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Pharmacology & Therapeutics 1996Over the years, a vast literature has accumulated on the adrenergic mechanisms controlling gut motility, blood flow, and mucosal transport. The present review is... (Review)
Review
Over the years, a vast literature has accumulated on the adrenergic mechanisms controlling gut motility, blood flow, and mucosal transport. The present review is intended as a survey of key information on the relevance of adrenergic mechanisms modulating gut motility and will provide an outline of our knowledge on the distribution and functional role of adrenoceptor subtypes mediating motor responses. alpha1-Adrenoceptors are located postsynaptically on smooth muscle cells and, to a lesser extent, on intrinsic neurons; alpha2-adrenoceptors may be present both pre- and postsynaptically, with presynaptic auto- and hetero-receptors playing an important role in the modulation of neurotransmitter release; beta-adrenoceptors are found mainly on smooth muscle cells. From a clinical standpoint, adrenoceptor agonists/antagonists have been investigated as potential motility inhibiting (antidiarrheal/antispasmodic) or prokinetic agents, although at present their field of application is limited to select patient groups.
Topics: Adrenergic Agents; Adrenergic Agonists; Adrenergic Antagonists; Adrenergic Fibers; Digestive System; Electrophysiology; Gastrointestinal Motility; Receptors, Adrenergic; Sympathectomy; Sympathetic Nervous System
PubMed: 8857303
DOI: 10.1016/0163-7258(95)02031-4 -
Archives of Physiology and Biochemistry Apr 2022Methylglyoxal (MG) is dicarbonyl aldehyde generated intracellularly from glucose and from some other compounds. Its increased formation is associated with several...
Methylglyoxal (MG) is dicarbonyl aldehyde generated intracellularly from glucose and from some other compounds. Its increased formation is associated with several harmful consequences. In the present study, short-term effects of MG on metabolism of isolated rat adipocytes were determined. Insulin-induced lipogenesis was unchanged by MG. However, epinephrine-stimulated lipolysis was shown to be significantly reduced in adipocytes exposed to 200 µM MG. This inhibitory effect was similar in the presence of low and high concentrations of glucose, and also in the presence of alanine. However, MG failed to affect lipolysis induced by forskolin (activator of adenylate cyclase), dibutyryl-cAMP (activator of PKA) and DPCPX (adenosine A receptor antagonist). It was also revealed that lipolysis was unchanged by MG in fat cells pre-incubated with this compound, and then stimulated with epinephrine alone. Our results suggest that MG may impair β-adrenergic signalling in rat adipocytes due to interaction with epinephrine, and thereby disturbs lipolysis.
Topics: Adipocytes; Adrenergic Agents; Animals; Lipolysis; Pyruvaldehyde; Rats; Rats, Wistar
PubMed: 31711314
DOI: 10.1080/13813455.2019.1684953 -
Comparative Biochemistry and... Jul 2023In squamate reptiles, extensive innervation of the heart and vascular beds allows for continuous modulation of the cardiovascular system by the autonomic nervous system....
In squamate reptiles, extensive innervation of the heart and vascular beds allows for continuous modulation of the cardiovascular system by the autonomic nervous system. The systemic vasculature is the main target of excitatory sympathetic adrenergic fibers, while the pulmonary circulation has been described as less responsive to both nervous and humoral modulators. However, histochemical evidence has demonstrated the presence of adrenergic fibers in pulmonary circulation. Besides, reduced responsiveness is intriguing since the balance of regulation between systemic and pulmonary vascular circuits has critical hemodynamic implications in animals with an undivided ventricle and consequent cardiovascular shunts. The present study investigated the role and functional relevance of α and β-adrenergic stimulation in regulating systemic and mainly the pulmonary circulations in a decerebrate, autonomically responsive rattlesnake preparation. The use of the decerebrate preparation allowed us to observe a new diverse functional modulation of vascular beds and the heart. In resting snakes, the pulmonary vasculature is less reactive to adrenergic agonists at 25 °C. However, the β-adrenergic tone is relevant for modulating resting peripheral pulmonary conductance, while both α- and β-adrenergic tones are relevant for the systemic circuit. Active dynamic modulation of both pulmonary compliance and conductance effectively counterbalances alterations in the systemic circulation to maintain the R-L shunt pattern. Furthermore, we suggest that despite the great attention given to cardiac adjustments, vascular modulation is sufficient to support the hemodynamic adjustments needed to control blood pressure.
Topics: Animals; Crotalus; Adrenergic Agents; Heart Ventricles; South America
PubMed: 37031853
DOI: 10.1016/j.cbpa.2023.111421 -
Comparative Biochemistry and... May 2022Catecholamines mediate the 'fight or flight' response in a wide variety of vertebrates. The endogenous catecholamine adrenaline increases heart rate and contractile...
Catecholamines mediate the 'fight or flight' response in a wide variety of vertebrates. The endogenous catecholamine adrenaline increases heart rate and contractile strength to raise cardiac output. The increase in contractile force is driven in large part by an increase in myocyte Ca influx on the L-type Ca current (I) during the cardiac action potential (AP). Here, we report a K- based mechanism that prolongs AP duration (APD) in fish hearts following adrenergic stimulation. We show that adrenergic stimulation inhibits the delayed rectifier K current (I) in rainbow trout (Oncorhynchus mykiss) cardiomyocytes. This slows repolarization and prolongs APD which may contribute to positive inotropy following adrenergic stimulation in fish hearts. The endogenous ligand, adrenaline (1 μM), which activates both α- and β-ARs reduced maximal I tail current to 61.4 ± 3.9% of control in atrial and ventricular myocytes resulting in an APD prolongation of ~20% at both 50 and 90% repolarization. This effect was reproduced by the α-specific adrenergic agonist, phenylephrine (1 μM), but not the β-specific adrenergic agonist isoproterenol (1 μM). Adrenaline (1 μM) in the presence of β and β-blockers (1 μM atenolol and 1 μM ICI-118551, respectively) also inhibited I. Thus, I suppression following α-adrenergic stimulation leads to APD prolongation in the rainbow trout heart. This is the first time this mechanism has been identified in fish and may act in unison with the well-known enhancement of I following adrenergic stimulation to prolong APD and increase cardiac inotropy.
Topics: Action Potentials; Adrenergic Agents; Adrenergic Agonists; Animals; Epinephrine; Myocardium; Myocytes, Cardiac; Oncorhynchus mykiss; Potassium
PubMed: 35143950
DOI: 10.1016/j.cbpa.2022.111161 -
Journal of Biochemical and Molecular... Nov 2022Doxorubicin (DOX) is a potent chemotherapeutic agent used for cancer treatment, however, DOX-induced cardiotoxicity is a serious clinical problem because it causes acute...
Doxorubicin (DOX) is a potent chemotherapeutic agent used for cancer treatment, however, DOX-induced cardiotoxicity is a serious clinical problem because it causes acute and chronic heart dysfunction. Many studies have indicated that the α1-adrenergic receptor protects the heart from pathologic stress through activation survival signaling, however, the mechanism remains largely unknown. Previous studies have detected that the phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of α1-adrenergic signaling in cardiac hypertrophy. Our present study aimed to investigate the role and underlying mechanism of PEX1 in cardiomyocyte survival during DOX-induced cardiotoxicity. Mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. We found that PEX1 expression was downregulated in DOX-treated murine hearts. PEX1 deficiency resulted in increased apoptosis, and conversely, PEX1 overexpression alleviated apoptosis induced by DOX in primary cardiomyocytes, as well as upregulated antiapoptotic genes such as BCL-2 and BCL-XL. Mechanistically, we identified that PEX1 might exert its antiapoptosis effect by playing a pivotal role in the action of α1-adrenergic signaling activation, which depends on the presence of GATA-4. Based on these findings, we supposed that PEX1 may be a novel transcription factor involved in cardiac cell survival and a promising candidate target for DOX-induced cardiotoxicity.
Topics: Mice; Animals; Cardiotoxicity; Adrenergic Agents; Doxorubicin; Myocytes, Cardiac; Apoptosis; Transcription Factors; Oxidative Stress; ATPases Associated with Diverse Cellular Activities
PubMed: 35979984
DOI: 10.1002/jbt.23196 -
Advances in Therapy Jul 2010Despite the availability of a wide range of effective blood pressure (BP)-lowering agents, a substantial proportion of patients with hypertension fail to achieve target... (Review)
Review
Despite the availability of a wide range of effective blood pressure (BP)-lowering agents, a substantial proportion of patients with hypertension fail to achieve target BP levels. The majority of patients with hypertension need a combination of two or more drugs to achieve BP targets and choice of second-line or subsequent-line therapy is an important consideration in hypertension management. Alpha-1-adrenoreceptor antagonists (alpha-blockers) have a BP-lowering effect broadly similar to the other antihypertensive drug classes and are effective as add-on therapy in patients with inadequately controlled hypertension. Alpha-blockers may also have therapeutic benefits that go beyond BP control, including improvements in lipid profile and glucose metabolism, as well as reducing the symptoms of benign prostatic hyperplasia. Urapidil has an alpha-blocking effect but, unlike other alpha-blockers, also has a central sympatholytic effect mediated via stimulation of serotonin 5HT(1A) receptors in the central nervous system. Several studies have suggested that oral urapidil is effective and well tolerated when used as second-line therapy in patients with BP inadequately controlled with other agents. Urapidil has also been shown to improve glucose and lipid metabolism in hypertensive patients with concomitant diabetes and/or hyperlipidemia. Intravenous urapidil is effective in the treatment of hypertensive crises, perioperative hypertension, and pre-eclampsia and may have a potential role in the management of acute stroke. In this review, the use of alpha-blockers in hypertension is discussed, with particular focus on urapidil for the lowering of BP in a variety of clinical settings.
Topics: Adrenergic alpha-Antagonists; Antihypertensive Agents; Drug Therapy, Combination; Humans; Hypertension; Piperazines; Serotonin Receptor Agonists
PubMed: 20652659
DOI: 10.1007/s12325-010-0039-0 -
Contraception Jun 1988The purpose of this study was to investigate the efficacy and the acceptability of Prazosin as a male contraceptive pill. Acceptable antifertility drugs for men are...
The purpose of this study was to investigate the efficacy and the acceptability of Prazosin as a male contraceptive pill. Acceptable antifertility drugs for men are proving difficult to produce, and the possibility of using pharmacological agents to block selectively or to inhibit normal sperm transport through the male genital tract is an interesting approach. Prazosin administered in doses up to 10 mg/day did not cause azoospermia following ejaculation. In conclusion, we have not been able to confirm either the efficacy or the acceptability of the alpha 1-adrenoceptor antagonist Prazosin as a male contraceptive drug. Homonnai et al. confirmed the fact that phenoxybenzamine blocks ejaculation, but it should be noted that although both drugs are alpha 1-adrenoceptor blocking agents, they are not chemically identical.
Topics: Adrenergic alpha-Antagonists; Contraceptive Agents, Male; Humans; Male; Prazosin; Semen; Sexual Behavior; Sperm Count
PubMed: 2899490
DOI: 10.1016/0010-7824(88)90008-x -
Survey of Ophthalmology Apr 2003Four criteria are used to evaluate the potential usefulness of an agent for neuroprotection in glaucoma: 1) the agent must have a target in the retina; 2) it must be... (Review)
Review
Four criteria are used to evaluate the potential usefulness of an agent for neuroprotection in glaucoma: 1) the agent must have a target in the retina; 2) it must be neuroprotective in animal models; 3) it must reach neuroprotective concentrations in the posterior segment after clinical dosing; and finally, 4) it must be shown to be neuroprotective in clinical trials. The alpha-2 adrenergic agonist brimonidine has met the first three criteria and clinical trials to establish the fulfillment of the fourth criterion are ongoing. The effects of brimonidine are mediated by its interaction with alpha-2 adrenergic receptors that are present in the retina. Activation of alpha-2 receptors by brimonidine has been shown to effectively promote the survival and function of retinal ganglion cells in a variety of animal models of optic injury relevant to glaucoma such as the chronic ocular hypertensive rat and rat optic nerve crush. Brimonidine has also been shown to be neuroprotective in the rat ischemia reperfusion model that evaluates general hypoxic damage to the whole retina. Clinical dosing of the topical formulation of brimonidine results in brimonidine concentrations in the posterior segment that are sufficient for both pharmacological activity at alpha-2 adrenergic receptors and neuroprotection. Finally, clinical trials are in progress to investigate the ability of brimonidine to protect human retinal ganglion cells and the visual field in glaucoma-related disease.
Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Brimonidine Tartrate; Glaucoma; Humans; Neuroprotective Agents; Quinoxalines; Receptors, Adrenergic, alpha-2; Retinal Ganglion Cells
PubMed: 12852434
DOI: 10.1016/s0039-6257(03)00004-3 -
American Journal of Hypertension Mar 2001Oxidized low-density lipoprotein (ox-LDL) is well known to play an important role in atherogenesis through the recruitment of monocytes into vessel walls and the...
Oxidized low-density lipoprotein (ox-LDL) is well known to play an important role in atherogenesis through the recruitment of monocytes into vessel walls and the deposition of cholesterol ester in the macrophages, which leads to the formation of lipid-rich plaque. It was assumed that only trace amounts of ox-LDL were present in plasma because the half-life of ox-LDL was only a few minutes. Recently, through the use of a monoclonal antibody against ox-LDL, a quantitative method to measure serum ox-LDL concentration has been developed. Metabolites of doxazosin, an alpha1-adrenergic antihypertensive agent, have been reported to inhibit oxidation of LDL in vitro. In this study, we investigated the in vivo effect of doxazosin on LDL oxidation using this new method to measure serum ox-LDL concentration. After the administration of doxazosin for 1 to 2 months, serum concentration of ox-LDL decreased significantly (P < .05). Although the reduction of ox-LDL concentration does not strictly indicate doxazosin's antiatherosclerotic effect, it may constitute one of doxazosin's additional weapons beside lowering blood pressure and serum lipid values in the prevention of atherosclerosis.
Topics: Adrenergic alpha-Antagonists; Anticholesteremic Agents; Antihypertensive Agents; Doxazosin; Female; Humans; Lipoproteins, LDL; Male; Oxidation-Reduction
PubMed: 11281239
DOI: 10.1016/s0895-7061(00)01263-2 -
Expert Opinion on Pharmacotherapy Dec 2018The pharmacological treatment of urinary incontinence and overactive bladder (OAB) has been, for a longer time, based on antimuscarinic agents. In recent years, two... (Review)
Review
INTRODUCTION
The pharmacological treatment of urinary incontinence and overactive bladder (OAB) has been, for a longer time, based on antimuscarinic agents. In recent years, two other pharmacological principles have been introduced for the treatment of OAB and urgency urinary incontinence: the β3-adrenergic agent mirabegron and botulinum neurotoxin. Meanwhile, there is lack of effective drugs for the treatment of stress incontinence.
AREAS COVERED
This literature review presents synthetic compounds aimed to treat female urinary incontinence that are in phase II-III clinical development.
EXPERT OPINION
Antimuscarinic agents will continue to represent the current gold standard for the first-line pharmacological management of OAB and urgency urinary incontinence. The class of β3-agonists will certainly expand with the discovery and clinical development of novel agents. Combination therapy of antimuscarinic agents and β3-agonists could offer an alternative treatment in these patients, including those with symptoms refractory to first-line monotherapy. A huge number of preclinical studies are underway in this field exploring the therapeutic potential of many novel compounds while some have advanced to clinical phases of development.
Topics: Adrenergic beta-3 Receptor Agonists; Female; Humans; Middle Aged; Muscarinic Antagonists; Urinary Incontinence
PubMed: 30304645
DOI: 10.1080/14656566.2018.1532502