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PubMed1996

Effects of aging on prejunctional control of neurotransmission in the rat.

In this study, we have looked in detail at the effects of aging on neurotransmission in isolated atria and intact heart in anesthetized rats, examining adult and aged animals. There was a diminished ability of the norepinephrine reuptake blocker cocaine to increase stimulation-evoked release of norepinephrine in aged rats and in terms of increasing the norepinephrine-evoked tachycardia in anesthetized rats, suggesting that the function of the reuptake process is diminished by aging. The ability of the alpha 2 adrenergic receptor agonist xylazine to inhibit release of norepinephrine neurotransmitter was also diminished in aged rats both in isolated tissues and in vivo in anesthetized animals. In further studies, the ability of the beta-adrenergic receptor agonists isoproterenol (beta 1 and beta 2 agonist) and procaterol (selective beta 2 agonist) to increase stimulation-evoked release of norepinephrine was examined. Both agonists produced a concentration-dependent facilitation of norepinephrine release in rats atria. Although isoproterenol and procaterol increased release in tissues from young and old animals, the magnitude of the increase was significantly reduced in tissues from old rats, so that beta-adrenergic receptor mediated facilitation was diminished. In summary, aging is associated with a decline in prejunctional modulation of neurotransmission, in terms of diminished norepinephrine reuptake, diminished prejunctional alpha 2 adrenergic receptor mediated inhibition and diminished prejunctional beta 2 adrenergic receptor mediated facilitation. TABLE 2 summarizes the possible effects of aging on noradrenergic neurotransmission. Overall, neurotransmission at rest may be little changed by aging, given that postjunctional responsiveness may fall, but scope for modulation may be diminished.

Adrenergic Fibers↗
PubMed1999

Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study.

Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.

Animals↗
PubMed1981

Characterization of beta-adrenoceptors in the dog saphenous vein.

In vitro experiments were carried out on strips of the dog saphenous vein to characterize beta-adrenoceptors mediating relaxation. Four beta-adrenoceptor agonists, isoproterenol, salbutamol, procaterol and alpha-(3,4,5-trimethoxyphenethylaminomethyl)-3,4-dihydroxybenzylalcohol hydrochloride (T-1583), all produced concentration-dependent relaxation of venous strips contracted by 10(-6) M methoxamine. These four drugs behaved as full agonists. In producing venous relaxation, procaterol was about 2.5 times more potent, and salbutamol and T-1583 were 7 and 98 times less potent than isoproterenol, on a molar basis. The concentration-relaxation response curves to the four agonists were shifted in a parallel way to the right by (t-butyl-amino-3-ol-2-propyl)oximino-9 fluorene hydrochloride (IPS 339), a selective beta 2-adrenoceptor antagonist, and by practolol. However, pA2-values for IPS 339 against the four agonists were all nearly 11.0, whereas those for practolol were all nearly 5.7. We conclude that beta-adrenoceptors in the dog saphenous vein mediating relaxation are predominantly on the beta 2 type.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Steroid-induced acute psychosis in a child with asthma: report of one case.

A 5-year-old girl was admitted due to severe asthmatic attack. She was treated with methylprednisolone (40 mg i.v. q6h), aminophylline (loading with 5 mg/kg and maintained with 0.6 mg/kg/hr i.v. drip), nebulized terbutaline sulphate (5 mg q6h), oral procaterol 12.5 micrograms bid, along with oxygen therapy. Acute psychotic reaction with visual hallucination, delusion, panic reaction and myoclonic movement of hands developed on day 3 of admission. The patient had no previous history of psychiatric problems. The theophylline level was 9.89 micrograms/ml at the moment of psychotic reaction. After the dose of methylprednisolone was reduced from 40 mg to 20 mg i.v. q6h and shifted to other anti-asthma treatment by procaterol metered dose inhaler via spacer, the psychotic reaction disappeared a few hours later. The psychotic reaction was thought to be due to steroid therapy since no other causes could explain the psychotic reaction.

Anti-Asthmatic Agents↗
PubMed1984

Pharmacological studies of mabuterol, a new selective beta 2-stimulant. II: Effects on the cardiovascular system and smooth muscle organs.

Effects of dl-1-(4-amino-3-chloro-5-trifluorome-thyl-phenyl)-2-tert.-bu tylamino-ethanol hydrochloride (mabuterol) on the cardiovascular system and smooth muscle organs were investigated in comparison with those of isoprenaline (isoproterenol), salbutamol and procaterol, and the following results were obtained. Mabuterol (i.v.) produced a dose-dependent decrease in the blood pressure at doses ranging from 0.3-1000 micrograms/kg, and the heart rate was slightly increased at 0.3-30 micrograms/kg but decreased at 100-1000 micrograms/kg in rats, cats and dogs. The effects of mabuterol on the blood pressure, total peripheral vascular resistance (TPR) and heart rate were respectively 14, 37 and 104 times less potent than those of isoprenaline and there were none on the maximum dp/dt in the left ventricle in cats. In dogs, mabuterol had 356 and 118 times less effect on the blood pressure and TPR than isoprenaline and slightly increased the heart rate and maximum dp/dt. Mabuterol (p.o.) decreased the blood pressure at doses ranging from 3 micrograms-100 mg/kg, and the heart rate was increased at 3 micrograms-10 mg/kg, but decreased at 100 mg/kg in conscious and anesthetized rats. In the guinea pig atria, mabuterol slightly increased the heart rate and contractile force, but in the electrically driven left atrium mabuterol had no effect whereas procaterol slightly increased the contractile force. Mabuterol inhibited the positive inotropic effect of isoprenaline at 10(-7) g/ml and decreased the maximum driving frequency at 3 X 10(-6) g/ml. Mabuterol was 3 times more potent in relaxing the isolated rat uterus, but 700 times less potent than isoprenaline in relaxing the rabbit jejunum. Mabuterol (p.o.) depressed the intestinal propulsion and was equipotent to isoprenaline and 2.5 times less potent than salbutamol. Mabuterol had no effect on alpha-adrenergic, acetylcholine and histamine receptors. These results suggest that mabuterol has a specific effect on beta 2-adrenoceptors with no beta 1-stimulation. In addition, mabuterol exhibited beta 1-blocking activity at dosages 200-300 times higher.

Adrenergic beta-Agonists↗
PubMed1995

Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase.

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Myocardial adenosine stimulates release of cyclic adenosine monophosphate from capillary endothelial cells in guinea pig heart.

Activation of coronary endothelial cell adenylate cyclase was studied in the isolated guinea pig heart by prelabelling endothelial adenine nucleotides using intracoronary infusion of [3H]-adenosine, and measuring the coronary efflux of [3H]-cyclic adenosine monophosphate (cAMP). Hypoxia (30% O2) caused a 4-fold increase in coronary release of [3H]-cAMP, which was decreased by 63% by infusion of the adenosine receptor antagonist, theophylline (50 microM). During normoxic control conditions, degrading adenosine to non-vasoactive inosine by intracoronary infusion of adenosine deaminase (1.7 U/ml) caused a 20% decrease in the release of [3H]-cAMP. The effect of adenosine deaminase was reversed by a specific enzyme inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride. Coronary efflux of [3H]-cAMP during intracoronary infusion of 1 microM adenosine triphosphate (ATP), adenosine diphosphate or adenosine monophosphate (AMP) (plus adenosine deaminase 8 U/ml) was only 13% of that due to 1 microM adenosine. Adenosine receptor blockers theophylline and CGS 15943A caused equivalent inhibition of the coronary vasodilator actions of adenosine and ATP. Intracoronary infusion of prostaglandin E1 and the beta 2-adrenergic agonist procaterol caused parallel, dose-dependent increases in coronary conductance and the venous release of [3H]-cAMP. It is concluded that (1) under both normoxic and hypoxic conditions, adenosine formed by the heart may activate endothelial cell adenylate cyclase via membrane adenosine receptors, (2) coronary receptors for adenosine and ATP share common ligand affinities but ATP receptors are not coupled to adenylate cyclase, and (3) other vasodilators known to activate endothelial adenylate cyclase in vitro cause parallel increases in coronary conductance and adenylate cyclase activity in the beating heart.

Adenosine↗
PubMed1986

Subendothelial beta 2-adrenoceptors in the rat vena cava: facilitation of noradrenaline release via local stimulation of angiotensin II synthesis.

Preparations of the cranial segment of the rat inferior vena cava preincubated with 3H-noradrenaline were superfused in the presence of desipramine and corticosterone. Tritium overflow was stimulated electrically (2 Hz). The experiments were carried out in spirally cut strips with or without intima or in segments ligated at both ends and superfused either on the adventitial side ("conventionally") or "inside out". In spirally cut strips electrically evoked 3H overflow was increased by isoprenaline and procaterol, but much less so by prenalterol. Adrenaline 1 nmol/l increased overflow, but at high concentrations it reduced it, just as noradrenaline did at all concentrations. The concentration-response curve for isoprenaline was shifted to the right by propranolol (apparent pA2:8.29) and even more so by ICI 118-551, whereas atenolol was less potent (apparent pA2:6.42). Rauwolscine which, given alone, increased the evoked 3H overflow antagonized the inhibitory effect of noradrenaline (apparent pA2:7.58). These findings indicate that beta 2- and alpha 2-adrenoceptors mediating facilitation and inhibition of noradrenaline release, respectively, are present in the vena cava. The response to isoprenaline (at all concentrations) was considerably lower in segments superfused "conventionally" than in spirally cut strips, but no difference was observed with respect to the effects of noradrenaline, rauwolscine and angiotensin II. The effect of isoprenaline was clearly more pronounced in segments superfused "inside out" than in segments superfused "conventionally". In spirally cut strips angiotensin II increased 3H overflow. This effect was antagonized by saralasin, suggesting the involvement of facilitatory angiotensin receptors. In spirally cut strips or segments superfused "inside out", saralasin or captopril considerably attenuated the facilitatory effect of isoprenaline on 3H overflow. Conversely, in the presence of isoprenaline, captopril inhibited the electrically evoked 3H overflow in spirally cut strips, whereas in the absence of isoprenaline, captopril was ineffective. In conclusion, angiotensin receptors and alpha 2-adrenoceptors appear to be located on the sympathetic nerve endings, but a major part of the beta 2-adrenoceptors probably is subendothelial (most likely on smooth muscle cells). Angiotensin II, synthesized in response to beta 2-adrenoceptor activation, probably stimulates angiotensin receptors on the noradrenergic nerves, leading to an increase in noradrenaline release.

Angiotensin II↗
PubMedDate not supplied

Suppression by adrenoceptor beta-agonists of vascular permeability increase and edema formation induced by arachidonate metabolites, platelet-activating factor, and tumor-promoting phorbol ester TPA.

Air-pouch-type inflammation was induced by injecting sodium carboxymethyl cellulose solution containing leukotriene C4 (LTC4, 3.20 x 10(-7) M, 0.2 micrograms/ml) and prostaglandin E2 (PGE2, 5.68 x 10(-6) M, 2.0 micrograms/ml), platelet-activating factor (PAF, 1 x 10(-6) M, 0.52 micrograms/ml), or 12-O-tetradecanoyl phorbol 13-acetate (TPA, 1.62 x 10(-6) M, 1.0 micrograms/ml) into an air pouch made on the dorsum of rats. Vascular permeability and tissue edema formation were significantly increased by injecting the phlogogen solution. The histamine level in the pouch fluid was dramatically increased by injecting TPA but not by LTC4 and PGE2, or PAF. Injection of isoproterenol or procaterol with the phlogogen solution produced dose-dependent suppression of both vascular permeability increase and tissue edema formation. However, the TPA-induced increase in the histamine level was not suppressed in parallel with the decrease of vascular permeability or tissue edema formation. These results indicate that beta-agonists suppress vascular permeability response and local tissue edema formation not by inhibiting mast cell degranulation, but by inhibiting the reactivity of the local vasculature to chemical mediators such as arachidonate metabolites, PAF, and histamine and serotonin released from mast cells.

Adrenergic beta-Agonists↗
PubMed2000

Characterization of beta-adrenoceptor subtypes in the ferret urinary bladder in vitro and in vivo.

In the present study, the beta-adrenoceptor subtypes distributed in the detrusor of the ferret were investigated in functional experiments in vitro and in vivo using a variety of beta-adrenoceptor agonists and antagonists. All the beta-adrenoceptor agonists tested relaxed the isolated detrusor strip, the rank order of potency being (+/-)-(R*, R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]phenoxy]- acetic acid sodium (BRL 37344A)>(+/-)-4-(3-t-butylamino-2-hydroxypropoxy) benzimidazol-2-one (CGP-12177A), isoprenaline and (R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1, 3-benzodioxole-2,2-dicarboxylate (CL 316,243)>dobutamine and procaterol. In antagonist experiment, 3-(2-allylphenoxy)-1-[(1S)-1,2, 3,4-tetrahydro-naphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR 58894A), but neither 2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-imidaz ole-2-yl)-phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulphonate (CGP-20712A) nor erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol hydrochloride (ICI-118,551), caused a rightward shift of the concentration-relaxation curve for isoprenaline. In in vivo experiments, isoprenaline and CL 316,243 each reduced bladder pressure in a dose-dependent manner. CL 316,243 was the only drug that did not produce any significant influences on blood pressure and heart rate at doses that reduced bladder pressure. The present functional study provides the first evidence that relaxation of the ferret detrusor by beta-adrenoceptor activation is mediated mainly via the beta(3)-adrenoceptor, as in the human detrusor.

Adrenergic beta-Agonists↗
PubMed1986

Successful treatment of oligospermic and azoospermic men with alpha 1-blocker and beta-stimulator: new treatment for idiopathic male infertility.

We studied the effect of oral administration of alpha 1-blocker and beta-stimulator on 20 idiopathically infertile men. Bunazosin (alpha 1-blocker, 2 mg/day) and procaterol (beta-stimulator, 100 micrograms/day) were given orally twice daily for 5 months. The administration of alpha 1-blocker and beta-stimulator elicited an increase in sperm output and seminal volume in 16 patients (80%). The increase in sperm output seems to be associated with relaxations of myoid cells, which lead to dilatation of stenotic areas of seminiferous tubules, occurring discontinuously, and subsequent maintenance of good tubular fluid flow. No adverse effects were observed in this series.

Adrenergic alpha-Antagonists↗
PubMed1998

Suitability of the old fowl rectal caecum preparation for investigating the selectivity of beta-adrenergic drugs.

We tested alpha- and beta-adrenergic drugs on isolated strips of fowl rectal caecum from 14- to 16-week-old Warren hens. Basal tone and spontaneous motility were dose-dependently reduced by isoprenaline and all the selective beta-agonists tested (except xamoterol) with the following order of potency: isoprenaline=fenoterol=procaterol=clenbuterol>dobutamine> SR58611A. The results indicate that this tissue preparation consists almost entirely of beta2-adrenoceptors. This preparation may, therefore, be considered a suitable assay for discriminating beta1- from beta2-agonists according to their selectivity.

Adrenergic alpha-Agonists↗
PubMed2004

A guinea pig model for cough variant asthma and role of tachykinins.

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged nonproductive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity, and slightly increased bronchial responsiveness. Animal model of cough variant asthma has not been reported. The aim of this study was to establish an animal model for studying detailed pathophysiology of cough variant asthma. Bronchial responsiveness to methacholine and cough reflex sensitivity to capsaicin were measured 72 hours after antigen (ovalbumin, OA) inhalation in actively sensitized guinea pigs. Next, cough number and specific airway resistance (sRaw) were measured during 20 minutes following reinhalation of OA solution, which was carried out 72 hours after the first OA inhalation, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALE) were measured. Bronchial responsiveness to methacholine, but not cough reflex sensitivity to capsaicin, was significantly increased 72 hours after the first inhalation of OA solution. Number of coughs, sRaw and total cell number in BALF increased significantly by the OA reinhalation, and the cough number and the increase in sRaw were significantly suppressed by beta2 agonist, procaterol. FK224, a specific neurokinin (NK) receptor antagonist, did not significantly influence the OA reinhalation-induced cough and increase in sRaw and total cell number in BALF in this model In conclusion, pathophysiologic feature of this animal model is similar to that of clinical cough variant asthma. Tachykinins may not play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.

Airway Resistance↗
PubMed2004

Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine?

Migraine is a common, debilitating condition affecting up to 15% of the population. The ventroposteromedial nucleus of the thalamus relays trigeminal sensory input to the primary somatosensory cortex. In vivo electrophysiological recordings were made from the cell bodies of thalamocortical relay neurons in rats. We investigated whether microiontophoretic ejection of beta antagonists could inhibit thalamocortical activity in response to superior sagittal sinus (SSS) stimulation. We also studied 'postsynaptic' actions of these drugs through their modulatory actions on L-glutamate-evoked third order neuronal firing. Propranolol inhibited responses to SSS stimulation (P < 0.001) and L-glutamate ejection (P < 0.001). This was due to an action on beta receptors as it could be partially reversed by co-ejection of isoproterenol (SSS, P = 0.02; L-glutamate, P = 0.006). Serotonin (5-HT) receptor antagonism did not contribute to propranolol's action since the 5-HT1A receptor antagonist, (S)-WAY 100135 (P = 0.2), and the 5-HT1B/1D receptor antagonist, GR127935 (P = 0.6), did not affect L-glutamate-evoked neuronal firing. Atenolol inhibited both responses (SSS, P = 0.003; L-glutamate, P < 0.001). The beta2 antagonist ICI 118,551 had no effect (SSS, P = 0.9; L-glutamate, P = 0.4), nor did the beta2 agonist procaterol (SSS, P = 0.6; L-glutamate, P = 0.9). SR 59230A (beta3 antagonist) also produced no significant inhibition (SSS, P = 0.7; L-glutamate, P = 0.2), indicating an inhibitory role for beta1 antagonists only. beta Blockers therefore may exert some of their therapeutic effects in migraine through beta1 adrenoceptor antagonist actions in the thalamus. Thalamic involvement in migraine is attractive given the complex and widespread nature of the sensory disturbance.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta 1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy.

We evaluated the amount of beta 1- and beta 2-adrenoceptors in human right and left atrium as well as in right and left ventricular wall obtained from heart transplant recipients who suffered from end-stage congestive cardiomyopathy. The total number of myocardial beta-adrenoceptors was assessed with the nonsubtype selective beta-adrenoceptor radioligand (-)[125I]iodocyanopindolol (ICYP); concomitantly, the number of beta 1-adrenoceptors was determined with the selective beta 1-adrenoceptor radioligand (-)[3H]bisoprolol. The number of beta 2-adrenoceptors was calculated by subtracting (-)[3H]bisoprolol binding sites from ICYP binding sites. With this technique, a beta 1/beta 2-ratio of approximately 65/35% for both atria and of approximately 75/25% for both ventricles was found. Identical results were obtained when the beta 1/beta 2-ratio was calculated indirectly by nonlinear regression analysis of competition curves of the selective beta 1-adrenoceptor antagonist bisoprolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 with ICYP binding. In addition, on atria and on ventricles, adenylate cyclase was activated by norepinephrine (presumably by beta 1- and beta 2-adrenoceptor stimulation) and by procaterol (by beta 2-adrenoceptor stimulation). It is concluded that in the human heart functional beta 1- and beta 2-adrenoceptors coexist on both atria and both ventricles. In end-stage congestive cardiomyopathy, there appears to be a selective down-regulation of cardiac beta 1-adrenoceptors, whereas beta 2-adrenoceptors are obviously not affected. This may explain the beneficial effects of beta 2-adrenoceptor agonists in severe heart failure.

Adenylyl Cyclases↗
PubMed1985

Comparison of the responses to drugs acting on adrenoreceptors and muscarinic receptors in human isolated corpus cavernosum and cavernous artery.

The contractile and relaxant effects of drugs which interact with adreno- and muscarinic receptors were investigated in isolated tissue from the human corpus cavernosum urethrae (CC) and the cavernous artery (Acc). Isolated CC preparations were contracted in a concentration-dependent fashion by noradrenaline (NA), phenylephrine and clonidine in the mentioned order of potency. Prazosin was 300 times more active than rauwolscine in inhibiting NA-induced contractions. In segments of the isolated Acc, clonidine was more potent than NA and phenylephrine, and prazosin and rauwolscine were about equieffective in inhibiting NA-induced contractions. Prazosin was more effective than rauwolscine in CC strips, and rauwolscine more effective than prazosin in Acc segments in inhibiting the noradrenergically mediated part of electrically induced contractions. Isoprenaline, prenalterol and procaterol each relaxed NA-contracted CC preparations in a concentration-dependent way; this effect was blocked by propranolol. Isoprenaline had no relaxant action in Acc segments. Neither acetylcholine (ACh) nor carbachol produced contraction in CC and Acc preparations. ACh, but particularly carbachol, had potent relaxant effects in NA-contracted CC preparations. This effect of ACh and carbachol was blocked by scopolamine. Relaxant, but less potent effects of the muscarinic receptor agonists were found in the Acc segments. It is suggested that there are important differences between penile arteries and erectile tissue proper in the response to adrenoreceptor and muscarinic receptor active drugs. The contractile effect of NA seems to be mediated mainly by alpha 1-adrenoreceptors in the CC and by alpha 2-adrenoreceptors in the Acc. It cannot be excluded that muscarinic receptor-mediated relaxation of NA-contracted CC preparations can be of importance for penile tumescence and erection.

Acetylcholine↗
PubMed1989

Beta-adrenoceptor blocking effects of a selective beta 2-agonist, mabuterol, on the isolated, blood-perfused right atrium of the dog.

1. Effects of (+/-)-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.- butylamino-ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood-perfused right atrium of the dog. 2. Mabuterol, injected into the sinus node artery of the isolated atrium, dose-dependently increased atrial rate and contractile force at doses of 0.01-10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3. The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4. Positive chronotropic and inotropic responses to mabuterol were dose-dependently inhibited by a selective beta 2-adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5. Mabuterol (1-300 nmol) dose-dependently inhibited both dobutamine- and procaterol-induced positive chronotropic and inotropic responses. 6. These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating beta 2-adrenoceptors, and that higher concentrations non-selectively block both beta 1-and beta 2-adrenoceptors.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Partial agonism and functional selectivity: a study on beta-adrenoceptor mediated effects in tracheal, cardiac and skeletal muscle.

Colterol, procaterol, sulfonterol, terbutaline and three monophenolic derivatives of terbutaline were examined with respect to their ability to react in vitro on beta-adrenoceptors in tissues isolated from guinea-pig. The effects measured were a) relaxation of the tracheal smooth muscle (mostly beta 2), b) depression of subtetanic contractions of the soleus muscle (beta 2), and c) increase in the force of the papillary muscle of the left ventricle (beta 1). Antagonistic effects were measured against isoprenaline as an agonist. The compounds studied showed a wide variation in selectivity, potency and intrinsic activity. All agonists showed a pronounced beta 2-selectivity, in general characterized by a higher intrinsic activity at beta 2- than at beta 1-adrenoceptors, while differences in affinity, as judged from the pA2-values were small. Partial agonists, such as sulfonterol, which did not cause a complete relaxation of a moderately contracted tracheal muscle, produced identical concentration-response curves from the trachea and soleus muscle. It is concluded that partial agonism at beta 1-adrenoceptors is an important factor for functional selectivity of beta 2-adrenoceptor agonists. On the other hand there seems to be no useful differences between the maximum effect elicited by a partial beta 2-adrenoceptor agonist on the skeletal muscle as compared with airway smooth muscle.

Adrenergic beta-Agonists↗