Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure.
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Adrenergic Agonists↗
Biomedical subjects
O E Brodde
Publications and source records attributed to O E Brodde.
[The importance of the myocardial adrenoreceptors and their therapeutic significance].
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Adrenergic alpha-Antagonists↗
[Essential hypertension: also a disease of the adrenoreceptors?].
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Animals↗
Beta- and alpha-adrenoceptor-agonists and -antagonists in chronic heart failure.
In patients with chronic heart failure, cardiac beta-adrenoceptor function is decreased, and this decrease is related to the degree of heart failure. Under these conditions, treatment with beta-adrenoceptor agonists seems to be of limited value as it might further down-regulate cardiac beta-adrenoceptors, resulting, finally, in a loss of therapeutic efficacy. However, beta-adrenoceptor antagonists might have beneficial effects, because they can protect the myocardium from the deleterious effects of elevated endogenous catecholamines and can, simultaneously, restore the previously down-regulated beta-adrenoceptor function. Stimulation of cardiac alpha-adrenoceptors, however, seems not to be of any therapeutic value in patients with chronic heart failure, because a) the number of alpha-adrenoceptors in the human heart is very low and its function is not completely understood, and b) no alpha-adrenoceptor agonist is presently available that selectively stimulates cardiac alpha-adrenoceptors without concomitantly activating vascular alpha-adrenoceptors. In acute myocardial ischemia, cardiac beta-adrenoceptors increase; this increase is--at least in early acute myocardial ischemia--accompanied by an increased beta-adrenoceptor functional responsiveness; thus, under these conditions, beta-adrenoceptor agonists again might not be of clinical value, while beta-adrenoceptor antagonists may exert beneficial effects, because they can block (over)activation of the sensitized beta-adrenoceptors by elevated endogenous catecholamines.
Coronary Disease↗
Physiology and pharmacology of cardiovascular catecholamine receptors: implications for treatment of chronic heart failure.
In the sympathetic nervous system the physiologic effects of the endogenous catecholamines noradrenaline (NA) and adrenaline (A) are mediated by alpha- and beta-adrenoreceptors (ARs). Both AR-types can be subdivided into two major subtypes: alpha-ARs into alpha-1 (predominant effect: vasoconstriction) and alpha-2 (presynaptic: inhibition of NA-release; postsynaptic: vasoconstriction), beta-ARs into beta-1 (cardiac effects, renal renin release, and lipolysis) and beta-2 (presynaptic: facilitation of NA-release; postsynaptic: vascular, bronchial, and uterine smooth muscle relaxation, glycogenolysis and possibly part of the A-mediated cardiac effects). During the last 30 years growing evidence has accumulated that dopamine (DA), the third endogenous catecholamine and the immediate precursor of NA, may also cause peripheral effects through stimulation of specific DA-receptors, in addition to its known action at alpha- and beta-ARs. It is now well accepted that at least two different DA-receptors are present in many peripheral tissues (DA1 and DA2), including those of the cardiovascular and autonomic nervous system. They seem to be involved in dilation of certain vascular beds, inhibition of NA-release during nerve stimulation, natriuresis, and aldosterone release. In chronic heart failure cardiac beta-AR function decreases (presumably due to endogenous "down-regulation" by the elevated catecholamines), and this decrease is related to the severity of heart failure (judged clinically by New York Heart Association functional class). The human heart contains both functional beta-1 and beta-2 ARs; cardiac beta-1 and beta-2 ARs seem to be differentially affected by different kinds of heart failure; in end-stage dilated cardiomyopathy beta-1 ARs are selectively reduced, whereas beta-2 ARs are nearly normal.(ABSTRACT TRUNCATED AT 250 WORDS)
Heart Failure↗
On the physiologic role of beta-2 adrenoceptors in the human heart: in vitro and in vivo studies.
To study the physiologic role of human myocardial beta-2 adrenoceptors, the beta adrenoceptor subtype(s) involved in the effects of catecholamines in vitro on the force of contraction and in vivo on heart rate were characterized. In vitro on both isolated electrically driven right and left atrial and left papillary muscle preparations, isoprenaline and adrenaline caused positive inotropic effects via beta-1 and beta-2 adrenoceptor stimulation. In the atria both beta-1 and beta-2 adrenoceptor stimulation increased contractile force to a maximum; in left papillary muscle, however, only beta-1 adrenoceptor stimulation maximally increased contractile force, whereas beta-2 adrenoceptor stimulation caused only submaximal increases. Noradrenaline, on the other hand, caused a positive inotropic effect nearly exclusively via atrial and ventricular beta-1 adrenoceptor stimulation. In vivo in 10 healthy volunteers isoprenaline-induced tachycardia was antagonized with equal potency by the beta-2 adrenoceptor-selective antagonist ICI 118,551 and the beta-1 adrenoceptor-selective antagonist bisoprolol indicating that it is mediated by cardiac beta-1 and beta-2 adrenoceptor stimulation to about the same degree. In contrast, exercise-induced tachycardia (that is mediated mainly by noradrenaline released from the neurons) was antagonized only by bisoprolol but not by ICI 118,551. It is concluded that in humans under normal physiologic conditions contractility and/or heart rate is regulated only by cardiac beta-1 adrenoceptors. In situations of stress, however, when large amounts of adrenaline are released from the adrenal medulla, stimulation of cardiac beta-2 adrenoceptors could contribute to additional increases in contractility, heart rate, or both.
Adrenergic beta-Agonists↗
Mitigation of beta 1- and/or beta 2-adrenoceptor function in human heart failure.
1. Patients with congestive heart failure (CHF) have an elevated activity of the sympatho-adrenal system. We have investigated several aspects of beta-adrenoceptor desensitization in such patients. 2. The positive inotropic response to isoprenaline was attenuated in CHF patients, and the pD2-values for isoprenaline's positive inotropic effect gradually decreased in more severe forms of the disease. Stimulation of adenylate cyclase by isoprenaline was also mitigated in cardiac membranes from patients with CHF. 3. We then studied the density of cardiac beta 1- and beta 2-adrenoceptors in order to understand the mechanism of beta-adrenoceptor desensitization in these patients. Our data show that cardiac beta 1-adrenoceptors are down-regulated in all forms of severe CHF, but that cardiac beta 2-adrenoceptor density decreases only in some forms of CHF including ischaemic cardiomyopathy and mitral valve disease. 4. In circulating mononuclear leucocytes (MNL) obtained from CHF patients at rest, isoprenaline- and prostaglandin E1-stimulated cAMP generation as well as cholera toxin and pertussis toxin catalyzed ADP ribosylation were similar to those in MNL from control patients. However, pretreatment of intact MNL with pertussis toxin enhanced cAMP generation in CHF patients but not in healthy control subjects, suggesting a tonic inhibitory effect of Gi in such patients. 5. We conclude that alterations of adrenoceptors and of their signal transduction might contribute to the desensitization of beta-adrenergic responses in CHF.
Heart Failure↗
Differential regulation of human cardiac beta-adrenergic and muscarinic receptors by chronic beta-adrenoceptor antagonist treatment.
In patients undergoing coronary artery bypass grafting chronic beta 1-adrenoceptor antagonist treatment increased right atrial beta 1-adrenoceptor number, did not affect beta 2-adrenoceptor number and decreased muscarinic M2-receptor number. Concomitantly, the M2-receptor-mediated negative inotropic effect of carbachol was reduced, while the beta 1-adrenoceptor-mediated positive inotropic effect of noradrenaline was not altered. The beta 2- adrenoceptor mediated positive inotropic effect of procaterol, however, was markedly enhanced. We conclude that chronic beta 1-adrenoceptor antagonist treatment increases beta 1-adrenoceptor number, sensitizes beta 2-adrenoceptor function and desensitizes M2-receptor function in the human heart.
Adrenergic beta-Antagonists↗
Cyclic AMP antagonizes mitogen-induced accumulation of inositol phosphates in human peripheral mononuclear leucocytes in vitro.
The effect of intracellular increases of cyclic adenosine monophosphate (cAMP) on the accumulation of inositol phosphates (IPs) in response to various mitogens in vitro in human peripheral mononuclear leucocytes (MNL) was investigated. The beta-adrenoceptor agonists inhibited mitogen-induced IPs-accumulation by about 30-50% with a rank order of potency isoprenaline greater than adrenaline much greater than noradrenaline. This rank order corresponded with the order of potency of the beta-adrenoceptor agonists to generate cAMP. The beta-adrenoceptor agonist-induced inhibition of IPs-accumulation in response to mitogen could be completely prevented by the beta 2-adrenoceptor selective antagonist ICI 118,551, but not by the beta 1-adrenoceptor selective antagonist CGP 20712A. Furthermore, the isoprenaline-induced inhibition of IPs-accumulation in response to mitogen could be enhanced by the phosphodiesterase inhibitor IBMX. We conclude that cAMP antagonizes mitogen-induced IPs-accumulation in human peripheral MNL in vitro.
Adrenergic beta-Agonists↗
Subclassification of peripheral dopamine receptors.
1. There is convincing evidence to suggest that two DA-receptor subtypes exist in the periphery, that can at best be differentiated by the potency of the antagonists SCH 23390 and domperidone: at DA-1 receptors the order of potency is SCH 23390 much greater than domperidone, at DA-2 receptors it is domperidone much greater than SCH 23390. 2. As in the adrenergic, muscarinic or 5-HT-receptor field, future studies employing both molecular biology and pharmacological approaches will show whether such a subclassification is sufficient to explain all peripheral effects of DA or whether DA-1 and DA-2 receptors have to be subdivided into further subtypes.
Animals↗
Chronic beta 1-adrenoceptor antagonist treatment sensitizes beta 2-adrenoceptors, but desensitizes M2-muscarinic receptors in the human right atrium.
1. In 64 patients undergoing coronary artery bypass grafting the effects of chronic beta 1-adrenoceptor antagonist (metoprolol, atenolol, bisoprolol) treatment on right atrial beta-adrenoceptor and muscarinic M2-receptor number and functional responsiveness were investigated. 2. The beta 1-adrenoceptor antagonists increased right atrial beta 1-adrenoceptor number, did not affect beta 2-adrenoceptor number, and decreased muscarinic M2-receptor number. 3. Concomitantly, activation of right atrial adenylate cyclase by 10 microM GTP, 10 microM isoprenaline and 1 microM forskolin was enhanced and inhibition by 100 microM carbachol was diminished. 4. On isolated, electrically driven right atria the beta 1-adrenoceptor-mediated positive inotropic effect of noradrenaline was - even with beta 1-adrenoceptor number increased - not altered, while the beta 2-adrenoceptor-mediated effect of procaterol was markedly enhanced. However, the carbachol-induced negative inotropic effect was decreased. 5. It is concluded that chronic beta 1-adrenoceptor antagonist treatment increases beta 1-adrenoceptor number and concomitantly sensitizes beta 2-adrenoceptor function, but desensitizes muscarinic M2-receptor function in the human heart.
Adenylyl Cyclase Inhibitors↗
Catecholamines increase lymphocyte beta 2-adrenergic receptors via a beta 2-adrenergic, spleen-dependent process.
We investigated the mechanisms underlying the increase in mononuclear leukocyte (MNL) beta 2-adrenergic receptor (AR) number and responsiveness after acute infusion of catecholamines. Infusion of isoproterenol and epinephrine, but not of norepinephrine, acutely increased MNL beta-AR density, and this was blocked by the beta 2-selective antagonist ICI 118,551 but not by the beta 1-selective antagonist bisoprolol, suggesting a beta 2-AR-mediated effect. Infusion of isoproterenol but not of norepinephrine also induced a lymphocytosis, with an increase in the number of circulating suppressor/cytolytic T (Ts/c)- and natural killer (NK)-cells but a decrease in helper T (Th)-cells, leading to a decreased Th-Ts/c-cell ratio. beta-AR density was higher in Ts/c-cells than in Th-cells. After isoproterenol infusion, beta-AR density was elevated in all lymphocyte subsets but not in monocytes or platelets, suggesting a lymphocyte-specific phenomenon. Infusion of isoproterenol in splenectomized patients did not alter lymphocyte subset composition and only slightly increased beta 2-AR density. In healthy subjects lymphocyte proliferation in response to various mitogens was attenuated after infusion of isoproterenol but not of norepinephrine; this effect was abolished in splenectomized patients. We conclude that the elevated MNL beta-AR density after acute exposure to beta-adrenergic agonists is caused by a release of lymphocyte subsets from the spleen into the circulation and/or by an exchange of lymphocyte subsets between the spleen and the circulation, whereby freshly released splenic lymphocytes appear to carry more beta-AR than those found in the circulation. This appears to impair immune responsiveness in a dual manner, by decreasing the Th-/Ts/c-cell ratio and by rendering lymphocytes more sensitive to the antiproliferative effects of catecholamines via a higher beta-AR density.
Adult↗
Agonist-induced desensitization of beta-adrenoceptor function in humans. Subtype-selective reduction in beta 1- or beta 2-adrenoceptor-mediated physiological effects by xamoterol or procaterol.
We investigated the effects of beta 2- (procaterol 2 x 50 micrograms/day for 9 days) and beta 1- (xamoterol 2 x 200 mg/day for 14 days) adrenoceptor agonists on lymphocyte beta 2-adrenoceptor density and beta 1- and beta 2-adrenoceptor in vivo function (assessed as isoprenaline-infusion-evoked hemodynamic effects and exercise-induced tachycardia) in healthy volunteers. Procaterol decreased lymphocyte beta 2-adrenoceptor density and all beta 2-adrenoceptor-mediated in vivo effects but did not affect beta 1-adrenoceptor-mediated in vivo effects. In contrast, xamoterol neither affected lymphocyte beta 2-adrenoceptors nor beta 2-adrenoceptor-mediated in vivo effects but decreased beta 1-adrenoceptor-mediated in vivo effects. It is concluded that in humans, generally long-term application of beta 1- or beta 2-adrenoceptor agonists causes desensitization of beta-adrenoceptor function but in a beta-adrenoceptor subtype-selective fashion.
Adrenergic beta-Agonists↗
Peripheral adrenergic receptors in hypertension.
Increased sympathoadrenal activity appears to play an important role in the development or maintenance of elevated blood pressure in hypertensive patients and various animal models of hypertension. Alterations of adrenergic receptor number or responsiveness might contribute to this increased activity. We therefore reviewed the data on adrenergic receptor alterations in hypertension with special emphasis on several key cardiovascular tissues (i.e., heart, vascular smooth muscle, and kidney) and on lymphocytes and platelets as human tissues available for such studies. The data suggest that the number of alpha-adrenergic receptors in hypertension is regulated by catecholamines, dietary salt intake, and genetic factors. Increases in renal alpha-adrenergic receptor number may be etiologic in genetic forms of essential hypertension. beta-Adrenergic receptor alterations in states of elevated blood pressure do not appear to be specific for genetic hypertension. Desensitization of beta-adrenergic receptor function in hypertensive animals and patients contrasts with reports of decreased, unchanged, and increased beta-adrenergic receptor number, suggesting that signal transduction of beta-adrenergic (and possibly other) receptors that stimulate adenylyl cyclase is disturbed in hypertension. The mechanisms of such heterologous desensitization in states of elevated blood pressure remain to be elucidated.
Animals↗
Effects of insulin-induced hypoglycemia on beta 2-adrenoceptor density and proliferative responses of human lymphocytes.
We studied the effects of insulin (0.1 IU/kg BW, iv)-induced hypoglycemia on lymphocyte beta 2-adrenoceptor function, lymphocyte subset distribution, and proliferative response to mitogen stimulation in 10 healthy volunteers. Thirty minutes after insulin injection plasma glucose levels were markedly decreased; concomitantly, plasma epinephrine levels had increased about 10-fold; plasma norepinephrine levels, however, increased only moderately. Lymphocyte beta 2-adrenoceptor density and the cAMP response to 10 mumol/L isoproterenol stimulation were elevated; lymphocyte Ts/c-cells had increased, whereas Th-cells had decreased, resulting in a decrease in the Th-/Ts/c-cell ratio from 1.7 to 1.0. These changes were accompanied by a significantly reduced lymphocyte proliferative response (measured as [3H]thymidine uptake) to mitogen stimulation. Two hours after insulin injection plasma catecholamines, lymphocyte beta 2-adrenoceptor function, lymphocyte subset distribution, and proliferative responses had returned to nearly preinsulin levels. We conclude that acute vigorous increases in endogenous epinephrine evoked by insulin-induced hypoglycemia are associated with increases in lymphocyte beta 2-adrenoceptor function, redistribution of lymphocyte subsets, and an (at least transiently) attenuated in vitro immune responsiveness.
Adult↗
The role of cardiac beta1- and beta2-adrenoceptor stimulation in heart failure.
Substantial evidence has accumulated that in the human heart both beta1- and beta2-adrenoceptors coexist. As a rule, the amount of beta2-adrenoceptors is higher in the atria (about 30% of the total beta-adrenoceptor population) than in the ventricular myocardium (about 20%). Both beta1- and beta2-adrenoceptors couple to adenylate cyclase and mediate positive inotropic effects of isoproterenol and epinephrine on isolated, electrically driven cardiac preparations. In the atria, stimulation of both beta1- and beta2-adrenoceptors causes maximal increases in contractile force; in the ventricular myocardium, however, only beta1-adrenoceptor stimulation maximally increases contractile force, whereas beta2-adrenoceptor stimulation evokes only submaximal increases. On the other hand, norepinephrine induces its positive inotropic effect on atrial and ventricular preparations solely via beta1-adrenoceptor stimulation. Because norepinephrine is the main transmitter of the human sympathetic nervous system, this indicates that under normal physiological conditions, the heart rate and contractility are under the control of cardiac beta1-adrenoceptors, whereas cardiac beta2-adrenoceptors play only a minor role, if at all. However, in situations of stress, when large amounts of epinephrine (acting at both beta1- and beta2-adrenoceptors with the same affinity) are released from the adrenal medulla, activation of cardiac beta2-adrenoceptors may contribute to an additional increase in heart rate and/or contractility. In chronic heart failure, cardiac beta-adrenoceptor function decreases (presumably due to endogenous "downregulation" by the elevated catecholamines), and this decrease is related to the severity of the disease (judged clinically by NYHA functional class). However, cardiac beta1- and beta2-adrenoceptors seem to be differentially affected in different kinds of heart failure: in end-stage dilated cardiomyopathy, beta1-adrenoceptors selectively decrease, whereas beta2-adrenoceptors are nearly normal. Under these (pathological) conditions, beta2-adrenoceptors may substitute for the loss in beta1-adrenoceptors, thereby maintaining contractility, at least partially. On the other hand, in end-stage ischemic cardiomyopathy, tetralogy of Fallot, and mitral valve disease, both beta1- and beta2-adrenoceptors concomitantly decrease. The reason for this differential regulation of cardiac beta1- and beta2-adrenoceptors in different forms of heart failure remains to be elucidated.
Adenylyl Cyclases↗
Subtype-selective modulation of human beta 1- and beta 2-adrenoceptor function by beta-adrenoceptor agonists and antagonists.
In healthy volunteers a 14-day treatment with the selective beta 1-adrenoceptor agonist xamoterol (2 x 200 mg/day) desensitized beta 1-adrenoceptor-mediated physiological effects, but did not affect beta 2-adrenoceptor-mediated effects; in contrast, a 9-day treatment with the selective beta 2-adrenoceptor agonist procaterol (2 x 50 micrograms/day) desensitized beta 1-adrenoceptor-mediated physiological effects, but did not affect beta 1-adrenoceptor-mediated effects suggesting that in general in man long-term treatment with beta-adrenoceptor agonists down-regulates beta-adrenoceptors, but in a beta-adrenoceptor subtype-selective manner. Similarly, in patients undergoing coronary artery bypass grafting chronic treatment with different beta-adrenoceptor antagonists without intrinsic sympathomimetic activity subtype-selectively up-regulated beta-adrenoceptors: non-selective antagonists (propranolol, sotalol) increased both cardiac beta 1- and cardiac, saphenous vein and lymphocyte beta 2-adrenoceptors, whereas beta 1-selective antagonists (metoprolol, atenolol, bisoprolol) increased only cardiac beta 1-, but not cardiac, saphenous vein or lymphocyte beta 2-adrenoceptors. Such a subtype-selective modulation of human beta 1- and beta 2-adrenoceptors should be taken into consideration when treating patients chronically with beta-adrenoceptor agonists and/or antagonists.
Adrenergic beta-Agonists↗
5-Hydroxytryptamine-receptor subtypes.
5-Hydroxytryptamine (5-HT) receptors were originally subclassified into the subtypes M and D based on the findings that 5-HT contracted the guinea-pig ileum by two different mechanisms: (a) directly by an effect on receptors located on smooth muscles (via D receptors), and (b) indirectly by an effect on neuronal receptors (M receptors), the activation of which caused acetylcholine release. With the introduction of radioligand-binding studies and the development of more selective 5-HT agonists and antagonists, it rapidly became apparent that this subclassification is an oversimplification, and it is now accepted that at least three, possibly four main families of 5-HT receptors exist: 5-HT1, 5-HT2, 5-HT3 and possibly 5-HT4 receptors. Furthermore, 5-HT1 receptors are not a homogeneous class, but are subdivided further into four subtypes: 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D. Whether 5-HT2 and 5-HT3 receptors are also a heterogeneous class of receptors is still a matter of controversy. Besides the differences in specific agonists and antagonists, 5-HT-receptor subtypes seem to differ also in their signal-transduction mechanisms. 5-HT1 receptors (with the exception of 5-HT1C) are coupled to adenylate cyclase, predominantly in an inhibitory fashion, but 5-HT1-mediated activation of adenylate cyclase has been also described. 5-HT2 receptors (and 5-HT1C) are coupled to PI turnover, while 5-HT3 receptors appear to be coupled directly to fast ion channels. On the other hand, 5-HT4 receptors couple obviously in an excitatory fashion to adenylate cyclase.
Adenylyl Cyclases↗