Functional β1 - and β2-adrenoceptors in the human myocardium

Functional β-adrenoceptor populations in the human heart were studied in vitro in electrically-paced strips of the right auricular and ventricular myocardium. The relative potency of selected agonists in producing inotropic responses (T_max, T′_max) in the presence of blockers for neuronal and extraneuronal uptakes was found to be as follows: isoprenaline > noradrenaline = adrenaline = salbutamol > dobutamine. Prenalterol had a negative inotropic effect in these preparations. The selective β₁ -(practoloI) and β₂-(H 35/25) blockers reduced inotropic responses to adrenaline (T_max, T′_max) and noradrenaline (T′_max) in the auricular strips. These results indicate the participation of β₂-adrenoceptors in inotropic responses in the human auricular and ventricular myocardium. For comparison, inotropic responses of electrically-paced rat myocardium to β-adrenergic agonists in the presence of blockers for neuronal and extraneuronal uptakes were likewise studied. The relative potencies for T_max were: noradrenaline = adrenaline > prenalterol > dobutamine = salbutamol. Given the high relative potency of salbutamol in the human myocardial strips (analogous to that previous shown in the β₂-dominated atria of the frog and trout) and the low relative potency of salbutamol in the rat tissue, these findings indicate a greater population of functionally active β₂-adrenoceptors in the human than in the rat myocardium.     

Functional alpha-adrenoceptors in human atrial preparations in the presence of beta-receptor blockade

Inotropic effects via cardiac alpha-adrenoceptors were studied in electrically driven auricular strips (1 Hz, 37 degrees C) from patients treated with beta-blockers for months prior to open heart surgery. Marked alpha-mediated positive inotropic effects were demonstrated with adrenaline (A), noradrenaline (NA) and phenylephrine (PHE) in the presence of beta-blocker and with blockers of the muscarinic receptor and of the neuronal and extraneuronal uptake mechanisms for the catecholamines. In the presence of approximately 10(-6) M propranolol the maximal effects as well as the potencies (pD2-values) for A and NA were not significantly different while higher than for PHE. The alpha 1-blocker, prazosin (10(-6) M), markedly reduced the pD2-values but not the intrinsic activities (alpha-values) for A, NA and PHE in the beta-blocked preparations. Methoxamine, however, induced negative inotropic responses at normal and low frequencies (1, 0.5 and 0.1 Hz) of stimulation, suggestive of non-specific, cardiodepressant effects. Other agonists with alpha-effects in other types of tissue (oxymethazoline, xylomethazoline and clonidine) were without effects on the force and velocity of contraction in the auricular strips under the present experimental conditions. The results show alpha 1-type of adrenoceptor-induced inotropic effects for A, NA and PHE during beta-blockade in human auricular strips, indicating that cardiac alpha 1-receptors may have clinical importance by increasing the inotropy of the human myocardium treated with beta-blocking agents.     

The inotropic and chronotropic effects of catecholamines on the dog heart

1. The chronotropic and inotropic responses of the denervated dog heart to intravenous infusions of noradrenaline, adrenaline and isoprenaline were studied.

2. The maximum rate of rise of pressure in the left ventricle of the heart, (dP/dt max) measured at a constant heart rate and mean systemic arterial pressure during each series of infusions, was used as an index of inotropic changes (Furnival, Linden & Snow, 1970).

3. The order of potency of the catecholamines in producing both chronotropic and inotropic effects was isoprenaline > adrenaline > noradrenaline.

4. For the same increase in heart rate produced by an infusion of a catecholamine, noradrenaline caused a greater inotropic effect than adrenaline, which in turn caused a greater increase than isoprenaline.

5. The chronotropic and inotropic effects of noradrenaline were potentiated by an intravenous injection of cocaine HCl (5 mg/kg), whereas those of isoprenaline were unchanged.

6. The relative difference between the responses to noradrenaline and isoprenaline was abolished by an intravenous injection of cocaine HCl.

7. It is concluded that the different relative chronotropic and inotropic effects of isoprenaline and noradrenaline are due to the greater uptake of noradrenaline by sympathetic nerve endings in the sinu-atrial node than in the muscle of the left ventricle.

     

Positive inotropic effect on the rat atrial myocardium compressed to 5, 10 and 30 bar

The contractile activity of spontaneously beating auricular preparations from the rat was studied during and after pressure exposure to 5, 10 and 30 bar in three series of experiments (compression and decompression rate: 1 bar min-1). The preparations were mounted in an organ bath within a pressure chamber and perfused with oxygenated preheated Krebs-Henseleit solution (37 degrees C, pH = 7.45) containing alpha-, beta- and muscarinic-receptor blockers and blockers of the neuronal and extraneuronal uptake mechanisms. No change in chronotropy of the cardiac preparations were observed during or after exposures to the pressures tested. Significant increase in cardiac contractility (20-40%, P less than 0.01) described by the peak tension (Tmax), the maximal velocity of tension rise (T'max) and fall (T'min) were apparent at 5 and 10 bar. Further significant elevations (60-80%, P less than 0.05) in Tmax, T'max and T'min were detected during exposure to 30 bar. The cardiac contractility increased rapidly with pressure, was approximately unchanged during stable elevated pressures at 5, 10 and 30 bar, but was maintained above control values 15 min after completed decompression. Since no change in chronotropy and loading of the preparations occurred, it is concluded that the increased contractility is due to a positive inotropy generated by the hydrostatic pressure. Furthermore, it is indicated that this positive inotropy is not related to adrenoceptor activation since the effect was achieved in the presence of alpha-, and beta-adrenoceptor blockade.     

Central hemodynamic effects of adrenaline with special reference to beta 2-adrenergic influence on heart rate and cardiac afterload in anesthetized cats

Central hemodynamic responses evoked by i.v. infusions of adrenaline and noradrenaline were studied in normovolemic anesthetized cats with intact adrenoceptors, after selective beta 2-blockade (ICI 118,551), and after nonselective beta-blockade propranolol). The results demonstrated the presence of an important beta 2-adrenergic component in the integrated response to 'physiological' doses of adrenaline contributing to increased cardiac output, decreased total peripheral resistance and virtually unchanged mean arterial blood pressure. Corresponding beta 2-adrenergic effects of noradrenaline were small. The beta 2-adrenergic effects of adrenaline on the heart seemed to be both direct and indirect. A moderate direct chronotropic response mediated by beta 2-adrenoceptors apparently was present but there was no evidence of a direct beta 2-adrenergic inotropic effect. An indirect, quite marked effect on the heart was accomplished by a beta 2-adrenergic vasodilator interaction with the alpha-adrenergic vasoconstrictor influence on the systemic resistance vessels. This caused a net decrease in total peripheral resistance, thereby preventing an undue increase in cardiac afterload (arterial pressure) which seemed to be essential for evoking 'optimal' increases in cardiac output. It is suggested that such adrenaline evoked indirect, beta 2-adrenergic improvement of cardiac performance is of functional importance in reflex sympatho-adrenal circulatory control.     

Inhibitory effects of desmethylimipramine, metanephrine and normetanephrine on the neuronal and extraneuronal accumulation of catecholamines in fish spleen

The effect of desmethylimipramine, metanephrine and normetanephrine on the neuronal and extraneuronal accumulation of radiolabelled adrenaline and noradrenaline were studied in the perfused spleen of the teleost fish, Atlantic cod, Gadus morhua. Desmethylimipramine was found to be a potent inhibitor for the neuronal accumulation of both adrenaline and noradrenaline in the cod spleen, suggesting similarities with the neuronal uptake mechanism in mammals. Metanephrine was found to inhibit the extraneuronal accumulation of noradrenaline, though not that of adrenaline, while normetanephrine did not change the extraneuronal accumulation of any of the catecholamines. Both metanephrine and normetanephrine were more potent neuronal uptake blockers than extraneuronal. Metanephrine inhibited only the neuronal accumulation of adrenaline, while normetanephrine inhibited neuronal accumulation of both catecholamines. It is concluded that adrenaline and noradrenaline accumulate differently in the adrenergic neurons of the cod spleen as was suggested earlier for noradrenaline and tyramine (Nilsson & Holmgren 1976). It is also evident from the study that the uptake mechanisms or accumulation of catecholamines in lower vertebrates such as fish may be different from corresponding mechanisms in mammals.     

Increased contribution of alpha 1- vs. beta-adrenoceptor-mediated inotropic response in rats with congestive heart failure

AIM: In failing myocardium the mechanical response to beta-adrenoceptor stimulation is attenuated. Alternative signalling systems might provide inotropic support when the beta-adrenoceptor system is dysfunctioning. Accordingly, the inotropic responses to alpha 1- and beta-adrenoceptor stimulation by the endogenous adrenoceptor agonist noradrenaline in non-failing and failing rat hearts were compared. METHODS: Chronic heart failure was induced in male Wistar rats by coronary artery ligation. Corresponding sham groups were prepared. After 6 weeks, papillary muscles from non-failing and failing hearts were isolated. Receptor binding studies were performed in the corresponding myocardium. The alpha 1-adrenoceptor-mediated inotropic response was not changed while the beta-adrenoceptor-mediated response was substantially reduced in failing compared with non-failing myocardium. RESULTS: No change in potency for the agonists was observed at the alpha 1-adrenoceptors, while an increased potency for the agonists at the beta-adrenoceptors was found during heart failure. The lusitropic response to beta-adrenoceptor stimulation was intact during heart failure. No over all change in affinity or number of either adrenoceptor type was observed in receptor binding studies. The alpha 1-adrenoceptor-mediated inotropic response became dominating compared with the beta-adrenoceptor-mediated one in failing rat myocardium in contrast to the dominating role of the latter in non-failing myocardium. The attenuation of the beta-adrenoceptor-mediated inotropic response in rat failing myocardium was not because of a reduced number of receptors. CONCLUSION: Increasing contractility through stimulation of alpha 1-adrenoceptors in situ by the endogenous agonist may be an alternative way of inotropic support during heart failure and even more so during beta-adrenoceptor blockade.     

Cell-enlargement-related polypeptides are induced via beta(1)-adrenoceptors in mouse parotids

Induction of cell and gland enlargement (growth-in-size) and induction of a group of secretory polypeptides (polypeptides C-G) seem to occur in close relationship in mouse parotid glands stimulated chronically by the nonselective beta-adrenergic agonist isoproterenol. To determine whether beta(1), beta(2), or both subtypes of beta-adrenergic receptors are involved in those responses, dose-dependency studies were carried out during a 7-day period of daily stimulations to assess the relative abilities of the selective beta-adrenergic agonists dobutamine (beta(1)) and salbutamol (beta(2)) to induce polypeptides C-G and growth-in-size. The relative abilities of the selective beta-adrenoceptor antagonists atenolol (beta(1)) and I.C.I. 118.551 (beta(2)) to interfere with the induction of both responses by chronic treatment with the various beta-adrenergic agonists were also studied. Parotid growth-in-size was assessed by evaluating wet weight, whole protein content, and light microscopy histology. The presence of polypeptides C-G was evaluated after SDS-polyacrylamide gel electrophoresis and Coomassie blue staining. Under these experimental conditions, dobutamine was found to be at least one order of magnitude more potent than salbutamol at inducing growth-in-size. Dobutamine was also found to be clearly stronger than salbutamol as an inducer of polypeptides C-G. On the other hand, atenolol was more effective than I.C.I. 118.551 at preventing the induction of polypeptides C-G and growth-in-size by isoproterenol, dobutamine, or salbutamol. Taken together, these results suggest that in mouse parotid glands, polypeptides C-G and growth-in-size are induced preferentially via adrenergic receptors of the beta(1)-subtype.     

Alteration in alpha- and beta-adrenoceptor profile of rabbit knee joint blood vessels due to acute inflammation

Experiments were performed to investigate the nature of - and -adrenoceptors in blood vessels supplying the posterior capsule of the acutely inflamed rabbit knee joint, and results were compared to findings from previous experiments on the normal joint, to assess any alteration which may occur in the adrenoceptor profile due to the inflammation process. Electrical stimulation of the posterior articular nerve resulted in vasoconstriction which was reversed to vasodilatation by phentolamine and yohimbine. The dose-response curves to close intra-arterial injection of -adrenoceptor agonists showed a rank-order potency of: adrenaline = phenylephrine = clonidine. The adrenaline dose-response curve was shifted to the right by administration of antagonists with a rank-order potency of: phentolamine = yohimbine = prazosin. At this stage of the experiments there was an equal response of 1- and 2-adrenoceptors in blood vessels of the acutely inflamed rabbit knee joint. In another group of animals the neurally mediated vasodilatation, which appeared after administration of phentolamine, was completely blocked by propranolol, and was reduced by about 50 % by atenolol. The dose-response curves to close intra-arterial injection of -adrenoceptor agonists showed a rank-order potency of: isoprenaline > salbutamol = dobutamine. The isoprenaline dose-response curve was shifted to the right by administration of antagonists with a rank-order potency of: propranolol > atenolol. These experiments also showed an almost equal response of 1- and 2-adrenoceptors in blood vessels of the acutely inflamed rabbit knee joint. Overall, compared to previous experiments on the normal joint in which 2- and 1-adrenoceptor responses predominated, acute inflammation resulted in a shift from 2- towards 1- and from 1- towards 2-adrenoceptor responses.     

Neuronal and extraneuronal uptake of L-3H-adrenaline and L-14C-noradrenaline in the fish spleen

The neuronal and extraneuronal uptake of adrenaline and noradrenaline in the isolated perfused spleen of the cod has been studied using radiolabelled amines. The neuronal uptake of adrenaline shows an optimum at 0.5 microgram/ml, but is less efficient than for noradrenaline in the concentration range 0.01-2.5 micrograms/ml. The neuronal uptake of noradrenaline accounts for 60-70% of the total (neuronal plus extraneuronal) uptake in the concentration range 0.01-1.0 microgram/ml. At higher concentrations (2.5-5.0 micrograms/ml) the importance of the extraneuronal uptake increases for both amines, to reach more than 90% of the total uptake at 5.0 micrograms/ml. The extraneuronal uptake shows equal efficiency for the two amines throughout the concentration range studied. It is concluded that the cod spleen possesses a neuronal uptake mechanism which shows a higher uptake efficiency for noradrenaline than for adrenaline, while the extraneuronal uptake mechanism shows no preference.     

Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

Summary To evaluate the negative inotropic effect of various Ca²⁺-antagonists in human myocardium without additional influences of preload, afterload, or frequency, we examined their effects on isometric force of contraction in isolated human papillary muscle strips and in auricular trabeculae. The 1,4-dihydropyridines isradipine, nitrendipine, and nifedipine, the phenylalkylamine verapamil, and the benzothiazepine diltiazem exerted concentration-dependent negative inotropic effects. The potency of the investigated Ca²⁺-antagonists was identical in papillary muscle strips of patients with only moderate clinical signs of heart failure undergoing mitral valve replacement-operation (NYHA II–III) and in terminally failing (heart transplantation, NYHA IV) human hearts. The IC₅₀ values were lower in auricular trabeculae than in papillary muscle strips. The difference was significant for nifedipine, nitrendipine, and verapamil. The restorative effects of external Ca²⁺ after pretreatment with Ca²⁺-antagonists were significantly less strong after pretreatment with 1,4-dihydropyridine than with non-dihydropyridines in papillary muscle strips. It is concluded that 1,4-dihydropyridines and verapamil and diltiazem did differently influence Ca²⁺-mediated increase in force of contraction. Moreover, a relation between the therapeutically active free plasma concentration in vivo and the negative inotropic potency in vitro can be found. This relation follows a rank order of potency for negative inotropism (isradipinenitrendipine 50 Effective concentration for half-maximal effect - EDTA Ethylenedinitriloacetate - FOC Force of contraction - FPC Free plasma concentration - IC₅₀ Inhibitory concentration required to decrease the developed force of contraction to 50% of basal value - NYHA New York Heart Association Class - PIE Increase in force of contraction - SEM Standard error of the mean Dedicated to Prof. Dr. med. F. Scheler on the occasion of his 65th birthday     

Comparison of β-adrenoceptors mediating vasodilatation in canine subcutaneous adipose tissue and skeletal muscle

Blood flow changes in response to various drugs in simultaneously autoperfused canine subcutaneous adipose tissue and gracilis muscle were compared to study the vascular β-adrenoceptors. Compared to isoprenaline the β₂-selective agonist salbutamol was 4–6 times more potent as a vasodilator in the muscle than in adipose tissue. Furthermore two β₁-selective agonists (Tazolol and H80/62) caused vasodilatation in adipose tissue but not in the gracilis muscle. When given by close i.a. injection after β-adrenoceptor blockade, adrenaline was a more potent vasoconstrictor than noradrenaline in both tissues. Before β-blockade, however, noradrenaline was the more potent vasoconstrictor in the gracilis muscle whereas adrenaline was more potent in adipose tissue. Intravenous infusion of adrenaline in doses causing vasodilatation in the muscle caused vasoconstriction in adipose tissue whereas intravenous infusion of noradrenaline caused vasoconstriction in both tissues. The present findings suggest that the β-adrenoceptors mediating vasodilatation in skeletal muscle are mainly of the β₂-type, whereas β₁-adrenoceptors seem to predominate in subcutaneous adipose tissue. Since adrenaline is a much more potent β₂- than β₁-agonist, these differences point to different roles of intravascular adrenaline in the two sites. In skeletal muscle circulating adrenaline is mainly a vasodilator whereas in subcutaneous adipose tissue it mainly acts as a vasoconstrictor.     

Autacoid and autonomic reactivity of sheep lung parenchymal strip and its modification by antigenic sensitization

Lung parenchymal strips (LPS) of horse plasma-sensitized and control sheep were studied isometrically in isolated organ baths and their responses to autacoid and autonomic agents were compared. Control LPS responded with contractions to histamine greater than carbachol greater than 5HT and relaxed to isoproterenol greater than adrenaline greater than phenylephrine. In sensitized LPS, adrenaline and phenylephrine-induced relaxations were converted to contractions and a new order of potency and efficacy for spasmogens was observed i.e. histamine greater than carbachol greater than adrenaline greater than phenylephrine greater than 5HT. Isoproterenol was also significantly (P less than 0.05) less potent and less effective in relaxing sensitized LPS compared to controls. Mepyramine, atropine and propranolol competitively antagonized their respective agonists (i.e. histamine, carbachol and isoproterenol) confirming the presence of H1-histaminergic, muscarinic-cholinergic and beta-adrenergic receptors respectively. The conversion of the relaxant effect of adrenaline and phenylephrine to a contraction supplemented by a significant reduction in isoproterenol activity suggests an impairment in the effective ratio of beta: alpha adrenoceptors in ovine LPS subsequent to antigenic sensitization.     

Separate roles for beta2- and beta3-adrenoceptors in memory consolidation

Consolidation of a labile memory which would not normally be stored can be achieved by intracerebral administration of noradrenaline. In a series of experiments using discriminated, one trial passive avoidance learning with the day-old chick, the effect of noradrenaline has been shown to be due to actions at different subtypes of adrenoceptors. The effect of noradrenaline is dose-dependent, with a moderate dose producing memory consolidation. However, higher doses of noradrenaline (0.3-10 nmol/hemisphere) prevent consolidation, an effect not seen with isoprenaline suggesting that these doses stimulate alpha-adrenoceptors. The promotion of memory consolidation by noradrenaline or isoprenaline at low doses was attributable to beta3-adrenoceptors and at medium doses to beta2-adrenoceptors. At higher doses of noradrenaline, there was alpha1-adrenoceptor-mediated inhibition of memory consolidation. Consolidation can also be achieved by administration of either beta2- or beta3-adrenoceptor agonists at specific times after training. Although these two adrenoceptors both promoted memory consolidation, there was a differential action on the stages of memory formation. The dose-response curve to the beta3- and the beta2-agonists was shifted by the appropriate antagonist but not by the antagonist at the other beta-adrenoceptor. Although beta1-adrenoceptors are present in chick brain, they do not seem to have a role in memory formation. These results explain why noradrenaline, acting at different adrenoceptors, can have different effects on memory formation with memory being either consolidated or inhibited depending on the dose. The findings also demonstrate a role in memory formation for beta3-adrenoceptors found in the brain. Agonists acting specifically at beta2- or beta3-adrenoceptors may be of value in diseases involving cognitive impairment.     

Functional alpha 1-adrenoceptors in the rat heart during beta-receptor blockade

In absence of beta-receptor blocking agents, alpha-adrenergic inotropic effects could be demonstrated in the rat myocardium for the synthetic alpha-agonists phenylephrine and methoxamine, but not for the naturally occurring catecholamines, adrenaline and noradrenaline. Other synthetic alpha-agonists were without effects. In the presence of the beta-receptor blocking agent, propranolol or timolol, marked alpha-effects were demonstrated for adrenaline and noradrenaline in both the right and left atria and the right ventricle. The results indicate that alpha-receptors may be functionally important in the beta-blocked myocardium.     

Comparison of beta-adrenoceptors mediating vasodilatation in canine subcutaneous adipose tissue and skeletal muscle.

Blood flow changes in response to various drugs in simulataneously autoperfused canine subcutaneous adipose tissue and gracilis muscle were compared to study the vascular beta-adrenoceptors. Compared to isoprenaline the beta 2-selective agonist salbutamol was 4--6 times more potent as a vasodilator in the muscle than in adipose tissue. Furthermore two beta 1-selective agonists (Tazolol and H80/62) caused vasodilatation in adipose tissue but not in the gracilis muscle. When given by close i.a. injection after beta-adrenoceptor blockade, adrenaline was a more potent vasoconstrictor than noradrenaline in both tissues. Before beta-blockade, however, noradrenaline was the more potent vasoconstrictor in the gracilis muscle whereas adrenaline was more potent in adipose tissue. Intravenous infusion of adrenaline in doses causing vasodilatation in the muscle caused vasoconstriction in adipose tissue whereas intravenous infusion of noradrenaline caused vasoconstriction in both tissues. The present findings suggest that the beta-adrenoceptors mediating vasodilatation in skeletal muscle are mainly ose tissue. Since adrenaline is a much more potent beta2- than beta1-agonist, these differences point to different roles of intravascular adrenaline in the two sites. In skeletal muscle circulating adrenaline is mainly a vasodilator whereas in subcutaneous adipose tissue it mainly acts as a vasoconstrictor.     

Functional α1-adrenoceptors in the rat heart during β-receptor blockade

In absence of β-receptor blocking agents, α-adrenergic inotropic effects could be demonstrated in the rat myocardium for the synthetic α-agonists phenylephrine and methoxamine, but not for the naturally occurring catecholamines, adrenaline and noradrenaline. Other synthetic α-agonists were without effects. In the presence of the β-receptor blocking agent, propranolol or timolol, marked α-effects were demonstrated for adrenaline and noradrenaline in both the right and left atria and the right ventricle. The results indicate that α-receptors may be functionally important in the β-blocked myocardium.     

Effects of dobutamine and salbutamol on haemodynamics and atrial natriuretic factor in patients with severe congestive heart failure.

The influence of two cardiac inotropic drugs, dobutamine and salbutamol, on plasma atrial natriuretic factor (ANF) was investigated in 20 patients with congestive heart failure. All were in New York Heart Association class-III or IV. The patients underwent right heart catheterization with determination of central pressures, cardiac output, and pulmonary arterial plasma ANF during incremental infusions with dobutamine or salbutamol. Fourteen patients completed the study. Both drugs induced comparable increases in cardiac index and decreases in total systemic vascular resistance (P less than 0.01) without significant changes in central pressures. Heart rate rose after salbutamol (P less than 0.05), but not after dobutamine. No changes in plasma ANF were observed after either of the drug infusions. ANF secretion rate was calculated from simultaneous measurements of ANF in right atrial and pulmonary arterial plasma before and after salbutamol infusion, and median values rose more than seven-fold (P less than 0.05). The results demonstrate that ANF secretion rate is augmented after beta-adrenergic agents, possibly by a direct beta 2-adrenergic stimulation, in patients with severe congestive heart failure, and that changes in plasma ANF are an insufficient measure of ANF release when patient samples are small.     

Noradrenaline-induced smooth muscle relaxation in the specific region of canine facial vein: implications for facial and cranial circulation

This study was performed to investigate the heterogeneity of physiological and pharmacological properties in segments of the facial veins with special reference to selective brain cooling. Canine facial veins were isolated and the isometric tension of each segment was measured using the organ bath technique. Vessels in the segments of the facial veins that run opposite to the buccal cavity automatically produced myogenic tone and tended to show spontaneous contractions, but vessels in other segments did not. When no contractile agent was used for precontraction, noradrenaline and adrenaline produced dose-dependent relaxations in the former venous segments, but contractions in the latter ones. A Schild plot analysis for metoprolol against denopamine and for ICI118,551 against salbutamol showed that the venous segments running opposite the buccal cavity contained both beta(1)- and beta(2)-adrenoceptors, but the other venous segments contained only beta(2)-adrenoceptors. Electrical field stimulation-induced tetrodotoxin-sensitive relaxations in the former venous segments were diminished by pretreatment with metoprolol, but not with ICI118,551, indicating that the electrical stimulation-induced relaxation may be related to the activation of beta(1)-adrenoceptors in the venous smooth muscles. In conclusion, the heterogeneity of the functional properties, especially in the distribution of beta-adrenoceptors, in different segments of canine facial veins was observed in the present study, and autoregulatory mechanisms, humoral mechanisms, and neural mechanisms were suggested to affect cranial venous drainage.     

Adrenaline produces the relaxation of guinea-pig airway smooth muscle primarily through the mediation of beta(2)-adrenoceptors.

The beta-adrenoceptor subtype that mediates adrenaline-induced relaxation was pharmacologically identified in smooth muscle cells of the isolated guinea-pig trachea. Adrenaline produced a concentration-dependent relaxation with a pD(2) value of 7.1. The concentration-response curve for adrenaline was shifted rightwards in a competitive fashion by the beta(1)-/beta(2)-nonselective antagonists propranolol and bupranolol, with pA(2) values of 8.85 and 8.97, respectively. Adrenaline-induced relaxation was not affected by the beta(1)-selective antagonists atenolol and CGP-20, 712A within the concentration ranges supposed to antagonize the beta(1)-subtype (atenolol, or=3x10(-6) M with a pA(2) value of 5.77. The concentration-response curve for adrenaline was also competitively antagonized by the beta(2)-selective antagonists butoxamine and ICI-118,551 with pA(2) values of 6.86 and 8.73, respectively. The pA(2) values of beta-adrenoceptor antagonists (propranolol, bupranolol, atenolol, butoxamine and ICI-118,551) tested against adrenaline were consistent with the values when tested against salbutamol, a beta(2)-selective adrenoceptor agonist. The present findings provide evidence that the relaxant response of the smooth muscle of the guinea-pig trachea to the adrenal medulla hormone, adrenaline, is mainly mediated through beta(2)-adrenoceptors.