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Biomedical subjects

J W Holaday

Publications and source records attributed to J W Holaday.

At least 127 records · Page 7Linked to original sources
PubMed1980

Endorphin-parasympathetic interactions in spinal shock.

We have recently shown that the opiate antagonist naloxone can partially reverse the hypotension which accompanies spinal cord transection, through actions on opiate receptors in the central nervous system. In the present studies we demonstrate that either vagotomy or atropine prevents the ability of naloxone to reduce the hypotension caused by spinal transection in the rat and cat. Since the peripherally acting methyl-atropine blocks the cardiovascular effects of centrally administered naloxone in this model, these findings imply an interaction between endorphin systems and central parasympathetic centers in spinal shock. This interaction results in a depression of cardiovascular function which is mediated through cholinergic vagal efferent pathways. Furthermore, the fact that naloxone reduces the hypotension following spinal transection, along with the role of the parasympathetic system in this process, appears to question the classic conception that such hypotension results entirely from interruption of descending sympathetic pressor pathways. Finally, the beneficial cardiovascular effects of naloxone in spinal shock may have important therapeutic implications in the management of spinal cord injury.

Animals↗
PubMed1980

Experimental endotoxin shock: the pathophysiologic function of endorphins and treatment with opiate antagonists.

The specific opiate-antagonist naloxone rapidly reverses hypotension caused by endotoxin, hypovolemia, and spinal transection. In endotoxin shock in rats, naloxone's effects were stereospecific and were observed with intravenous (iv) doses as low as 0.1 mg/kg. In endotoxin shock in dogs, naloxone treatment significantly improved both cardiovascular parameters and survival. Naloxone, given iv, similarly improved blood pressure and survival in rat and canine models of hypovolemic shock. Moreover, intracerebroventricular (ivt) naloxone at a dose of 10 micrograms restored blood pressure after hypovolemia; this effect was blocked by hypophysectomy. In addition naloxone, given ivt, stereospecifically restored blood prssure after spinal shock. From these findings it is suggested that (1) pituitary endorphins are pathophysiologic factors in shock; (2) endorphins' cardiodepressant effects are mediated by opiate receptors within the central nervous system; and (3) use of opiate antagonists may be of therapeutic benefit in the treatment of shock in humans.

Animals↗
PubMed1980

Naloxone reversal of hypovolemic shock in dogs.

The endogenous opiate ligand, beta-endorphin, is released during stress. We tested the hypothesis that endorphins may be involved in the pathophysiology of hemorrhagic shock by using the opiate receptor blocking agent, naloxone. Two groups of five anesthetized dogs were instrumented to monitor cardiovascular performance and subjected to a protocol in which they were bled into a reservoir to lower mean arterial pressure to 45 mmHg and maintained at that pressure for one hour. At that time the reservoir was clamped and on group of dogs received an intravenous bolus of naloxone (2 mg/kg) and an infusion at 2 mg/kg-hr. These dogs demonstrated a prompt increase in arterial pressure, left ventricular dp/dtmax and cardiac output. The shed blood was returned at t = 2 hr and drug infusion continued for 2 hours. The control group of dogs received saline in equivalent volume. The control dogs died within 30 minutes of clamping the reservoir while all five treated dogs survived beyond 72 hours (P less than 0.02). These data suggest the involvement of endorphins acting on opiate receptors as part of the pathophysiology in this shock model.

Animals↗
PubMed1980

Naloxone treatment of endotoxin shock: stereospecificity of physiologic and pharmacologic effects in the rat.

Endogenous opiates (endorphins) like exogenous opiates can, even in small doses, profoundly depress blood pressure and heart rate. Since endorphins are released in response to stressors, it appeared possible that endorphins might be released during shock and serve to further reduce blood pressure. We used the specific opiate-antagonist naloxone to block there anticipated effects of endorphins in a conscious rat endotoxin-shock model. Naloxone treatment resulted in a rapid increase in mean arterial pressure (MAP) in animals made hypotensive by endotoxin administration. Naloxone was effective in reversing this hypotension at a dose as small as 0.1 mg/kg. This therapeutic effect of naloxone was stereospecific: (-)-naloxone reversed the hypotension, although its stereoisomer (+)-naloxone did not. A single 10 mg/kg i.v. bolus injection of naloxone significantly improved MAP for a period of 30 min, and MAP remained elevated as compared to saline controls for approximately 2 hr. Bolus injections of naloxone followed by continuous i.v. infusion produced similar changes in MAP. Despite the rapid effect of naloxone in restoring MAP toward base-line levels, 24 hr survival was not significantly improved by this narcotic antagonist. This suggests that factors other than hypotension are critical determinants of survival in this rat model. Collectively, these findings support the hypothesis that endorphins are hypotensive factors in endotoxin shock and suggest that the therapeutic effects of naloxone are specific and are mediated by the opiate receptor.

Animals↗
PubMed1979

Opiate antagonists: a role in the treatment of hypovolemic shock.

The opiate antagonist naloxone has been used to treat shock following acute blood loss in conscious rats. Naloxone treatment rapidly increased mean arterial pressure and pulse pressure in this new shock model. More importantly, these blood pressure changes were sustained and survival was significantly increased with maloxone as compared with placebo treatment. From these findings, it may be inferred that endorphins may play a role in the pathophysiology of hypovolemic shock. It is suggested that narcotic antagonists may prove to be of therapeutic value in the treatment of shock.

Animals↗
PubMed1979

Adrenal steroids indirectly modulate morphine and beta-endorphin effects.

The pharmacological effects of morphine or the postulated physiological opiate, beta-endorphin, were compared in adrenalectomized and sham control animals. Pretreatment of adrenalectomized rats and mice with the synthetic glucocorticoid dexamethasone 2 hr before opiate injections abolished the adrenalectomy-induced sensitization to parenteral opiates. This effect of dexamethasone was completely blocked by cycloheximide, a protein-synthesis inhibitor. After parenteral injection ot tritiated morphine, total tritium counts in the blood and brains of adrenalectomized mice were greater than in sham controls; this effect was also blocked by dexamethasone pretreatment. Administration of SKF 525-A before morphine produced results which suggest that this putative inhibitor of the mixed-function oxidase metabolizing enzyme system also alters opiate potency. Collectively, these studies provide evidence that adrenalectomy causes a decrease in morphine metabolism which enhances the parenteral potency of this opiate through increased bioavailability. Furthermore, the dexamethasone reversal of this effect appears to depend upon its de novo induction of protein components of the opiate-metabolizing system. The possibility that a physiological interplay between endorphins and corticosteroids exists is suggested by the dexamethasone blockade of both the pharmacological effects and the toxicity of intravenous beta-endorphin in adrenalectomized mice.

Adrenal Cortex Hormones↗
PubMed1978

Endorphins may function in heat adaptation.

Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure precipitates an increase in colonic temperature, an increase in escape attempts, and a decrease in body weight. These changes are accompanied by signs associated with hyperthermia such as salivation, diarrhea, and an abnormal extended posture. Although brain endorphin involvement is possible, hypophysectomy diminishes the intensity and magnitude of these naloxone effects, indicating that the naloxone effect in intact animals may be due to a functional antagonism of pituitary endorphins. These observations suggest that endorphins attenuate physiological responses to thermal and noxious stimuli triggered in common neuroanatomical pathways by heat.

Adaptation, Physiological↗