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1.
FASEB J ; 37(1): e22679, 2023 01.
Article in English | MEDLINE | ID: mdl-36515675

ABSTRACT

Enamel formation (amelogenesis) is a two-step process whereby crystals partially grow during the secretory stage followed by a significant growth expansion during the maturation stage concurrent with an increase in vectorial Ca2+ transport. This requires tight regulation of cytosolic Ca2+ (c Ca2+ ) concentration in the enamel forming ameloblasts by controlling Ca2+ influx (entry) and Ca2+ extrusion (clearance). Gene and protein expression studies suggest that the plasma membrane Ca2+ -ATPases (PMCA1-4) are likely involved in c Ca2+ extrusion in ameloblasts, yet no functional analysis of these pumps has been reported nor whether their activity changes across amelogenesis. PMCAs have high Ca2+ affinity and low Ca2+ clearance which may be a limiting factor in their contribution to enamel formation as maturation stage ameloblasts handle high Ca2+ loads. We analyzed PMCA function in rat secretory and maturation ameloblasts by blocking or potentiating these pumps. Low/moderate elevations in c Ca2+ measured using the Ca2+ probe Fura-2-AM show that secretory ameloblasts clear Ca2+ faster than maturation stage cells through PMCAs. This process was completely inhibited by an external alkaline (pH 9.0) solution or was significantly delayed by the PMCA blockers vanadate and caloxin 1b1. Eliciting higher c Ca2+ transients via the activation of the ORAI1 Ca2+ channel showed that the PMCAs of maturation ameloblasts were more efficient. Inhibiting PMCAs decreased the rate of Ca2+ influx via ORAI1 but potentiation with forskolin had no effect. Our findings suggest that PMCAs are functional Ca2+ pumps during amelogenesis regulating c Ca2+ upon low and/or moderate Ca2+ stimulus in secretory stage, thus participating in amelogenesis.


Subject(s)
Ameloblasts , Amelogenesis , Rats , Animals , Amelogenesis/genetics , Ameloblasts/metabolism , Cell Membrane , Cytosol , Dental Enamel
2.
Cell Signal ; 76: 109811, 2020 12.
Article in English | MEDLINE | ID: mdl-33075487

ABSTRACT

Resveratrol (RESV) is one of the most abundant polyphenol-stilbene compounds found in red wine with well-established cardioprotective and antihypertensive effects. Hyperactivity of the sympathoadrenal axis seems to be one of the major contributing factors in the pathogenesis of human essential hypertension. Alterations in outward voltage-dependent potassium currents (IK) and inward voltage-dependent sodium (INa), calcium (ICa) and nicotinic (IACh) currents, CCs excitability, Ca2+ homeostasis, and catecholamine exocytosis were previously related to the hypertensive state. This raised the issue of whether in vivo long-term RESV treatment can directly act as a modulator of Ca2+ influx or a regulator of ion channel permeability in CCs. We monitored outward and inward currents, and cytosolic Ca2+ concentrations ([Ca2+]c) using different pharmacological approaches in CCs from normotensive (WKY) and hypertensive (SHR) animals chronically exposed to trans-RESV (50 mg/L/v.o, 28 days). The long-term RESV treatment prevented the increase of the systolic blood pressure (SBP) in SHR, without reversion of cardiac hypertrophy. We also found an increase of the outward IK, reduction in inward INa,ICa, and IACh, and the mitigation of [Ca2+]c overload in CCs from SHR at the end of RESV treatment. Our data revealed that electrophysiological alterations of the CCs and in its Ca2+ homeostasis are potential new targets related to the antihypertensive effects of long-term RESV treatment.


Subject(s)
Antihypertensive Agents/pharmacology , Chromaffin Cells/drug effects , Hypertension/drug therapy , Resveratrol/pharmacology , Animals , Calcium/metabolism , Chromaffin Cells/pathology , Male , Primary Cell Culture , Rats , Rats, Inbred SHR , Rats, Inbred WKY
3.
Eur J Pharmacol ; 803: 65-77, 2017 May 15.
Article in English | MEDLINE | ID: mdl-28322841

ABSTRACT

It is known that chronic ethanol (EtOH) consumption leads to hypertension development and has been associated with deleterious effects on the cardiovascular system. Whether this condition alters calcium (Ca2+) signaling and exocytosis in adrenal chromaffin cells (CCs) as the case is for genetic hypertension, is unknown. We explored this question in four randomized experimental groups, male Wistar Kyoto (WKY/EtOH) and Spontaneously Hypertensive (SHR/EtOH) rats were subjected to the intake of increasing EtOH concentrations (5-20%, for 30 days) and their respective controls (WKY/Control and SHR/Control) received water. WKY/EtOH developed hypertension and cardiac hypertrophy; blood aldehyde dehydrogenase (ALDH) and H2O2 were also augmented. In comparison with WKY/Control, CCs from WKY/EtOH had the following features: (i) depolarization and higher frequency of spontaneous action potentials; (ii) decreased Ca2+ currents with slower inactivation; (iii) decreased K+ currents; (iv) augmented K+-elicited cytosolic Ca2+ transients ([Ca2+]c); (v) enhanced K+-elicited catecholamine release. These cardiovascular, blood and CCs changes were qualitatively similar to those undergone by SHR/Control and SHR/EtOH. The results suggest that the hypertension elicited by chronic EtOH has pathogenic features common to genetic hypertension namely, augmented [Ca2+]c transients and catecholamine release from their CCs.


Subject(s)
Alcohol Drinking/adverse effects , Catecholamines/metabolism , Chromaffin Cells/drug effects , Chromaffin Cells/metabolism , Electrophysiological Phenomena/drug effects , Hypertension/chemically induced , Hypertension/pathology , Action Potentials/drug effects , Animals , Calcium/metabolism , Chromaffin Cells/pathology , Cytosol/drug effects , Cytosol/metabolism , Ethanol/pharmacology , Hypertension/metabolism , Hypertension/physiopathology , Male , Potassium/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Time Factors
4.
Am J Drug Alcohol Abuse ; 42(1): 63-76, 2016.
Article in English | MEDLINE | ID: mdl-26579734

ABSTRACT

BACKGROUND: Acute cocaine withdrawal syndrome (ACWS) is characterized as a set of organic alterations triggered by abrupt discontinuation of chronic cocaine consumption, usually occurring at 24-40 hours after withdrawal. However, little is known about the relationship between central and peripheral sympathetic neurotransmission during ACWS. OBJECTIVE AND METHODS: We investigated the mechanisms involved in central and peripheral sympathetic neurotransmission and how ACWS affects the sympathetic functionality. Cocaine was administered twice daily for 5 days in Wistar rats (at least 5 in each group): on the first and second day, 15 mg/kg/i.p.; third day, 20 mg/kg/i.p.; and finally in the last two days, 30 mg/kg/i.p. Subsequently, at 1, 24, 48 and 120 h after cocaine administration the following experiments were done: (i) at the central level, behavioral tests of open-field and elevated plus maze; and (ii) at the peripheral level, tests of catecholamine release, function of α2-adrenergic receptors (α2-ARs), imidazoline receptors (I(1,2)-Rs), L-type voltage-gated (Ca(v1.2)) Ca(2+) channels and α1-ARs. RESULTS: During ACWS, rats showed hypolocomotion and exacerbation of anxiogenic-effects 24 h after cocaine withdrawal. Likewise, a decrease in the catecholamine release and activity of α2-ARs/I(1,2)-Rs at 24-48 h after cocaine withdrawal was observed. A decrease in Ca(v1.2) channels and α1-ARs function at 48 h after cocaine withdrawal was observed. CONCLUSIONS: The relationship of central and peripheral sympathetic neurotransmission during ACWS possibly due to a failure in activation and/or inactivation of presynaptic α2-ARs/I(1,2)-Rs, may offer a potential target for attenuating ACWS.


Subject(s)
Cocaine/adverse effects , Substance Withdrawal Syndrome/physiopathology , Substance Withdrawal Syndrome/psychology , Sympathetic Nervous System/physiology , Synaptic Transmission/physiology , Animals , Calcium Channels, L-Type/physiology , Catecholamines/metabolism , Imidazoline Receptors/physiology , Male , Maze Learning , Motor Activity , Rats , Receptors, Adrenergic, alpha-1/physiology , Receptors, Adrenergic, alpha-2/physiology , Substance Withdrawal Syndrome/metabolism , Vas Deferens/physiopathology
5.
Life Sci ; 108(1): 34-43, 2014 Jul 11.
Article in English | MEDLINE | ID: mdl-24831557

ABSTRACT

AIMS: Alcohol withdrawal syndrome (AWS) is characterized by a set of physiological modifications triggered by abrupt withdrawal and/or decreasing consumption of ethanol (EtOH), which may manifest 16-48 h after ceasing consumption. The relationship between the effects of AWS and central and peripheral sympathetic neurotransmission is unknown. This study investigates the possible mechanisms on the sympathetic system during periods of AWS. MAIN METHODS: Male Wistar rats were treated with EtOH (6-10 g/kg/day/v.o. 5 days). Subsequently, 1h, 24h, 48 h and 120 h after administration of the last dose of EtOH, the animals were sacrificed, and their vas deferens (VD) were removed to perform the following evaluations: (a) concentration-effect curves of sympathetic agonist; (b) activity of α2-adrenoreceptor; (c) function of voltage-dependent calcium channels (Cav); and (d) release of endogenous catecholamines measured in real time coupled to HPLC. KEY FINDINGS: The results showed that the maximum effects of contraction were increased by agonists tested in at 24h and 48 h EtOH withdrawal. The inhibitory affinity (pIC50) of guanfacine was decreased 24h EtOH withdrawal. The function of Cav was also decreased as pIC50 values dropped 24h and 48 h EtOH withdrawal. The release of catecholamines increased 48 h after EtOH withdrawal. It is suggested that AWS triggers hyperactivity in peripheral sympathetic neurotransmission. SIGNIFICANCE: The mechanisms underlying hyperactivity are possibly explained by a failure of autoregulation from catecholamines released by α2-adrenoreceptors and/or an increase of Cav function, which may be potential targets to attenuate the symptoms of AWS at the peripheral level.


Subject(s)
Calcium Channels/metabolism , Ethanol/administration & dosage , Substance Withdrawal Syndrome/physiopathology , Synaptic Transmission , Vas Deferens/metabolism , Adrenergic alpha-2 Receptor Agonists/administration & dosage , Adrenergic alpha-2 Receptor Agonists/pharmacology , Animals , Catecholamines/metabolism , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Guanfacine/administration & dosage , Guanfacine/pharmacology , Inhibitory Concentration 50 , Male , Muscle Contraction/drug effects , Rats , Rats, Wistar , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/metabolism , Time Factors
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