naloxone and Uremia

The role of endogenous opioids on the reflex cardiovascular control of chronic uraemic patients was investigated. The opiate antagonist naloxone administered intravenously caused a significant increase in the abnormal Valsalva manoeuvre ratio in nine chronic uraemic patients, but it had no effect in six diabetic patients with normal renal function, whose response to the Valsalva manoeuvre was similar to that of chronic uraemic patients. Naloxone had no effect in eight normal subjects. The increase in the Valsalva ratio observed in uraemic patients was due to restoration of the parasympathetically mediated reflex bradycardia of the release phase of the manoeuvre. Naloxone did not modify supine and standing blood pressure and heart rate in any group. Endogenous opioids may be involved in the defective autonomic control of heart rate in uraemic patients.

Topics: Adult; Autonomic Nervous System Diseases; Blood Pressure; Chronic Disease; Diabetes Mellitus; Drug Evaluation; Heart Rate; Humans; Male; Middle Aged; Naloxone; Reflex, Abnormal; Uremia; Valsalva Maneuver

Topics: Administration, Cutaneous; Analgesics, Opioid; Drug Interactions; Drug Therapy, Combination; Fentanyl; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pruritus; Substance Withdrawal Syndrome; Uremia; Withholding Treatment

In ten chronic uremic patients on regular hemodialysis treatment in vitro experiments revealed that stimulation of opioid receptors with morphine did not significantly change the mitogen-induced proliferative response of peripheral blood lymphocytes and interleukin-2 (IL-2) receptor expression on PHA-stimulated lymphocytes, while it appreciably decreased surface transferrin (Trf) receptor expression on PHA-stimulated lymphocytes. However, metenkephalin inhibited mitogen-induced proliferation and surface Trf receptor expression on uremic lymphocytes without affecting IL-2 receptor expression on PHA-stimulated cells. In ten healthy subjects opioid receptor agonists did not significantly affect mitogen-induced proliferation of lymphocytes, except for the inhibitory effect of 10(-8) M morphine in relation to lymphocytes stimulated with an optimal pokeweed mitogen (PWM) concentration. At the same time, opioid receptor agonists depressed surface IL-2 and Trf receptor expression on PHA-stimulated normal lymphocytes. In most of our experiments naloxone itself, a non-selective competitive opioid receptor antagonist, decreased mitogen-induced lymphocyte proliferation and IL-2 and Trf receptor expression on PHA-stimulated lymphocytes. Moreover, most frequently naloxone did not reverse inhibitory effects of opioid receptor agonists on lymphocytes. The results seem to indicate that opioid receptor stimulation by high metenkephalin concentrations, which are observed in the uremic blood plasma, may share the responsibility for immunodeficiency in chronic uremic patients. Next, in the presence of opioid receptor agonists directions of changes in the mitogen-induced proliferative response may not follow the alterations of IL-2 and Trf receptor expression on both uremic and normal lymphocytes. Finally the results also suggest that naloxone may possibly exert effects which are independent of its action on opioid receptors on lymphocytes.

Topics: Adult; Chronic Disease; Enkephalin, Methionine; Female; Humans; In Vitro Techniques; Lymphocyte Activation; Lymphocytes; Male; Morphine; Naloxone; Receptors, Interleukin-2; Receptors, Opioid; Receptors, Transferrin; Uremia

Defective regulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion is the primary defect leading to the inhibition of pituitary gonadotropin secretion and its consequences such as androgen deficiency and infertility in experimental uremia. Previous studies using indirect methods to study presumptive GnRH release and the function of GnRH-secreting neurons have suggested functional disturbances of GnRH neurosecretion; however, the precise biochemical mechanisms involved were not defined. Therefore, in order to clarify the mechanisms of aberrant regulation of hypothalamic GnRH secretion in experimental uremia, we examined basal secretion of GnRH from mediobasal hypothalamus (MBH) in vitro and the GnRH-secretory responses to naloxone, an opiate receptor antagonist in experimental uremia. Using a static incubation system, adult male rats, either intact or castrate, with subtotal nephrectomy demonstrated a significant reduction of GnRH secretion by 25% in intact and by 40% in castrate uremic male rats compared with their nonuremic controls. In contrast, hypothalamic GnRH content of uremic animals was increased significantly (6% in intact and 14% in castrate uremic rats). Despite the fall in basal GnRH release from MBH, the MBH GnRH release response to in vitro stimulation by an opioid blocker (naloxone) and a membrane-depolarizing agent (veratrine) were not diminished in uremic male rats. These findings suggest that the inhibition of pituitary gonadotropin secretion in experimental uremia is likely to be due to a functional defect in suprahypothalamic regulation of GnRH secretion rather than an intrinsic defect in the GnRH-secreting neurons. Further studies are required to clarify the nature of the neuromodulator interactions involved.

Topics: Animals; Gonadotropin-Releasing Hormone; Hypothalamus, Middle; In Vitro Techniques; Kidney; Male; Naloxone; Rats; Rats, Inbred Strains; Secretory Rate; Testis; Uremia; Veratrine

Previous studies have demonstrated that abolition of the naloxone-stimulated increase in plasma LH levels is characteristic of hypothalamic dysfunction in experimental uremia. This study aimed to further characterize the nature of the defect in hypothalamic opiatergic mechanisms in experimental uremia. Specifically, we have tested the hypothesis that naloxone resistance was due to either opioid receptor dysfunction or diminished opioid peptide levels. Administration of naloxone (2 mg/kg, iv) to cannulated freely mobile rats confirmed previous observations that despite marked increases in plasma LH in control rats, plasma LH levels were unaffected in uremic male rats (P = 0.001 for group x time interaction). In a second experiment, morphine (2 mg/kg) or saline diluent was given quasi-continuously as small aliquots before each blood sample during the pulse studies of castrate mature male rats that had undergone either subtotal nephrectomy or sham operation. After the administration of morphine, uremic rats exhibited a 60% reduction in mean LH levels (14.9 +/- 1.4 vs. 6.0 +/- 0.7 ng/ml) attributable to a 42% reduction in LH pulse frequency (3.6 +/- 0.4 vs. 2.1 +/- 0.5 peaks/3 h) and a 60% reduction in LH pulse amplitude (4.7 +/- 0.5 vs. 1.9 +/- 0.3 ng/ml). The preservation of sensitivity to morphine despite complete naloxone resistance raised the alternate hypothesis of depletion of endogenous opiate peptide levels in the uremic hypothalamus. This hypothesis was tested by measuring the beta-endorphin content of the medial basal hypothalamus (MBH) in a rat beta-endorphin RIA. Rat MBH beta-endorphin content was not significantly altered specifically by either uremia or castration. We conclude, therefore, that naloxone resistance of plasma LH in experimental uremia is not due to either defects in opioid receptor function or reduced hypothalamic beta-endorphin content. Instead, we suggest that uremia may diminish the release of endogenous opioid peptides that interact with GnRH neurons from the MBH.

Topics: Animals; beta-Endorphin; Biomechanical Phenomena; Endorphins; Hypogonadism; Hypothalamus; Hypothalamus, Middle; Luteinizing Hormone; Male; Naloxone; Pulsatile Flow; Rats; Rats, Inbred Strains; Uremia

The role of endogenous opioids in the control of gonadotropin secretion in uremic male rats was investigated using the narcotic antagonist, naloxone. In order to eliminate the effect of weight loss due to uremia-induced anorexia as a cause of previously described altered gonadotropin secretion in uremia, we also studied a group of normal pair-fed control animals who exhibited a weight loss comparable to that of the uremic animals. Naloxone administration had no effect on the basal or LRH-stimulated peak concentrations of LH and FSH in the normal or the uremic rats. Basal and LRH-stimulated gonadotropin responses in the pair-fed rats were comparable to those seen in the normal rats. Similarly, opioid blockade produced no change in the basal or LRH-stimulated gonadotropin responses in the pair-fed animals. Testosterone concentrations were significantly lower in the uremic and pair-fed animals compared to the normal rats. The data suggest that experimental renal failure is not associated with altered opioidergic tone, as it relates to gonadotropin secretion, or to diminished sensitivity of the gonadotroph to LRH stimulation. The decreased testosterone concentration seen in the uremic and pair-fed rats may reflect abnormalities in gonadal hormone secretion due to primary pathology occurring at the level of the gonad. These abnormalities may be reflected as diminished Leydig cell sensitivity to LH. The inappropriately low concentrations of LH in the presence of low testosterone together with normal gonadotropin response to exogenous LRH also suggest an abnormal secretion of endogenous LRH. It is not clear whether this presumed abnormality in LRH secretion is a primary event or is related to decreased testosterone production by the testes in the uremic and pair-fed rats.

Topics: Animals; Endorphins; Follicle Stimulating Hormone; Luteinizing Hormone; Male; Naloxone; Rats; Rats, Inbred Strains; Uremia

The role of endogenous opioids in the control of thyroid-stimulating hormone (TSH) secretion in uremic male rats was investigated using the narcotic antagonist naloxone. In order to eliminate the effect of weight loss due to uremia-induced anorexia as a cause of altered TSH secretion in uremia, we also studied a group of normal control animals who were pair-fed with the uremic animals, so that their weights were comparable to that of the uremic animals. Naloxone administration produced a significant increase in the basal concentration of TSH response to TRH (5 micrograms i.v.) was significantly blunted in the uremic animals compared to the normal controls and the starved animals. Naloxone administration did not alter the peak thyrotropin-releasing hormone (TRH) stimulated TSH response in any of the experimental groups of rats. Because of the possibility that the effects of naloxone on TSH secretion in the uremic rats were related to impaired clearance of the naloxone in those animals, an additional group of normal rats was given twice the dose of naloxone administered to the uremic animals. The higher dose of naloxone was similarly without effect on the basal or TRH-stimulated TSH secretion in this group. The data suggest that experimental renal failure is associated with diminished sensitivity of the thyrotroph to TRH stimulation and that this blunted sensitivity cannot be abolished by blockade of endogenous opioids by naloxone. Opioid blockade does, however, increase basal TSH secretion in uremic animals, suggesting an increase in endogenous opioidergic tone in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Endorphins; Male; Naloxone; Rats; Rats, Inbred Strains; Thyroid Hormones; Thyrotropin; Uremia

Uremia results in a decrease in food intake. In the present study we investigated whether opiates known to stimulate feeding would alter food intake in rats made uremic by 1 and 5/6 nephrectomy. Morphine increased food intake in sham nephrectomized rats, but failed to alter food intake in uremic animals and depressed the ingestion of rat chow in a group of weight restricted rats. Butorphanol tartrate increased feeding in sham and uremic animals but did not alter intake in the weight restricted group. Higher doses of butorphanol were needed to stimulate feeding in the uremic rats compared to the sham group, suggesting a relative resistance to opioid-induced feeding in the uremic rats. The opiate antagonist, naloxone, suppressed food intake in the uremic and sham groups more effectively than in the weight restricted rats. These data suggest that the opioid feeding system functions in a reduced fashion in uremic rats, but probably is not the sole factor involved in producing the anorexia associated with uremia.

Topics: Animals; Anorexia; Body Weight; Butorphanol; Endorphins; Feeding Behavior; Male; Morphinans; Morphine; Naloxone; Rats; Rats, Inbred Strains; Uremia

In 5 uremic patients the role of opioid peptides in dialysis-induced hypotension was investigated through the administration of naloxone. An intravenous bolus injection of 1 mg of naloxone was administered immediately before starting a routine hemodialysis session and was repeated when the patients' systolic arterial pressure sank below 90 mm Hg. In our patients, naloxone had no effect on the resting arterial pressure or on dialysis-induced hypotension.

Topics: Blood Pressure; Female; Humans; Hypotension; Kidney Failure, Chronic; Male; Naloxone; Renal Dialysis; Uremia

In companion studies we have shown that chronic uremic male rats are infertile and hypoandrogenic and have lowered basal LH levels. Fertility was restored by either human CG (hCG) or testosterone treatment. Testicular steroidogenic responses to hCG in vivo and in vitro were normal or excessive, indicating that hypothalamic-pituitary dysfunction was the predominant early lesion in uremic hypogonadism. Further studies were undertaken to characterize the nature of the central defects in regulation of pituitary LH secretion. Uremic rats have reduced MCRs for rat LH (rLH) (61%), rat FSH (rFSH) (47%), and LHRH (41%). Pituitary gonadotropin and hypothalamic LHRH content were unchanged in uremic rats. Pituitary rLH and rFSH responses to LHRH stimulation in vivo and in vitro were quantitatively normal or excessive, with delayed peaks suggesting that uremic pituitary gonadotrope secretion is deficient due to lack of appropriate hypothalamic LHRH drive rather than intrinsic pituitary defects. Despite reduced pituitary gonadotropin secretion in intact uremic rats, castration induced paradoxical excessive increases in pituitary LHRH binding, serum rLH, and rFSH beyond those of nonuremic controls. Paradoxical postcastration hyperresponses of serum rLH and rFSH were not due to circulating immunoreactive fragments of gonadotropins or undernutrition. Dysfunction of the uremic hypothalamus was further characterized in vivo by lack of rLH responsiveness to naloxone and hypersensitivity to negative testicular feedback in castrate-steroid-replaced and intact rats. These data demonstrate that uremic hypogonadism is principally due to aberrant hypothalamic regulation of pituitary LH secretion resembling those of the immature rat or seasonally regressed animal. This recrudescence of the inactive regulatory state in a disease model suggests that common mechanisms are operative in orderly gonadal withdrawal under hostile or inappropriate environments and may underly the reversibility of human uremic hypogonadism with successful renal transplantation.

Topics: Animals; Flutamide; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hypogonadism; Hypothalamo-Hypophyseal System; Hypothalamus; Luteinizing Hormone; Male; Metabolic Clearance Rate; Naloxone; Orchiectomy; Pituitary Gland; Rats; Uremia

We studied the effect of the opiate antagonist naloxone on the response to Valsalva manoeuvre in nine dialysis patients, in six diabetics with normal renal function whose response to Valsalva manoeuvre was similar to that of dialysis patients and in eight healthy subjects. Naloxone caused a progressive increase in the subnormal Valsalva ratio in dialysis patients but it did not cause any change in diabetics nor in healthy subjects. The increase in Valsalva ratio observed in dialysis patients was due to restoration of the parasympathetically mediated reflex bradycardia of the release phase of the manoeuvre. Endogenous opioids may be responsible for the baroreflex dysfunction of dialysis patients.

Topics: Adult; Endorphins; Humans; Male; Middle Aged; Naloxone; Pressoreceptors; Renal Dialysis; Uremia; Valsalva Maneuver

Topics: Aged; Female; Humans; Naloxone; Pruritus; Uremia

Topics: Adult; Blood Pressure; Enkephalin, Methionine; Heart Rate; Humans; Male; Middle Aged; Naloxone; Pressoreceptors; Reflex, Abnormal; Renal Dialysis; Uremia; Valsalva Maneuver