STUDY - Technical - New Dacian's Medicine
Physiology
and Pharmacology of the Vegetative Nervous System (2)
Translation Draft
We've reached the peripheral dopaminergic system. In addition to its role as a neurotransmitter in the central nervous system, dopamine also functions as an inhibitory transmitter in the carotid sinus and sympathetic ganglia. It is also assumed that there is a distinct peripheral dopaminergic system. Dopamine causes a number of responses that cannot be attributed to classical stimulation of adrenergic receptors (it relaxes the lower esophageal sphincter, delays the emptying of the stomach, produces vasodilation in the mesenteric and renal arterial circulation, inhibits aldosterone secretion, directly stimulates renal excretion of sodium and inhibits NE release at the level of sympathetic nerve endings through a presympathetic inhibitory mechanism). Mediation of these dopaminergic effects in vivo is little known. Dopamine doesn't seem to be a circulating hormone.
Let's look at the adrenergic receptors now. Catecolamines influence effector cells by interacting with specific receptors on the cell surface. When stimulated by catecholamines, adrenergic receptors initiate a series of membranary changes, followed by a cascade of intracellular events, culminating in a measurable response. Two broad categories of catecholamine responses reflect the activation of two adrenergic receptor populations, called alpha and beta. Both alpha and beta receptors have been further divided into subtypes, which perform different functions and are susceptible to differentiated stimulation and blocking.
Alpha-adrenergic receptors that mediate vasoconstriction, intestinal relaxation and pupil dilation. E and NE are approximately as alpha receptor agonists. Distinct subtypes of alpha1 and alpha2 receptors are recognized. Initially, postsynaptic or post-junctional alpha-adrenergic receptors in the effector cells were designated alpha1, while prejunctional alpha-adrenergic receptors at the sympathetic nerve endings were designated as alpha2.
Currently, it is recognized that non-neural (postsynaptic) processes are also mediated by alpha2 receptors. Alpha1 receptors mediate the effects of classical alpha, including vasoconstriction (phenylephrine and methoxamine are selective alpha1 agonists, and prazosin is a selective alpha1 antagonist). The alpha2 receptor mediates presynaptic inhibition of NE release from adrenergic nerve endings, as well as other responses, including inhibition of AC release from cholinergic nerve endings, inhibition of lipolysis in adipocytes, inhibition of insulin secretion, stimulation of platelet aggregation and vasoconstriction in certain vascular beds. Alpha2-specific agonists include clonidine and alpha-methylnorepinephrine (these agents, the latter being derived from alpha-methyldopa in vivo, exert an antihypertensive effect by interacting with alpha2 receptors in sympathetic centers in the brain stem, which regulate blood pressure). Yohimbina is a specific alpha2 antagonist.
The "turn" of beta-adrenergic receptors has come. Physiological events associated with beta-adrenergic receptor responses include: stimulation of contractility and heart rate, vasodilation, bronchodilation and lipolysis. Beta receptor responses can also be divided into two types. Beta1 receptors respond equally to E and NE and mediate cardiac stimulation and lipolysis. The beta2 receptor is more sensitive to E than TO NE and mediates responses such as vasodilation and bronchodilation. Isoproterenol stimulates, and propanolol blocks beta1 and beta2 receptors.
Other agonists and antagonists with partial selectivity for beta1 or beta2 receptors were used for therapeutic purposes, when the desired response predominantly involved one of the two subtypes. Both pharmacological and molecular geneticstudies have demonstrated the existence of a distinct beta3-adrenergic receptor that promotes lipolysis in white and brown fat tissue, as well as the production of caloric energy in brown fat tissue. The human beta3-adrenergic receptor has been cloned and a distinct polymorphism has been observed, which may be associated with weight gain, insulin resistance and type 2 diabetes mellitus. The beta3-adrenergic receptor has a higher affinity for NE than for E and, unlike beta1 and beta2 receptors, does not exhibit desensitization. Synthetic agonists for the beta3 receptor, currently in the study, have a potential role in the treatment of obesity by increasing metabolism.
Specific dopaminergic receptors, distinguished from classical alpha and beta-adrenergic receptors, are found in the central and peripheral nervous system and in several non-neuronal tissues. Two types of dopaminereceptor receptors have different functions and different second messengers. Dopamine is a potent agonist for both types of receptors: the action of dopamine is antagonized by phenothiasides and tioxanthins. The D1 receptor mediates vasodilation in the renal, mesenteric, coronary and cerebral territory. Phenoldopam is a selective, investigative agonist of the D1 receptor. The D2 receptor inhibits the transmission of nerve impulses in the sympathetic ganglia, inhibits the release of NE from sympathetic nerve endings by action on the presynaptic membrane, inhibits the release of prolactin from the pituitary gland and causes vomiting. Selective d2 receptor agonists include: bromocriptin, lergotril and apomorphine, while butirofenones, such as haloperidol (active in the central nervous system), domperidone (do not cross the blood-brain barrier easily) and sulpiride (a benzamide) are relatively selective antagonists of D2 receptors.
Let's "discuss" some things about the structure and function of adrenergic receptors. Adrenergic receptors belong to a superfamily of flat-protein, related G-protein membranary proteins, of which the visual protein (rodopsin) and muscarinic cholinergic receptors belong. These proteins have analogous sequences and, as is apparent from the properties of constituent amino acids, a similar topography in the structure of the cell membrane. Characteristic features include 7 hydrophobic transmembrane sequences containing 22-28 amino acids each. Membranary sequences, especially M-7s, appear to be important for the characteristic binding of the agonist.
It's the turn to hook up the receiver with the cellular response. The major mediators of adrenergic cellular responses (and many others) belong to a family of regulating cellular proteins called G proteins, which, when activated, bind the guanosine triphosphate (GTP) nutre. The best described G proteins are those that stimulate or inhibit adenylatcyclase, proteins designated G8 and Gi respectively (receptor action is therefore associated with adenylate-cyclase stimulation and cause intracellular growth of cyclic monophosphate adenosine (APMc)), which in turn leads to the activation of protein-kinase A and other AMPc-dependent protein-kinases.
Consecutive phosphorylation of some proteins alters the activity of some enzymes and the function of other proteins, culminating in the cellular response characteristic of stimulated tissue. The alpha2 receptor, the M2 subtype of the muscarinic cholinergic receptor and the D2 receptor are coupled with Gi, causing adenylcyclasis activity to decrease and THE AMPc concentration to decrease. Consecutive changes in enzyme activity and function of other proteins cause a number of alternative, frequently opposite cellular responses. Although many alpha2 responses can be explained by inhibition of adenylate-cyclase, other mechanisms may be involved as bin.
The alpha1 adrenergic receptor (as well as the M1 subtype of the acetylcholine receptor) appears to be coupled with a different G protein, which activates phospholipase C (this protein G has not been so well characterized and is sometimes designated Gq. The action of the receptor stimulates phospholipase C, which catalyzes the release of phospholipids attached to the membrane, in particular phosphatidilinositol-4,5-biphosphate - PIP2 - with the production of inositol-1 ,4,5-triphosphate - IP3 - and 1,2-diacilglycerol - DAG -, both acting as second messengers). IP3 rapidly mobilizes calcium from the intracellular deposits of the endoplasmic reticulum, producing an increase in free cytoplasmic calcium, which, itself and on the calcium-calmodulin-dependent protein-kinase pathway, influences cell processes appropriate to the stimulated cell.
The transient increase in calcium, produced by IP3 by release from intracellular deposits, is strengthened in the presence of continuous agonist stimulation by changes in the membrane flow of calcium from the extracellular environment through mechanisms that are incomplete characterized. DAG, the second second messenger produced under the action of phospholipase C on PIP2 (as on other membranary phospholipids), remains associated with the cell membrane and activates proteinkinase C, which has different substrates from those of calcium-calmodulin dependent kinases stimulated by IP3. Protein phosphoryllation, stimulated by proteinkinase C, contributes to specific tissue responses on the paths are little known. Increased intracellular calcium also potentiates the activation of proteinkinase C.
I'm going to complete this post with the regulation of adrenergic receptors. Prolonged exposure to alpha or beta-adrenergic agonists decreases the number of adrenergic receptors in the effector cells. Although the biochemical mechanisms involved are unclear, the internalization of the beta-adrenergic receptor in the cell occurs during exposure to the agonist in certain systems, suggesting that internal translocation contributes to the decrease in the number of receptors in these circumstances. Changing the concentration of the agonist may also affect the affinity of the agonist receptor.
Adrenergic receptors that use adenylate-cyclase as a second messenger (beta and alpha2 adrenergic receptors) exist in high and low affinity states (exposure to agonist decreases the proportion of receptors in increased affinity). These changes in adrenergic receptors, induced by adrenergic agonists, are called homologous regulation. Changes in the density and affinity of adrenergic receptors, induced by agonists, appear to contribute to the decrease of physiological response, which occurs after prolonged exposure of the effector tissue to the adrenergic agonist, a phenomenon known as tachyfilaxia or desensitization. Adrenergic receptors are also influenced by other factors, besides adrenergic agonists, a process called heterological regulation.
Increasing the affinity of the alpha-adrenergic receptor, for example, may emphasize the potentiation of alpha-adrenergic responses that occur in response to the low temperatures of the external environment. Thyroid hormones potentiate beta receptor responses by changing their number and the effectiveness of coupling receptor action with physiological response. Estrogens and progesterone alter the sensitivity of the myometer to catecholamines by effects on alpha-adrenergic receptors. Glucocorticoids can influence adrenergic function, antagonizing the decrease of agonist-induced adrenergic receptors and thus counteracting tachyphilaxia in response to intense adrenergic stimulation. Alterations in sensitivity to catecholamines may also occur as a consequence of post-receptor changes, although these remain little known.
That's it for today... We will continue (next time) with the physiology of the sympatoadrenergic system. Until then: Love, Gratitude and Understanding!
We've reached the peripheral dopaminergic system. In addition to its role as a neurotransmitter in the central nervous system, dopamine also functions as an inhibitory transmitter in the carotid sinus and sympathetic ganglia. It is also assumed that there is a distinct peripheral dopaminergic system. Dopamine causes a number of responses that cannot be attributed to classical stimulation of adrenergic receptors (it relaxes the lower esophageal sphincter, delays the emptying of the stomach, produces vasodilation in the mesenteric and renal arterial circulation, inhibits aldosterone secretion, directly stimulates renal excretion of sodium and inhibits NE release at the level of sympathetic nerve endings through a presympathetic inhibitory mechanism). Mediation of these dopaminergic effects in vivo is little known. Dopamine doesn't seem to be a circulating hormone.
Let's look at the adrenergic receptors now. Catecolamines influence effector cells by interacting with specific receptors on the cell surface. When stimulated by catecholamines, adrenergic receptors initiate a series of membranary changes, followed by a cascade of intracellular events, culminating in a measurable response. Two broad categories of catecholamine responses reflect the activation of two adrenergic receptor populations, called alpha and beta. Both alpha and beta receptors have been further divided into subtypes, which perform different functions and are susceptible to differentiated stimulation and blocking.
Alpha-adrenergic receptors that mediate vasoconstriction, intestinal relaxation and pupil dilation. E and NE are approximately as alpha receptor agonists. Distinct subtypes of alpha1 and alpha2 receptors are recognized. Initially, postsynaptic or post-junctional alpha-adrenergic receptors in the effector cells were designated alpha1, while prejunctional alpha-adrenergic receptors at the sympathetic nerve endings were designated as alpha2.
Currently, it is recognized that non-neural (postsynaptic) processes are also mediated by alpha2 receptors. Alpha1 receptors mediate the effects of classical alpha, including vasoconstriction (phenylephrine and methoxamine are selective alpha1 agonists, and prazosin is a selective alpha1 antagonist). The alpha2 receptor mediates presynaptic inhibition of NE release from adrenergic nerve endings, as well as other responses, including inhibition of AC release from cholinergic nerve endings, inhibition of lipolysis in adipocytes, inhibition of insulin secretion, stimulation of platelet aggregation and vasoconstriction in certain vascular beds. Alpha2-specific agonists include clonidine and alpha-methylnorepinephrine (these agents, the latter being derived from alpha-methyldopa in vivo, exert an antihypertensive effect by interacting with alpha2 receptors in sympathetic centers in the brain stem, which regulate blood pressure). Yohimbina is a specific alpha2 antagonist.
The "turn" of beta-adrenergic receptors has come. Physiological events associated with beta-adrenergic receptor responses include: stimulation of contractility and heart rate, vasodilation, bronchodilation and lipolysis. Beta receptor responses can also be divided into two types. Beta1 receptors respond equally to E and NE and mediate cardiac stimulation and lipolysis. The beta2 receptor is more sensitive to E than TO NE and mediates responses such as vasodilation and bronchodilation. Isoproterenol stimulates, and propanolol blocks beta1 and beta2 receptors.
Other agonists and antagonists with partial selectivity for beta1 or beta2 receptors were used for therapeutic purposes, when the desired response predominantly involved one of the two subtypes. Both pharmacological and molecular geneticstudies have demonstrated the existence of a distinct beta3-adrenergic receptor that promotes lipolysis in white and brown fat tissue, as well as the production of caloric energy in brown fat tissue. The human beta3-adrenergic receptor has been cloned and a distinct polymorphism has been observed, which may be associated with weight gain, insulin resistance and type 2 diabetes mellitus. The beta3-adrenergic receptor has a higher affinity for NE than for E and, unlike beta1 and beta2 receptors, does not exhibit desensitization. Synthetic agonists for the beta3 receptor, currently in the study, have a potential role in the treatment of obesity by increasing metabolism.
Specific dopaminergic receptors, distinguished from classical alpha and beta-adrenergic receptors, are found in the central and peripheral nervous system and in several non-neuronal tissues. Two types of dopaminereceptor receptors have different functions and different second messengers. Dopamine is a potent agonist for both types of receptors: the action of dopamine is antagonized by phenothiasides and tioxanthins. The D1 receptor mediates vasodilation in the renal, mesenteric, coronary and cerebral territory. Phenoldopam is a selective, investigative agonist of the D1 receptor. The D2 receptor inhibits the transmission of nerve impulses in the sympathetic ganglia, inhibits the release of NE from sympathetic nerve endings by action on the presynaptic membrane, inhibits the release of prolactin from the pituitary gland and causes vomiting. Selective d2 receptor agonists include: bromocriptin, lergotril and apomorphine, while butirofenones, such as haloperidol (active in the central nervous system), domperidone (do not cross the blood-brain barrier easily) and sulpiride (a benzamide) are relatively selective antagonists of D2 receptors.
Let's "discuss" some things about the structure and function of adrenergic receptors. Adrenergic receptors belong to a superfamily of flat-protein, related G-protein membranary proteins, of which the visual protein (rodopsin) and muscarinic cholinergic receptors belong. These proteins have analogous sequences and, as is apparent from the properties of constituent amino acids, a similar topography in the structure of the cell membrane. Characteristic features include 7 hydrophobic transmembrane sequences containing 22-28 amino acids each. Membranary sequences, especially M-7s, appear to be important for the characteristic binding of the agonist.
It's the turn to hook up the receiver with the cellular response. The major mediators of adrenergic cellular responses (and many others) belong to a family of regulating cellular proteins called G proteins, which, when activated, bind the guanosine triphosphate (GTP) nutre. The best described G proteins are those that stimulate or inhibit adenylatcyclase, proteins designated G8 and Gi respectively (receptor action is therefore associated with adenylate-cyclase stimulation and cause intracellular growth of cyclic monophosphate adenosine (APMc)), which in turn leads to the activation of protein-kinase A and other AMPc-dependent protein-kinases.
Consecutive phosphorylation of some proteins alters the activity of some enzymes and the function of other proteins, culminating in the cellular response characteristic of stimulated tissue. The alpha2 receptor, the M2 subtype of the muscarinic cholinergic receptor and the D2 receptor are coupled with Gi, causing adenylcyclasis activity to decrease and THE AMPc concentration to decrease. Consecutive changes in enzyme activity and function of other proteins cause a number of alternative, frequently opposite cellular responses. Although many alpha2 responses can be explained by inhibition of adenylate-cyclase, other mechanisms may be involved as bin.
The alpha1 adrenergic receptor (as well as the M1 subtype of the acetylcholine receptor) appears to be coupled with a different G protein, which activates phospholipase C (this protein G has not been so well characterized and is sometimes designated Gq. The action of the receptor stimulates phospholipase C, which catalyzes the release of phospholipids attached to the membrane, in particular phosphatidilinositol-4,5-biphosphate - PIP2 - with the production of inositol-1 ,4,5-triphosphate - IP3 - and 1,2-diacilglycerol - DAG -, both acting as second messengers). IP3 rapidly mobilizes calcium from the intracellular deposits of the endoplasmic reticulum, producing an increase in free cytoplasmic calcium, which, itself and on the calcium-calmodulin-dependent protein-kinase pathway, influences cell processes appropriate to the stimulated cell.
The transient increase in calcium, produced by IP3 by release from intracellular deposits, is strengthened in the presence of continuous agonist stimulation by changes in the membrane flow of calcium from the extracellular environment through mechanisms that are incomplete characterized. DAG, the second second messenger produced under the action of phospholipase C on PIP2 (as on other membranary phospholipids), remains associated with the cell membrane and activates proteinkinase C, which has different substrates from those of calcium-calmodulin dependent kinases stimulated by IP3. Protein phosphoryllation, stimulated by proteinkinase C, contributes to specific tissue responses on the paths are little known. Increased intracellular calcium also potentiates the activation of proteinkinase C.
I'm going to complete this post with the regulation of adrenergic receptors. Prolonged exposure to alpha or beta-adrenergic agonists decreases the number of adrenergic receptors in the effector cells. Although the biochemical mechanisms involved are unclear, the internalization of the beta-adrenergic receptor in the cell occurs during exposure to the agonist in certain systems, suggesting that internal translocation contributes to the decrease in the number of receptors in these circumstances. Changing the concentration of the agonist may also affect the affinity of the agonist receptor.
Adrenergic receptors that use adenylate-cyclase as a second messenger (beta and alpha2 adrenergic receptors) exist in high and low affinity states (exposure to agonist decreases the proportion of receptors in increased affinity). These changes in adrenergic receptors, induced by adrenergic agonists, are called homologous regulation. Changes in the density and affinity of adrenergic receptors, induced by agonists, appear to contribute to the decrease of physiological response, which occurs after prolonged exposure of the effector tissue to the adrenergic agonist, a phenomenon known as tachyfilaxia or desensitization. Adrenergic receptors are also influenced by other factors, besides adrenergic agonists, a process called heterological regulation.
Increasing the affinity of the alpha-adrenergic receptor, for example, may emphasize the potentiation of alpha-adrenergic responses that occur in response to the low temperatures of the external environment. Thyroid hormones potentiate beta receptor responses by changing their number and the effectiveness of coupling receptor action with physiological response. Estrogens and progesterone alter the sensitivity of the myometer to catecholamines by effects on alpha-adrenergic receptors. Glucocorticoids can influence adrenergic function, antagonizing the decrease of agonist-induced adrenergic receptors and thus counteracting tachyphilaxia in response to intense adrenergic stimulation. Alterations in sensitivity to catecholamines may also occur as a consequence of post-receptor changes, although these remain little known.
That's it for today... We will continue (next time) with the physiology of the sympatoadrenergic system. Until then: Love, Gratitude and Understanding!
Dorin, Merticaru