Influence of alpha-adrenoceptor blockade on antigen- and propranolol-induced bronchoconstriction in guinea-pigs in vivo

1. Beta-adrenoceptor antagonists, such as propranolol, can provoke severe bronchoconstriction only in asthmatic subjects. Recently, we developed a guinea-pig model of propranolol-induced bronchoconstriction (PIB) and the purpose of this study was to investigate the role of alpha-adrenergic nerve pathways in this reaction. 2. Phentolamine administered after an antigen challenge did not inhibit PIB; however, its administration before the antigen challenge significantly inhibited the antigen-induced bronchoconstriction and also bronchoconstriction induced by methacholine inhalation. 3. We conclude that the alpha-adrenergic nerve system is not involved in the development of PIB following allergic reaction in our guinea-pig model.     

Vascular alpha-adrenoceptor blockade by E. coli endotoxin in the rat

It has been previously shown that Escherichia coli endotoxin (ENDO) reduces the pressor effect of phenylephrine. This work attempted to define precisely the involvement of vascular alpha-adrenoceptors in this action. The dose-response curves of three alpha-agonists noradrenaline, St 587 and B-HT 933 in pithed rats were shifted rightwards by pretreatment (i.v. injection of 10 and 100 micrograms/kg) with ENDO. ENDO 10 and 30 micrograms shifted the dose-response curve of noradrenaline in perfused rat kidney. It can be suggested that ENDO has a potent blocking action on vascular alpha-adrenoceptors without evident discrimination between alpha 1 and alpha 2 subtypes.     

Influence of autonomic blockade on the reduction in myocardial performance produced by clonidine

Clonidine (15 μg/kg, i.v.) induced an increase followed by a long-lasting decrease in blood pressure and reduced heart rate and cardiac output of dogs. All the indices of myocardial performance were decreased: maximal rate of rise in left ventricular pressure, max dP/dt/I.P. (I.P. = ventricular pressure at max dP/dt), pressure time index. The left ventricular end diastolic pressure was increased even when stroke work was decreased. The curve relating dP/dt to the developed pressure was flattened. These facts indicate that clonidine decreased myocardial contractility. Ventricular volumes were not altered. Pacing of the heart after clonidine did not lead to a recovery of cardiac output and myocardial contractility.To analyze the role of the sympathetic and vagal tones on these factors, 5 groups of dogs were used: (1) reserpinized, (2) reserpinized with both vagus nerves cut, (3) with β-adrenoceptor (S 2395, 50 μg/kg) and muscarinic receptor (atropine, 50 μg/kg) blockade, (4) with both vagus nerves cut, and (5)_with both carotid sinus nerves cut.Heart rate was markedly reduced in group 1 but not change in group 2 and 3 3; in groups 4 and 5, heart rate was decreased but to a smaller extent than in control dogs. Therefore the decrease in sympathetic tone and the increase in vagal tone were responsible for the bradycardia. The increase in the vagal tone was apparently due to potentiation of the influence of baroreceptor impulses.The maximal rate of rise in left ventricular pressure did not change in groups 1,2, and 3, but was decreased in groups 4 and 5, indicating that the loss of the sympathetic tone was responsible for the reduction in myocardial contractility.Cardiac output was not changed significantly in groups 2,3 and 4, but decreased in groups 1,3 and 5. The loss of the sympathetic tone and the bradycardia when very marked appear to reduce cardiac output.Left ventricular end diastolic pressure rose in groups 1 and 2, and was increased only transiently in groups 4 and 5. The decrease in myocardial contractility, the changes in blood pressure, the bradycardia and possibly the reduced venous return appear to be the factors influencing this parameter.Blood pressure shows the usual biphasic changes, an increase followed by a decrease in groups 3,4 and 5, did not change in group 1, and was only increased in group 2. The loss of the sympathetic tone was therefore responsible for this effect.     

Reversal of alpha-adrenoceptor blockade by propranolol in isolated rat pulmonary artery

Pulmonary artery rings were prepared from rats (group I to VI, n = 5-7 per group) in order to investigate if a beta-adrenoceptor antagonist interferes with the effect of alpha-adrenoceptor blockade. In I, four cumulative noradrenaline (NA) dose-response curves (10(-9) to 10(-3) M) were constructed. In II, NA curves were constructed first, without blockers, then in the presence of phentolamine (10(-6) M), then propranolol (10(-8) M), then phentolamine plus propranolol (10(-8) M). III, IV and V were treated similar to II, except that atenolol (10(-8) M), ICI 118,551 (10(-8) M) and propranolol (10(-6) M), respectively, were added instead of propranolol (10(-8) M). In VI, NA (10(-6) M) was added followed by phentolamine and then propranolol (10(-9) to 10(-6) M). Phentolamine shifted the NA curve to the right with an increase in the EC50 value. Propranolol but not atenolol or ICI 118,551, reduced the elevated EC50 values caused by phentolamine. In group VI, the increase in force by NA was reduced by phentolamine; the effect of phentolamine was completely abolished by propranolol. Thus, propranolol interferes with the effect of phentolamine in the rat pulmonary artery.     

Renal effects of alpha-adrenoceptor blockade during furosemide diuresis in conscious rats.

Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective alpha-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n = 6) was compared with time control animals (n = 9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n = 9), 0.3 (n = 6), 1.0 (n = 7) and 3.0 mg/kg/hr (n = 6). Phentolamine infusion reduced norepinephrine-induced increase in blood pressure at all three dose levels (n = 5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65 +/- 3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52 +/- 3% during furosemide alone. At steady-state conditions (120-180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi = 48 +/- 2% versus 39 +/- 1% in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular alpha-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

The reversal of phenoxybenzamine-produced alpha-adrenoceptor blockade by the isomers of propranolol and INPEA

Isomers of propranolol and N-isopropyl-p-nitrophenylethanolamine (INPEA) were used to demonstrate that there are two mechanisms by which the β-adrenoceptor blocking agents will reverse phenoxy-benzamine-produced α-adrenoceptor blockade. In the seminal vesicle preparation, prior administration of either isomer initially protected the receptors from phenoxybenzamine blockade when the contact time for phenoxybenzamine was short. The isomers were equi-effective, suggesting that this action is independent of β-adrenoceptor blocking activity. When the contact time of phenoxybenzamine was prolonged, the ability of the isomers to protect the α-receptors was lost. In the rat blood pressure preparation, after the development of phenoxybenzamine-produced α-adrenoceptor blockade, (-)- and (±)-propranolol or (-)- and (±)-INPEA, in doses that produced marked β-adrenoceptor blocking activity, partially reversed the α-adrenoceptor blockade. Identical doses of (+)-propranolol or (+)-INPEA, which exhibited weak β-adrenoceptor blocking activity did not produce any reversal. The reversal of phenoxybenzamine-produced α-adrenoceptor blockade in this situation appears therefore to be dependent upon the development of β-adrenoceptor blockade.     

The effects of alpha-adrenoceptor blockade on dopamine-induced renal vasodilation and natriuresis

Summary To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pretreatment with the selective postsynaptic alpha₁-adrenoceptor antagonist prazosin in normal volunteers and in patients with renal disease and moderately impaired renal function.Prazosin (1 mg p. o. every 4 h) in 7 volunteers did not significantly affect baseline values but impaired the response of effective renal plasma flow (ERPF) and filtration fraction (FF) to infusions of dopamine in doses ranging from 0.5 to 8 g/kg per minute and completely abolished the dopamine-induced increase in sodium excretion. In 7 patients with renal disease and a glomerular filtration rate (GFR) ranging from 38–85 ml/min pretreatment with prazosin did not affect baseline ERPF, GFR or FF or their response to dopamine infusion, but sodium excretion and its response to dopamine infusion were reduced (fractional excretion of sodium at baseline 1.78 without and 0.89 with prazosin pretreatment).We conclude that alpha₁-adrenoceptor blockade with prazosin abolishes the effects of exogenous dopamine on sodium excretion in normal man. Prazosin also impairs the renal vasodilatory action of dopamine. However, the effect on sodium excretion is not directly related to inhibition of dopamine-induced renal vasodilation since in patients with renal disease prazosin also markedly reduces sodium excretion but does not influence the renal hemodynamic effects of dopamine. Send offprint requests to A. J. Smit at the above address     

Effects of tetramethylpyrazine on heart rate and pupil diameter in rats

The alpha-adrenergic nature of tetramethylpyrazine (TMPZ), a commonly used cardiovascular drug in China, was studied with a combined bradycardia and mydriasis model in the pentobarbital anesthesized rat. Intravenous injections of TMPZ at 1-30 mg/kg failed to change heart rate or pupil size, whereas iv injections of both clonidine (alpha 2-adrenoceptor agonist, 1-30 micrograms/kg) and methoxamine (alpha 1-adrenoceptor agonist, 10-300 micrograms/kg) caused dose-dependent bradycardia and mydriasis. Pretreatment of rats with TMPZ (30 mg/kg) did not significantly change clonidine- or methoxamine-induced bradycardia or mydriasis. However, when TMPZ was injected 2 min after clonidine administration (30 micrograms/kg), while the mydriasis reached a maximum, it slightly but significantly reversed the clonidine-induced mydriasis for 15-20 s. In contrast, the alpha 2-adrenoceptor antagonist idazoxan (6 micrograms/kg) caused the same degree of reduction of the clonidine-induced mydriasis for greater than 2 min. Our results suggested that TMPZ at the doses studied did not have alpha-adrenoceptor agonistic activities, but may have slight alpha 2-adrenoceptor antagonistic activities.     

Effect of presynaptic alpha-adrenoceptor blockade on responses to cardiac nerve stimulation in anesthetized dogs.

Phentolamine caused significant potentiation of chronotropic responses to cardioaccelerator nerve stimulation (CANS) in pentobarbital-anesthetized dogs without impairing neuronal reuptake of norepinephrine. In a separate group of dogs, desipramine produced slight augmentation of CANS responses which were potentiated further by phentolamine administration. These results provide support for the hypothesis that presynaptic alpha-adrenergic receptors play an inhibitory role in sympathetic neurotransmission and demonstrate that this mechanism is also functioning during stimulation of the cardioaccelerator nerve in pentobarbital-anesthetized dogs.     

Effectiveness of pyridostigmine in reversing neuromuscular blockade produced by soman.

The effects of pyridostigmine pretreatment on the neuromuscular blockade produced by soman in anaesthetized, atropinized animals have been studied on the soleus and anterior tibialis muscle (rhesus monkeys, cats and rabbits) and the gastrocnemius muscle (guinea-pigs and rats). Pyridostigmine pretreatment produced a complete recovery of neuromuscular function following blockade by soman; the rate of recovery was similar in all the species, suggesting a common mechanism of action. In the absence of pyridostigmine or if pyridostigmine was delayed until after blockade by soman, there was no recovery of neuromuscular function. Detailed studies in the guinea-pig showed that the recovery of neuromuscular function was related to the dose of soman and to the degree of carbamoylation of blood cholinesterase at the time of nerve agent challenge, i.e. to the dose of pyridostigmine and the time interval between the administration of pyridostigmine and soman. It is suggested that the effectiveness of pyridostigmine pretreatment is due to the carbamoylation of a portion of the tissue acetylcholinesterase, which protects it against irreversible inhibition by soman: after poisoning spontaneous decarbamoylation produces sufficient free acetylcholinesterase to restore normal function.     

Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance.

1. Cardiac performance and vascular resistance was studied in seven healthy men by radionuclide cardiography and venous plethysmography before and after alpha-adrenoceptor blockade with phentolamine and after combined alpha-adrenoceptor, beta-adrenoceptor (propranolol) and parasympathetic (atropine) blockade. 2. During alpha-adrenoceptor blockade heart rate and cardiac output increased considerably and left ventricular ejection fraction increased because of increased contractility. Systemic vascular resistance fell both during alpha-adrenoceptor blockade alone and during combined blockade. The increase in calf blood flow was of the same magnitude after combined blockade and after alpha-adrenoceptor blockade alone, and was considerably higher than the fall in systemic vascular resistance. Plasma catecholamine concentrations increased after phentolamine, but the changes were blunted when propranolol and atropine were added. 3. These results indicate that peripheral vasoconstriction especially that exerted by alpha-adrenoceptor nervous tone in skeletal muscle restricts left ventricular emptying of the intact heart. During pharmacologic blockade of the sympathetic and parasympathetic nervous system at rest the chronotropic state is augmented, whereas preload and inotropy are unaffected.     

The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice.

Because the pain sensation is subjective, it is difficult to evaluate the responses to analgesic drugs. Some analgesics that affect the central nervous system are known to change the pupil diameter. The pupil diameter is a more objective criterion that shows the drug effect. We studied the relation between the pupil diameter and analgesia responses to morphine and antidepressants by using the selective micro-receptor agonist morphine (2 and 4 mg/kg), the noradrenaline reuptake inhibitor desipramine (7.5 and 10 mg/kg), the mixed serotonergic and noradrenergic uptake inhibitor and cholinergic receptor antagonist amitriptyline (2.5 and 5 mg/kg), and the selective serotonin reuptake inhibitor sertraline (2.5 and 5 mg/kg) in mice. Both monocular microscopy to assess pupil measurement and the hot-plate test to assess nociceptive thresholds were used in the same animals. We found that morphine played an important role in both mydriasis and analgesia, whereas amitriptyline and desipramine had a greater effect on pupil response than on nociception. Sertraline produced antinociception without causing a change in pupil diameter. As a result, although the pupil response is an important criterion in evaluating the analgesic effect of morphine, it is not possible to put forward the same criterion for the antidepressant drugs. Because different neurotransmitters are involved in pupil and pain mechanisms of antidepressant drugs, it is difficult to evaluate the analgesic response with the pupil diameter.     

Effect of alpha-adrenoceptor blockade on the 0.4 Hz sympathetic rhythm in conscious rats

1. The present study examined the origin of the 0.4 Hz rhythm in renal sympathetic nerve activity (RSNA) in rats. It was anticipated that, after elimination of 0.4 Hz oscillations of arterial pressure (AP) by alpha-adrenoceptor blockade, the persistence or disappearance of a 0.4 Hz rhythm in RSNA would point to an endogenous (central oscillator) or baroreflex origin, respectively. 2. Arterial pressure and RSNA were recorded in seven conscious rats, before and after acute alpha-adrenoceptor blockade with phentolamine (5 mg/kg, i.v.). In each condition, power and coherence spectra were calculated over 15 min periods of rest. 3. In control conditions, highly coherent AP and RSNA oscillations were observed near 0.4 Hz. After phentolamine administration, spectral power in the mid-frequency (0.27-0.74 Hz) band was significantly reduced for both AP and RSNA and maximum power was shifted towards 0.7 Hz. 4. The disappearance of the RSNA rhythm at 0.4 Hz after phentolamine administration favours the hypothesis of a baroreflex origin. The new oscillation near 0.7 Hz can derive either from the activity of a previously unrecognized central oscillator or from a faster feedback mechanism involving cotransmitters of noradrenaline acting with shorter time constants (e.g. ATP).     

Combined alpha- and beta-adrenoceptor blocking drug AH 5158: further studies on alpha-adrenoceptor blockade in anaesthetized animals.

1. AH 5158, 5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)salicylamide, competitively antagonised phenylephrine-induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses alpha-adrenoceptor blocking activity. 2. In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anesthetized dogs. Thus, at the lowest dose-level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the beta-adrenoceptor-mediated cardia stimulant action of noradrenaline. 3. The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4. Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5. These results are consistent with the hypothesis that AH 5158 blocks a cocaine-sensitive inactivation process for noradrenaline in addition to blocking alpha- and beta-adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6. The implications of these findings are discussed.     

Influence of alpha-adrenoceptor agonists and antagonists on imipramine-induced hypothermia in mice

Effects of adrenoceptor agonists and antagonists on imipramine-induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10-40 mg x kg(-1)), alpha2-adrenoceptor agonist clonidine (0.05-0.1 mg x kg(-1)), alpha1-adrenoceptor agonist phenylephrine (6 mg x kg(-1)) and alpha1-adrenoceptor antagonist prazosin (1-4 mg x kg(-1)) but not alpha2-adrenoceptor antagonist yohimbine (1-4 mg x kg(-1)) induced significant hypothermia. The hypothermic response induced by imipramine (10-30 mg x kg(-1)) was not altered by clonidine (0.05-0.1 mg x kg(-1)) or phenylephrine (2-6 mg x kg(-1)). The response of imipramine (10-30 mg x kg(-1)) was reduced significantly by yohimbine (2 mg x kg(-1)) and was potentiated by prazosin (1 mg x kg(-1)). The hypothermic effect of clonidine (0.1 mg x kg(-1)) and imipramine (20 mg x kg(-1)) were also decreased significantly by different doses of yohimbine (1-4 mg x kg(-1)). The hypothermia induced by different doses of prazosin (1-4 mg x kg(-1)) was not altered by yohimbine (2 mg x kg(-1)) or by low dose of imipramine (10 mg x kg(-1)). It is concluded that alpha2-adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.     

The effect of a single oral dose of pergolide on intraocular pressure and pupil diameter.

1. The ocular hypotensive effect of a single oral dose of 25 micrograms pergolide, a dopamine 2-receptor agonist, was studied in 12 normal human volunteers, using a non-invasive method. 2. An oral dose of timolol 20 mg was used as a positive control. 3. The effects of both drugs on pupil diameter were also studied, using a photographic method. 4. Considering the first 6 h post-dosing measurements, using multiple linear regression analysis comparing drug with placebo and including the baseline values as continuous independent variables, both pergolide and timolol had a significant ocular hypotensive effect in both eyes (P less than 0.0001) with no significant effects on pupil diameter. 5. Further topical application studies in normal and glaucomatous eyes are needed to evaluate the usefulness of pergolide in the treatment of glaucoma.     

Comparison of blockade at α-adrenoceptors by thymoxamine and phentolamine in peripheral arteries and veins of man

1. The antagonism at alpha-adrenoceptors by thymoxamine and phentolamine of the response to noradrenaline was investigated in the limb veins and arteries of man.2. Brachial artery infusions of thymoxamine (40 mug/min) produced rises in resting arterial flow of up to 100%. When infused mixed with noradrenaline, thymoxamine (40 mug/min) attenuated the blood flow response to noradrenaline. Blockade was of a similar degree to that which occurred following a 10 min infusion of phentolamine (40 mug/min).3. Local intravenous infusion of thymoxamine (400-2,000 ng/min) mixed with noradrenaline attenuated the venoconstrictor response to noradrenaline. The degree of attenuation was similar to that seen after a 10 min infusion of phentolamine (500 ng/min). Blockade after thymoxamine did not last longer than 16 minutes. Neither thymoxamine nor phentolamine altered resting venous compliance.4. Local intravenous infusions of thymoxamine (500 ng/min) and phentolamine (500 ng/min) abolished the sympathetically mediated venoconstriction produced by overbreathing.5. Systemic injection of thymoxamine (0.1 mg/kg) did not block the reduction in forearm arterial flow produced by locally infused noradrenaline. In two out of three experiments, however, it produced some antagonism of noradrenaline induced venoconstriction. Systemic phentolamine (5 mg) blocked the effect of noradrenaline in the arterial bed, but antagonized its actions in the veins in only one out of three experiments.