Publications by authors named "Joseph F Discala"

5 Publications

  • Page 1 of 1

Systemic Administration of Tempol, a Superoxide Dismutase Mimetic, Augments Upper Airway Muscle Activity in Obese Zucker Rats.

Front Pharmacol 2022 9;13:814032. Epub 2022 Feb 9.

Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, School of Medicine, Case Western Reserve University, Cleveland, OH, United States.

Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMG) and diaphragmatic (EMG) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1-100 mg/kg) increased EMG without changing EMG in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1-25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.
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http://dx.doi.org/10.3389/fphar.2022.814032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864283PMC
February 2022

Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats.

Front Pharmacol 2021 22;12:749084. Epub 2021 Sep 22.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United states.

We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts the cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective of the present study was to determine whether Tempol is able to reverse the effects of morphine on arterial blood-gas (ABG) chemistry in freely-moving Sprague Dawley rats. The intravenous injection of morphine (10 mg/kg) elicited substantial decreases in pH, pO and sO that were accompanied by substantial increases in pCO and Alveolar-arterial gradient, which results in diminished gas-exchange within the lungs. Intravenous injection of a 60 mg/kg dose of Tempol 15 min after the injection of morphine caused minor improvements in pO and pCO but not in other ABG parameters. In contrast, the 100 mg/kg dose of Tempol caused an immediate and sustained reversal of the negative effects of morphine on arterial blood pH, pCO, pO, sO and Alveolar-arterial gradient. In other rats, we used pulse oximetry to determine that the 100 mg/kg dose of Tempol, but not the 60 mg/kg dose elicited a rapid and sustained reversal of the negative effects of morphine (10 mg/kg, IV) on tissue O saturation (SpO). The injection of morphine caused a relatively minor fall in mean arterial blood pressure that was somewhat exacerbated by Tempol. These findings demonstrate that Tempol can reverse the negative effects of morphine on ABG chemistry in freely-moving rats paving the way of structure-activity and mechanisms of action studies with the host of Tempol analogues that are commercially available.
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http://dx.doi.org/10.3389/fphar.2021.749084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493249PMC
September 2021

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge.

Open J Mol Integr Physiol 2013 Nov;3(4):166-180

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The aim of this study was to determine whether morphine depresses the ventilatory responses elicited by a hypoxic challenge (10% O, 90% N) in conscious rats at a time when the effects of morphine on arterial blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient and minute ventilation (V) had completely subsided. In vehicle-treated rats, each episode of hypoxia stimulated ventilatory function and the responses generally subsided during each normoxic period. Morphine (5 mg/kg, i.v.) induced an array of depressant effects on ABG chemistry, A-a gradient and V (via decreases in tidal volume). Despite resolution of these morphine-induced effects, the first episode of hypoxia elicited substantially smaller increases in V than in vehicle-treated rats, due mainly to smaller increases in frequency of breathing. The pattern of ventilatory responses during subsequent episodes of hypoxia and normoxia changed substantially in morphine-treated rats. It is evident that morphine has latent deleterious effects on ventilatory responses elicited by hypoxic challenge.
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http://dx.doi.org/10.4236/ojmip.2013.34022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103751PMC
November 2013

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge.

Open J Mol Integr Physiol 2013 Aug;3(3):134-145

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO, decreases in pO and sO) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated.
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http://dx.doi.org/10.4236/ojmip.2013.33019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103749PMC
August 2013

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats.

Respir Physiol Neurobiol 2014 Jan 24;191:95-105. Epub 2013 Nov 24.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106-4984, USA. Electronic address:

This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient.
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http://dx.doi.org/10.1016/j.resp.2013.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391496PMC
January 2014
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