muscarinic or endothelium-dependent mechanisms, and 3) the effects might partially be due to calcium entry antagonistic properties.

Effect of carvedilol on venous return: A mechanism of reduction in blood pressure.

We studied the effect of carvedilol, a beta-blocker with a potent alpha-blocking activity, on venous return in anesthetized dogs. Though 3 micrograms/kg of carvedilol caused a slight increase in blood pressure and total peripheral resistance, these changes disappeared by further doses of the agent. On the other hand, each dose of carvedilol (3-100 micrograms/kg) decreased venous return significantly and dose-dependently. These results indicate that the hypotensive effect of carvedilol mainly depends on the decrease in venous return rather than arterial vasodilation.

Effects of Intracavernosal Trazodone Hydrochloride: Animal and Human Studies

Trazodone hydrochloride is an oral antidepressant agent which has been associated with the improvement of erections in impotent men and the development of prolonged erections or priapism in potent men. An in vivo study in animal and human subjects was performed to gain experience with the effect of intracavernosal trazodone. In the anesthetized New Zealand White rabbit, intracavernosal trazodone or its major metabolite m-chlorophenylpiperazine (m-CPP) produced full penile erection in 76% and 84% of animals studied respectively with doses ranging from one to 15mg. On the other hand, intracavernosal administration of five mg. papaverine resulted in a prolonged erection in 90% of animals studied. In 13 selected volunteer patients, intracavernosal trazodone caused tumescence but not full penile erection with corporal body pressures of 28.2 ± 5.8mm. Hg. Intracavernosal papaverine or papaverine and phentolamine in these subjects resulted in significantly higher corporal body pressures of 58 ± 18mm. Hg (p < .05). Intracavernosal administration of alpha adrenoceptor agonists but not normal saline resulted in complete detumescence of trazodone- or m-CPP-induced prolonged erection in the animal studies. Intracavernosal trazodone results in erectile activity that appears in part based on its local alpha blocking activity but like other intracavernosal alpha-blocking agents is not as effective in initiating penile erections as are intracavernosal agents that directly induce smooth muscle relaxation. (J. Urol., 144: 1277–1282, 1990)

Adrenoceptor-Blocking Activity and Cardiohemodynamic Effects of Carvedilol in Animals

The beta-blocking activities of a new beta-adrenoceptor blocking drug, carvedilol, evaluated in isolated atria and trachea of the guinea pig were 2.0 (beta 1) and 3.2 times (beta 2), respectively, as potent as those of propranolol. Carvedilol exhibited the alpha-blocking activities in the aorta of guinea pigs and rats. Carvedilol was 2 and 50 times less potent in guinea pigs and rats, respectively, than prazosin as an alpha-blocker. Thus, the alpha-blocking activities were twice as potent as the beta-blocking activity in the rat and one-fifth that of the beta-blocking activity in the guinea pig. In anesthetized open-chest dogs, the beta-blocking activity of carvedilol was 1.5 times more potent than that of propranolol and had 3.8 times the alpha-blocking activity. Thus, carvedilol is a nonselective beta-blocking drug with a potent alpha-blocking activity. Carvedilol and propranolol showed dose-dependent and significant decreases in the blood pressure, total cardiac output, left ventricular pressure, dp/dt, heart rate, coronary flow, and oxygen consumption in anesthetized open-chest dogs. Carvedilol decreased the total peripheral resistance significantly (the decrease was not proportional to the decreases in the blood pressure at high doses), while propranolol increased it significantly and dose-dependently. These results indicate the importance of alpha-adrenoceptor blocking activity in the decrease in blood pressure produced by carvedilol.

Dilevalol

Dilevalol, the RR-stereoisomer of labetalol, is a non-cardioselective beta-adrenoceptor antagonist with substantial partial beta 2-agonist and negligible alpha 1-blocking activity. Reduction in blood pressure during dilevalol administration is associated with peripheral vasodilatation, and heart rate remains essentially unchanged. Following oral administration, dilevalol is completely absorbed. Once-daily administration is possible, due to a long elimination half-life. Large well-controlled trials reveal that dilevalol is equivalent in antihypertensive efficacy to metoprolol, the ACE inhibitors captopril and enalapril, and the calcium antagonist nifedipine. Smaller noncomparative and comparative trials demonstrate the blood pressure-lowering effects of dilevalol and suggest an efficacy at least equivalent to that of the 'pure' beta-blockers atenolol and propranolol and the alpha 1-blockers urapidil and doxazosin. Dilevalol appears to be well tolerated, the most frequent adverse effects being dizziness, headache and diarrhoea in only about 7% of patients each. Unlike alpha 1-blockers and labetalol, dilevalol is not commonly associated with orthostatic hypotension. Thus, data suggest that dilevalol, with its distinctive pharmacological profile, is likely to be a useful addition to the options currently available for treating patients with mild to moderate essential hypertension.

Differential Effects of 3 Beta Blockers on Lipid Peroxidation in Hyperthyroid Muscle.

To determine whether beta blockade protects against the acceleration of lipid peroxidation in hyperthyroid rat soleus (slow-oxidative) muscle, in vivo chronic (3 weeks) effects of 3 beta blockers with different ancillary properties on mitochondrial oxidative enzymes, antioxidant enzymes, and thiobarbituric acid-reactive substances were investigated. The rats were rendered hyperthyroid by the administration of thyroxine and treated simultaneously with either carteolol (a nonselective blocker with partial agonist activity; 30 mg/kg/day), atenolol (a beta 1-selective blocker; 50 mg/kg/day), or arotinolol (a nonselective blocker with weak alpha-blocking action; 50 mg/kg/day) over a 3 week period. Hyperthyroidism induced tachycardia, an increase in the mitochondrial oxidative enzymes, manganese (mitochondrial) superoxide dismutase and thiobarbituric acid-reactive substances, and a decrease in the other antioxidant enzymes. The tachycardia was alleviated completely by either atenolol or arotinolol, but partially by carteolol. Arotinolol, but neither carteolol nor atenolol, inhibited the increase in oxidative enzymes and thiobarbituric acid-reactive substances. The levels of antioxidant enzymes were minimally affected by the beta-blocker treatment. Beta 2-, and possibly alpha- as well, but not beta 1-, blockade suppressed mitochondrial hypermetabolism and protected against peroxidative injury in the hyperthyroid soleus muscle. Partial agonist activity was not beneficial.

α2-Adrenergic Control of Growth Hormone (GH) Secretion in Conscious Male Rabbits: Involvement of Endogenous GH-Releasing Factor and Somatostatin*

In an attempt to clarify the regulatory role in GH secretion of central alpha-adrenergic and dopaminergic mechanisms, the effects of iv administration of alpha 1- and alpha 2-adrenergic antagonists and dopaminergic antagonists were investigated in undisturbed conscious male rabbits. During a 6-h observation period (1030-1630 h), control animals demonstrated spontaneous pulsatile GH secretion with mean (+/- SEM) 6-h GH levels of 6.49 +/- 0.54 ng/ml (n = 16). Intravenous injection of yohimbine (YOM; an alpha 2-antagonist), chlorpromazine (CPZ), and haloperidol (HAL; dopamine and alpha-adrenergic antagonists) completely suppressed this pulsatile GH secretion (mean 6-h GH levels, 2.98 +/- 0.24, 3.48 +/- 0.24, and 2.91 +/- 0.29 ng/ml, respectively; P less than 0.001), whereas prazosin (an alpha 1-antagonist), pimozide (a selective dopamine antagonist), sulpiride, and YM-09151-2 (YM; D2-specific antagonists) failed to affect the GH secretory pattern (mean 6-h GH levels, 6.61 +/- 0.73, 6.71 +/- 0.56, 5.44 +/- 0.44, and 6.87 +/- 1.44 ng/ml, respectively). While an iv injection of 2 micrograms synthetic human GH-releasing factor-(1-44)-NH2 (hGRF) induced GH rises in prazosin-, HAL-, pimozide-, sulpiride-, and YM-treated rabbits as well as control rabbits, YOM and CPZ completely abolished these GH responses to hGRF injection. An iv injection of 10 ml antisomatostatin gamma-globulin caused a prompt and transient GH rise, followed by a sustained elevation of GH trough levels in normal control rabbits. YOM treatment completely abolished this highly oscillated GH release. However, suppression by YOM or CPZ of hGRF-induced GH rises was significantly reversed by iv administration of 10 ml antisomatostatin gamma-globulin. Therefore, the inhibitory effect of YOM and CPZ on both episodic GH release and hGRF-induced GH rises is due to the enhanced release of somatostatin, with a simultaneous suppression of endogenous GRF. On the other hand, HAL, possessing a weaker alpha-blocking action than CPZ, blunted pulsatile GH secretion, but only modestly suppressed hGRF-induced GH rises. These results suggest the following. 1) Central alpha 2-adrenergic mechanisms play a more important role in the regulation of GH secretion than alpha 1-adrenergic mechanisms in the rabbit as well as in other species. 2) The alpha 2-adrenergic blockade causes suppression of the release of hypothalamic GRF and enhanced release of endogenous somatostatin, thereby suppressing GH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Do both adrenaline and noradrenaline stimulate cardiac α‐adrenoceptors to induce positive inotropy of rat atria?

1. The positive inotropic responses of rat paced left atria to adrenaline and noradrenaline were recorded. Desmethylimipramine (DMI, 1 microM) and metanephrine (10 microM) were initially present throughout. 2. The positive chronotropic responses of spontaneously beating right atria to adrenaline were used as a reference. In these, pindolol, in increasing concentrations, caused progressive shift of the concentration-response curves to the right, which yielded a pA2 value (8.15) compatible with antagonism of beta-adrenoceptors. 3. The left atrial tension responses to adrenaline showed an initial progressive displacement by pindolol (up to 3 microM) which gave an unexpectedly low pA2 value (6.48). However, with further increases in pindolol concentration there was no additional shift of the curve. In the presence of pindolol (3 microM), prazosin (0.1 microM) displaced the curve to the right but the pA2 value derived from this shift (7.75) was less than expected for alpha 1-adrenoceptor antagonism. 4. When the experiments in the presence of pindolol (3 microM) were repeated in the absence of DMI, prazosin displaced the concentration-response curves for adrenaline-induced left atrial tension to a greater extent and the pA2 value (8.76) was now compatible with adrenaline stimulating typical alpha 1-adrenoceptors. 5. The concentration-response curves for noradrenaline-induced left atrial tension were also progressively displaced to the right by pindolol (0.1, 0.3 and 1.0 microM). These concentrations yielded a Schild plot of unity slope and a pA2 value of 7.94 +/- 0.04. This was not significantly different from the pA2 value of 8.02 +/- 0.07 determined for pindolol against isoprenaline in the left atria, which indicates a normal interaction of noradrenaline with beta-adrenoceptors in the absence and presence of low concentrations of pindolol. 6. A further increase in the concentration of pindolol to 3 microM failed to induce an additional shift of the noradrenaline curves, whether a 'before and after' antagonist or a 'naïve tissue' design was adopted. Similarly, the rightwards shift of the concentration-response curves by timolol reached a limit as the concentration was increased. In all cases the limit of shift occurred at a noradrenaline EC50 value of 5-10 microM. 7. At the limit of beta-adrenoceptor antagonism, prazosin and dibenamine did not displace the noradrenaline curves further. The residual inotropic response to noradrenaline therefore appeared to be mediated via neither alpha- nor beta-adrenoceptors. 8. DMI, in the absence of beta-blockade, produced the potentiation of adrenaline and noradrenaline expected of a neuronal uptake inhibitor. However, in the presence of pindolol, there was no potentiation of the right atrial rate response to adrenaline while its left atrial tension responses were antagonized. This suggested that DMI was acting as an alpha-adrenoceptor antagonist. It also explained the less-than-expected shift by prazosin of the adrenaline responses in the presence of both pindolol and DMI, the latter drug already exerting some alpha-blocking activity. In contrast, the left atrial tension responses to noradrenaline in the presence of pindolol (1 microM) were neither potentiated nor antagonized by DMI. 9. When the effects of prazosin upon left atrial tension responses to noradrenaline in the presence of pindolol (10 microM) were examined in the presence of a lower concentration of DMI (O.1 microM) or cocaine (1O microM), again there was no further shift of the curve. However, when the effect of prazosin) The Macmillan Press Ltd 1989 598 K.L. WILLIAMSON & K.J. BROADLEY was examined in the absence of DMI, but in the presence of pindolol (1 and 1O microM) or timolol (3 microM), there was a small shift of the curves by prazosin (0.1 microM). This yielded pA2 values of 7.19, 7.34 +/- 0.1 and 7.66 +/- 0.09, which were at least one order of magnitude less than literature values and that obtained with adrenaline (8.76 +/- 0.18), and are not consistent with noradrenaline stimulating an alpha 1-adrenoreceptor in the presence of beta-adrenoceptor blockade, the increase in left atrial tension by noradrenaline does not appear to be mediated by beta l- or typical alpha-adrenoceptors. This is in contrast to adrenaline which in these conditions stimulates typical alpha 1-adrenoceptors.

Blocking action of berberine on various receptors in rat anococcygeus muscle.

The contractile responses of rat anococcygeus muscle to phenylephrine, acetylcholine and 5-hydroxytryptamine in relation to berberine and to their specific antagonists were studied separately. The effects of phenylephrine and acetylcholine were blocked by berberine as well as by atropine. But the alpha-blocking action of atropine was exhibited only at high concentration. The anococcygeus muscle response to phenylephrine was competitively inhibited by berberine with a PA2 value of 6.4. The contraction induced by acetylcholine was competitively inhibited by atropine (PA2 = 8.7), whereas berberine, which differs basically from atropine, shifted the dose-response curve for acetylcholine non-parallelly to the right with its maximal response reduced concomitantly. Its pD2(1) value was 4.6. This suggests that the antagonistic action of berberine may be exerted non-specifically through a site beyond the M-cholinergic receptor. Berberine also relaxed the contraction of anococcygeus muscle induced by 5-hydroxytryptamine. The contractile responses to histamine and isoprenaline were seen only at high concentration. In addition, the response to isoprenaline was little affected by propranolol in our experiment.

Alpha Blockers and Vasodilating Beta Blockers - Influence on Factors Involved in the Pathogenesis of Vascular Disease in Patients with Hypertension

Antihypertensive drugs that interact with adrenoceptors have certain advantages and disadvantages (on the treatment of hypertension). Alpha-1 antagonists such as prazosin have favorable effects on plasma lipids but may produce excessive postural falls in blood pressure, particularly following the initial dose. Recently developed alpha-1 antagonists (doxazosin, terazosin) have longer durations of action than prazosin, allowing less frequent administration. Beta blockers may be cardioprotective but in contrast to alpha-1 antagonists tend to have adverse effects on plasma lipids. Drugs with combined beta and alpha-1 blocking activity such as labetalol have favorable metabolic effects but postural hypotension remains a problem. Recently developed drugs with different alpha-1/beta blocking ratios that differ from labetalol may prove to be more popular clinically. Several beta blockers with vasodilator activity which is not due to alpha-1 blockade have also been developed. These drugs appear to have favorable metabolic effects similar to drugs with alpha-1 blocking activity, but do not cause postural hypotension.

Effects of Beta-Adrenergic Blockers with Different Ancillary Properties on Lipid Peroxidation in Hyperthyroid Rat Cardiac Muscle.

To determine whether beta-blockade protects rat heart against thyroxine (T4)-induced accelelation of lipid peroxidation, in vivo effects of 3 beta-blockers with different ancillary properties on the mitochondrial oxidative enzyme, antioxidant enzymes and lipid peroxide were investigated. The rats were rendered hyperthyroid by adding T4 to their drinking water for 3 weeks and were treated simultaneously with either carteolol (a blocker with partial agonist activity; 30 mg/kg/day), atenolol (50 mg/kg/day) or arotinolol (a blocker with weak alpha-blocking action; 50 mg/kg/day). The T4-induced tachycardia was alleviated completely by either atenolol or arotinolol, but only partially by carteolol. Cytochrome c oxidase activity in the heart muscle was increased by T4 with a parallel increase in manganese (mitochondrial) superoxide dismutase. Atenolol, but neither carteolol nor arotinolol, suppressed this increase. Similarly, the T4-induced acceleration of lipid peroxidation was suppressed by atenolol alone. Glutathione peroxidase was markedly decreased, and both copper zinc (cytosolic) superoxide dismutase and catalase were also decreased or tended to be decreased by T4. The levels of these 3 enzymes were only minimally affected by the beta-blocker treatments. These results suggest that beta-blockade suppresses mitochondrial hypermetabolism and protects heart muscle against oxidative stress in hyperthyroidism, and that the ancillary properties of beta-blockers such as partial agonist activity and alpha-blocking action negate the protection.

Do hybrid drugs offer an additional benefit over pure alpha1-blockade for hypertensive patients?

Alpha-blocking drugs, although effective antihypertensive agents, often cause tachycardia, faintness and postural hypotension. Hybrid drugs such as labetalol, which has beta- as well as alpha-blocking action, ketanserin, which has 5-hydroxytryptamine (5HT)-blocking as well as alpha-blocking action, and urapidil, which appears to have a central effect as well as an alpha-blocking action, produce fewer side effects attributable to alpha-blockade. Urapidil appears to be an effective antihypertensive drug with a wide spectrum of action and few side effects.

Clinical pharmacology of urapidil

Animal investigations suggest that the mechanism of the antihypertensive effect of urapidil may be complex. Suggestions have included an alpha 1-blocking action, a weak beta 1-blocking effect, an interaction with a serotonin receptor and a central depression of sympathetic tone. Peripheral alpha 1-blocking activity has been demonstrated in man, and a shift to the right in the dose-response curve to phenylephrine has been found after administration of urapidil, while responses to angiotensin are not affected. Evidence for beta 1-blocking activity is marginal, but urapidil does not inhibit the exercise-induced increase in the heart rate, and there is only some suggestion of a possible inhibition of isoprenaline-induced tachycardia. Possible central activity may be deduced from the observation that while lower single doses reduce blood pressure and increase the heart rate, with higher doses the hypotensive effect continues but the tachycardia no longer occurs. However, lower doses of urapidil lead to an increase in noradrenaline levels, while changes in renin are less constant, but there has been a report that a high dose reduced vanillylmandelic acid excretion. Urapidil reduces peripheral resistance along with arterial pressure, and cardiac output is increased. In spite of a reduced arterial pressure, renal blood flow is maintained, presumably due to dilation of renal vessels. Urapidil is well absorbed orally with a bioavailability of about 70% and a tmax at about 4 h after a sustained release capsule. It is metabolized in the liver with a t1/2 of 4.7 h. In conclusion there is evidence that urapidil is an alpha 1-blocking drug in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic receptor effects and antihypertensive actions of beta-adrenoceptor-blocking agents with ancillary properties.

The acute antihypertensive effects and possible underlying mechanisms of 3 beta-adrenergic-blocking drugs with alpha-blocking activity, i.e. labetalol, drugs with alpha-blocking activity, i.e. labetalol, nipradilol and arotinolol, were studied in conscious spontaneously hypertensive rats (SHR) and compared with the effects of prazosin, propranolol and hydralazine. Prazosin produced a dose-dependent antihypertensive effect which paralleled inhibition of the pressor response to phenylephrine. Labetalol (30 mg/kg), nipradilol (30 and 100 mg/kg) and arotinolol (30 and 100 mg/kg) also produced a fall in blood pressure. However, inhibition of the pressor response to phenylephrine was not seen in association with the antihypertensive effect after the lower dose of nipradilol and arotinolol. Propranolol (100 mg/kg) did not lower blood pressure. These results suggest that a mechanism(s) other than an alpha-adrenergic-blocking effect plays a role in the acute antihypertensive effects produced by the lower dose of nipradilol and arotinolol.

Novel phenoxyalkylamine derivatives. V. Synthesis, alpha-blocking activity and quantitative structure-activity analysis of alpha-[(phenoxyethylamino)propyl]-alpha-phenylacetonitrile derivatives.

α-[(Phenoxyethylamino) propyy]-α-phenylacetonitrile derivatives possessing various substituents on the benzene ring (A ring) at the phenylacetonitrile moiety, on the quaternary carbon atom and on the benzene ring (B ring) at the phenoxy moiety, and exhibiting various degrees of ablocking activity, were prepared. The variations in the activity were analyzed qualitatively as well as quantitatively by using physicochemical substituent parameters and a regression technique. The effect of substituents on the A ring was rationalized in terms of a parabolic function of their hydrophobic parameter. As regards substituents on the quaternary carbon atom, alkyl groups were desirable for high activity. The effects of substituents on the B ring were such that an optimum hydrophobic condition exists and that an alkoxy substituent at the o-position as well as smaller substituents at the m-and p-positions are favorable for high activity. The analysis for the combined series of analogs where substituents on the A and B rings are varied showed the existence of an optimum hydrophobicity for the whole molecule for the transport process of the molecule, besides above-mentioned various position-specific structural effects.