naloxone and Hypertension

The incidence of clonidine overdose is increasing, yet there is a paucity of new information regarding treatment options for clonidine toxicity. Reported treatment approaches vary widely, demonstrating the lack of science on which current treatment is based. Available research needs to be reassessed. Neurotransmitters, receptors, endogenous opioids, and baseline sympathetic tone determine the clinical response to clonidine as well as the potential response to drug therapy following clonidine overdose. This article reviews aspects of clonidine toxicity that need to be further investigated. Multicenter research trials will be required to evaluate new treatment options.

Topics: Adolescent; Adrenergic alpha-Agonists; Adult; Clonidine; Drug Overdose; Female; Humans; Hypertension; Infant; Male; Middle Aged; Naloxone; Narcotic Antagonists

Topics: Anesthetics, Local; Anti-Bacterial Agents; Charcoal; Drug Synergism; Drug Therapy, Combination; Epinephrine; Humans; Hypertension; Migraine Disorders; Naloxone; Parkinson Disease

Multi-infarct dementia (MID) characteristically presents with an acute event followed by a stepwise and fluctuating downhill course. Progression is generally considered the consequence of recurrent stroke (Hachinski, 1983): the mainstay of treatment, therefore, is the prevention of further ischemic events.

Topics: Cerebrovascular Disorders; Dementia, Multi-Infarct; Dihydroergotoxine; Humans; Hypertension; Naloxone; Piracetam; Pyrrolidines

Opiates are now known to be important modulators of cardiovascular function in both the normotensive and hypertensive states. There is accumulating evidence that endogenous opiates are elevated in models of hypertension of various etiologies including genetic and renovascular hypertension. Early evidence for elevated opiates in hypertension arose from observations that hypertensive humans and rats with genetic or experimental hypertension exhibited hypoalgesia in various tests of pain sensitivity. Because pain and cardiovascular regulatory systems have in common a number of brain loci, cardiovascular effects of opiates and opiate blockade were studied. These studies have shown that opiate blockade can attenuate the development of hypertension and reduce blood pressure in chronic hypertension possibly via actions on the baroreflexes and/or by modulating the centrally mediated pressor actions of angiotensin II.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiovascular System; Endorphins; Hypertension; Hypertension, Renovascular; Models, Cardiovascular; Naloxone; Narcotics; Pain; Pressoreceptors; Shock

Topics: Aged; Animals; Blood Pressure; Dogs; Humans; Hypertension; Male; Naloxone

Topics: Animals; Binding Sites; Cardiovascular System; Cerebrovascular Disorders; Endorphins; Humans; Hypertension; Naloxone; Narcotic Antagonists; Pressoreceptors; Shock; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone; Wounds and Injuries

Topics: Animals; Brain; Brain Ischemia; Cardiovascular Physiological Phenomena; Cardiovascular System; Endorphins; Enkephalins; Humans; Hypertension; Hypotension; Morphine; Naloxone; Pressoreceptors; Receptors, Opioid; Reflex; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone

Topics: Acidosis; Adult; Alcohol Drinking; Alkalosis; Animals; Child, Preschool; Circadian Rhythm; Dogs; Electrolytes; Female; Humans; Hypercapnia; Hypertension; Hypotension; Hypoxia; Infant; Lung; Male; Mice; Naloxone; Narcotics; Neurotransmitter Agents; Rats; Temperature; Thyroid Gland; Time Factors

The opioid system is involved in blood pressure regulation in both normal humans and patients with essential hypertension.. The objective of the study was to investigate the effects of a high-dose infusion of beta-endorphin, an opioid peptide, on blood pressure and on the hormonal profile in healthy subjects and in hypertensive patients and the mediation played by opioid receptor agonism.. According to a randomized double-blind design, 11 healthy subjects (controls) and 12 hypertensive inpatients (mean age, 38.9 and 40.4 yr, respectively) received 1-h iv infusion of beta-endorphin (250 mug/h) and, on another occasion, the same infusion protocol preceded by the opioid antagonist naloxone (8 mg).. Hemodynamic and hormonal measurements were performed at established times during the infusion protocols.. At baseline, circulating beta-endorphin, norepinephrine, and endothelin-1 in hypertensive patients were significantly (P < 0.05) higher than in controls. In controls, beta-endorphin reduced blood pressure (P < 0.01) and circulating norepinephrine (P < 0.02) and increased plasma atrial natriuretic factor (P < 0.003) and GH (P < 0.0001). In hypertensive patients, beta-endorphin decreased systemic vascular resistance (P < 0.0001), blood pressure (P < 0.0001), and plasma norepinephrine (P < 0.0001) and endothelin-1 (P < 0.0001) and raised circulating atrial natriuretic factor (P < 0.0001), GH (P < 0.0001), and IGF-I (P < 0.0001). These hemodynamic and hormonal responses to beta-endorphin in hypertensive patients were significantly (P < 0.0001) greater than in controls but were annulled in all individuals when naloxone preceded beta-endorphin infusion.. High doses of beta-endorphin induce hypotensive and beneficial hormonal effects in humans, which are enhanced in essential hypertension and are mediated by opioid receptors.

Topics: Adult; beta-Endorphin; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Hormones; Humans; Hypertension; Male; Middle Aged; Naloxone; Narcotic Antagonists; Receptors, Opioid

Topics: Administration, Oral; Administration, Rectal; Adolescent; Adult; Aged; Arrhythmias, Cardiac; Colic; Constipation; Dizziness; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Hypotension; Infusions, Intravenous; Injections, Intravenous; Injections, Subcutaneous; Intubation, Gastrointestinal; Male; Middle Aged; Naloxone; Narcotic Antagonists; Nausea; Neostigmine; Parasympathomimetics; Retrospective Studies; Treatment Outcome

After hyperventilation, systolic and diastolic blood pressure (BP) significantly decreased in 14 hypertensive patients (group 1), did not change in 9 (group 2) and increased in 8 (group 3). Basal BP, norepinephrine and dynorphin B levels were higher in group 1 than in groups 2 and 3. The decrease in BP after hyperventilation was associated with a decrease in plasma norepinephrine, Met-enkephalin and dynorphin B and an increase in beta-endorphin. Naloxone abolished the hyperventilation-induced BP and norepinephrine decreases. Our findings indicate that hyperventilation may select hypertensive patients with different sympatho-adrenergic activity and that the increase in beta-endorphin reduces BP response to hyperventilation in patients with high sympatho-adrenergic tone.

Topics: Aged; beta-Endorphin; Blood Pressure; Cross-Over Studies; Dynorphins; Enkephalin, Methionine; Female; Heart Rate; Humans; Hypertension; Hyperventilation; Male; Middle Aged; Naloxone; Norepinephrine; Time Factors

Pain sensitivity decreases with increasing resting blood pressure. This blood pressure-pain interaction may be mediated by endogenous opioids which have been shown to affect both blood pressure and nociception. To test this hypothesis, we measured mean arterial blood pressure (MAP), central venous pressure (CVP), heart rate (HR), muscle sympathetic nerve activity (MSNA), serum catecholamines, and individual pain rating scales during 2 min periods of noxious mechanostimulation (skin fold pinching) in nine young (26 +/- 2 year), male normotensive (NT) subjects and in 12 age and weight matched males with borderline hypertension (BHT). Measurements were performed before and after the i.v. administration of naloxone (0.15 mg/kg) and placebo in a randomized double-blind cross-over trial. In the pre-naloxone trials, pain led to similar changes in MAP, CVP, MSNA and plasma catecholamines in the two groups except for a higher increase in HR in the BHT group as compared to the NT group (3 +/- 1 vs. 1 +/- 1 bpm; P < 0.005). Opioid blockade with naloxone increased MSNA responses to pain in the NT group (from 5 +/- 1 to 9 +/- 1 bursts/min, and, from 100 +/- 23 to 204 +/- 36 units/min, respectively; P < 0.05) but did not significantly affect the MSNA response to pain in the BHT group. Pain induced responses of MAP, CVP, and catecholamines were not altered by naloxone in either group. Overall, there was a highly significant inverse correlation between pain perception and resting blood pressure which was not significantly affected by naloxone. The BHT subjects exhibited a lower pain perception compared to the NT subjects (P < 0.005). Naloxone increased pain rating in the NT group (from 194 +/- 9 to 218 +/- 13; P < 0.005) but not in the borderline hypertensive group (160 +/- 8 vs. 168 +/- 10; P = 0.36). Except for a decreased HR response in the BHT group, placebo had no effect on the responses to pain. Our data do not indicate a major role of the endogenous opioid system for the blood pressure-pain interaction in man. Endogenous opioids affect pain perception and sympathetic nerve activity responses to pain in normotensive men but their activity seems to be attenuated in borderline hypertensive subjects. Therefore, the lower pain sensitivity in human essential hypertension is probably mediated by non-opioid mechanisms.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Hemodynamics; Humans; Hypertension; Male; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Reference Values; Sympathetic Nervous System

To determine the effects of prior exercise and naloxone on haemodynamics, muscle sympathetic nerve activity, pituitary hormones and ambulatory blood pressure.. We studied 14 mild hypertensive and 14 normotensive subjects on two days. After baseline measurements, subjects were randomly allocated to vehicle or naloxone (0.4 mg/kg) 30 min before 45 min treadmill exercise.. In both groups blood pressure, stroke volume, and calf and total peripheral resistances were lower 1 h after exercise, whereas sympathetic activity was unchanged. In normotensive subjects naloxone abolished this calf vasodilation without altering muscle sympathetic nerve activity, and attenuated these haemodynamic aftereffects of exercise, implying a peripheral opioidergic mechanism. Naloxone had no haemodynamic effect in hypertensive subjects. In normotensives there was an inverse relationship between changes in blood pressure and sympathetic activity after vehicle and exercise. This was transformed by naloxone into a positive relationship (r = 0.69, P < 0.02) similar to that observed in hypertensives after vehicle and exercise. Naloxone did not alter the latter positive relationship. Naloxone altered exercise-induced changes in prolactin and luteinizing hormone, but only in normotensive males. In both groups ambulatory blood pressures and heart rates over 2 h after subjects left the laboratory were higher than the values recorded at baseline or 1 h after exercise, and were unaffected by naloxone.. The depressor effect of exercise is due to peripheral vasodilation, occurs in the absence of sympathetic withdrawal and is short-lived. Endogenous opioids, activated by running, participate in the haemodynamic, sympathoneural and pituitary hormone aftereffects of exercise in normotensive subjects, whereas in hypertensives these aftereffects of exercise are achieved through non-opioidergic mechanisms. These observations are consistent with the concept that activation of endogenous opioid systems by exercise is impaired in mild hypertension.

Topics: Adrenergic Fibers; Adult; Atrial Natriuretic Factor; Blood Pressure; Exercise; Female; Hemodynamics; Humans; Hypertension; Male; Muscle, Skeletal; Naloxone; Norepinephrine; Plasma Volume

Cardiac output is increased in many young subjects with mild essential hypertension. The purpose of these experiments was to determine if activation of endogenous endorphin systems contributes to this increase. We investigated the acute effects of the opioid antagonist, naloxone, on Doppler-derived stroke volume, cardiac output and systemic blood pressure in young hypertensive (n = 9) and normotensive (n = 9) subjects. On two separate sessions, naloxone (0.4 mg/kg) was administered intravenously over 10 min to resting subjects according to a random, double-blind study design. Stroke volume and cardiac output were determined before and 10 min after the injection; heart rate and blood pressure were measured at 1 min intervals before and up to 20 min after the injection. Baseline blood pressure, stroke volume, and cardiac output were higher in hypertensive than in normotensive subjects. Naloxone had no immediate effect on blood pressure, heart rate, stroke volume, or total peripheral resistance in either group. These results indicate that: (1) naloxone has no immediate haemodynamic effect in young hypertensive or normotensive subjects, and (2) the higher stroke volume and cardiac output of young subjects with mild essential hypertension cannot be attributed to activation of endogenous opioid systems that are antagonized by naloxone.

Topics: Adult; Blood Pressure; Cardiac Output; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Male; Naloxone; Stroke Volume; Vascular Resistance

To investigate the effects of the endogenous opioid system on plasma atrial natriuretic factor (ANF) levels during sympathetic hyperactivity.. We studied the young normotensive offspring of parents who both had essential hypertension, who are characterized by a hyperactive sympathetic nervous system.. We assessed plasma beta-endorphin, met-enkephalin, dynorphin B, ANF and noradrenaline levels, blood pressure and heart rate values in eight normotensive offspring and in 10 young normotensive subjects with no family history of hypertension (controls) at rest and during two exercise tests: the first test performed with the infusion of placebo (1.5 ml/min saline) and the second test with the infusion of an opioid antagonist (9.5 micrograms/kg per min naloxone hydrochloride). ANF and opioids were radioimmunoassayed after chromatographic pre-extraction.. At rest plasma met-enkephalin, dynorphin B, ANF and noradrenaline values in the normotensive offspring were significantly higher than in the controls. Exercise with placebo significantly raised all hormonal and haemodynamic parameters in the two groups. This increase was significantly higher in the normotensive offspring than in the controls. Naloxone did not modify any parameter in either group at rest, but it enhanced further the rise in plasma noradrenaline levels induced by exercise in both groups. A similar effect of naloxone during exercise was observed for plasma ANF levels in the normotensive offspring.. Our findings show that plasma met-enkephalin, dynorphin B, ANF and noradrenaline levels at rest and during exercise are higher in normotensive offspring than in controls. The effects of naloxone indicate that in normotensive offspring at rest the opioid system does not affect ANF release, whereas during exercise it attenuates ANF hypersecretion, possibly by reducing noradrenaline release.

Topics: Adult; Atrial Natriuretic Factor; beta-Endorphin; Disease Susceptibility; Dynorphins; Endorphins; Enkephalin, Methionine; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male; Naloxone; Norepinephrine; Opioid Peptides; Physical Exertion; Radioimmunoassay

The purpose of the present study was to determine if opioid agonism (beta-endorphin) and antagonism (Naloxone) exert rheological and cardiovascular effects in normal humans and in patients with essential hypertension. Eight hypertensive patients were matched for age, sex, and body habitus (body mass index, waist to hip ratio) with eight normotensive healthy subjects. In all subjects, heart rate and blood pressure (continuous automatic recording), blood and plasma viscosity, fibrinogen, hematocrit, and platelet aggregation to ADP were evaluated during an infusion of human synthetic beta-endorphin (0.5 mg/h). On a different day and in randomized order, the subjects were submitted to another beta-endorphin infusion preceded by an i.v. naloxone bolus (5 mg in 5 min). beta-Endorphin and naloxone failed to significantly alter heart rate or blood pressure in both normotensive and hypertensive subjects. In hypertensive patients, beta-endorphin significantly increased blood viscosity and ADP-induced platelet aggregation, but only the former effect was naloxone-sensitive. In normotensive subjects, beta-endorphin caused a transient but significant decrease of platelet aggregation that was reversed by naloxone. These data suggest that beta-endorphin may play some role in the inhibitory control of platelet aggregation in normal subjects. An altered responsiveness of some rheological determinants to beta-endorphin seems to be present in human hypertension.

Topics: Adenosine Diphosphate; Adult; beta-Endorphin; Blood Pressure; Blood Viscosity; Cardiovascular System; Female; Fibrinogen; Heart Rate; Hematocrit; Humans; Hypertension; Male; Middle Aged; Naloxone; Platelet Aggregation; Rheology

The effects of fish oil and naloxone on blood pressure, catecholamines, and endorphins during the cold pressor test were evaluated in a randomized, double-blind, placebo-controlled, two-way crossover trial of normotensive and medication-free hypertensive men (n = 13 each). Subjects were given 5 gm omega-3 fatty acids per day or placebo for 30 days with a 1-month washout between interventions. The cold pressor test (hand in ice water for 5 minutes) was done at the end of the treatment periods. Intravenous naloxone (10 mg) or placebo was given before the cold pressor test. Fish oil-treated, normotensive, or hypertensive groups had similar changes in blood pressure, plasma catecholamine levels, and beta-endorphins during the cold pressor test, but naloxone treatment was associated with fivefold and tenfold increases in plasma epinephrine and cortisol levels, respectively. Naloxone may modulate sympathomedullary discharge through blockade of endorphin activity. It is unlikely that endorphins are involved in the blood pressure increase during the cold pressor test or that fish oil alters this response.

Topics: Adult; beta-Endorphin; Blood Pressure; Chromatography, High Pressure Liquid; Cold Temperature; Double-Blind Method; Epinephrine; Fatty Acids, Omega-3; Fish Oils; Humans; Hydrocortisone; Hypertension; Infusions, Intravenous; Naloxone; Norepinephrine; Pain Measurement; Random Allocation

It has been reported that naloxone, an opiate receptor antagonist, blunts the hypotensive effect of captopril in normotensives. However, our previous data did not show any interaction between captopril given acutely and naloxone (0.1 mg/kg) in hypertensives. To test whether a greater naloxone dose could interfere with the hemodynamic effect of chronically administered captopril, 12 male hypertensives were studied: Six of them had been under captopril treatment (50 mg tid) for at least 1 month, whereas the others had been drug free for the same time. Both groups randomly received a saline or naloxone (0.2 mg/kg) infusion for 1 hour, and blood pressure, heart rate, PRA, plasma aldosterone, adrenaline, and noradrenaline were measured at regular intervals before, during, and after naloxone infusion. In drug-free hypertensives, naloxone tended to reduce blood pressure slightly and did not modify heart rate, PRA, plasma aldosterone, adrenaline, or noradrenaline. In captopril-treated hypertensives, naloxone did not blunt the hypotensive effect of captopril, but rather enhanced it, without changing the heart rate, adrenaline, and noradrenaline. Moreover, naloxone increased the renin-stimulating action and did not modify the aldosterone-inhibiting effect of captopril. Our results show that the hemodynamic action of captopril given chronically is not influenced by opioid receptor blockade and therefore that the antihypertensive effect of this drug seems to be unrelated to the activation of the opioidergic system.

Topics: Adult; Blood Pressure; Captopril; Heart Rate; Humans; Hypertension; Male; Middle Aged; Naloxone; Time Factors

In a randomized, double-blind crossover study 13 untreated patients with mild essential hypertension were exposed to submaximal bicycle exercise. Sixty minutes before ergometry 10 mg metoclopramide or placebo, and 10 min before exercise 0.4 mg naloxone or placebo, were given intravenously. Plasma adrenocorticotrophic hormone, beta-endorphin and cortisol levels increased significantly after ergometry, whether performed after placebo, naloxone, metoclopramide or metoclopramide + naloxone treatment. However, only naloxone administration potentiated plasma adrenocorticotrophic hormone, beta-endorphin and cortisol responses to workload. Plasma levels of adrenocorticotrophic hormone, beta-endorphin and cortisol were 45 +/- 14 pg/ml, 6.2 +/- 1.2 pmol/l and 141 +/- ng/ml, respectively, after ergometry, when performed after placebo, but these values were increased to 61 +/- 10 pg/ml, 11.4 +/- 2.8 pmol/l and 207 +/- 22 ng/ml, respectively, after naloxone treatment. This naloxone-induced potentiation of hormonal release was blocked by metoclopramide pretreatment, suggesting a close interaction between dopaminergic and opioidergic mechanisms, regulating hormonal responses to physical exercise.

Topics: beta-Endorphin; Dopamine; Female; Humans; Hypertension; Male; Metoclopramide; Naloxone; Physical Exertion; Stress, Physiological

To evaluate whether opioid receptor blockade might modulate sympathetic-adrenal activity, we studied the effects of placebo or naloxone administration on plasma catecholamine (CA) levels in a group of 13 normal subjects and 15 hypertensive patients suspected to have a pheochromocytoma. Diagnostic evaluation confirmed the presence of pheochromocytoma in 9 patients. Among these, 4 had a unilateral epinephrine (E)-secreting tumor, 3 had bilateral E-secreting tumors due to multiple endocrine adenomatosis type IIa, and 2 had a unilateral norepinephrine (NE)-secreting tumor. In each subject studied, CA secretion was evaluated by calculating the area (0-30 min) under the plasma hormone curves after placebo or naloxone administration. In normal subjects naloxone caused a significant increase (P less than 0.005) of E secretion, whereas NE did not change. Similarly, in the group of hypertensive patients, E secretion increased after naloxone (P less than 0.01). In pheochromocytoma patients naloxone caused a significant increase in E (P less than 0.05) and NE (P less than 0.01) secretion from E-producing tumors but no increase in the patients with NE-secreting pheochromocytomas. The study suggests that CA secretion from normal and pathological chromaffin tissue is modulated by endogenous opioids; this modulation seems particularly evident in patients with E-secreting pheochromocytoma.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Catecholamines; Chromaffin System; Female; Humans; Hypertension; Male; Middle Aged; Naloxone; Pheochromocytoma; Receptors, Opioid

Six patients maintained on 50-100 mg captopril, for 2-25 months, were administered captopril 50 mg orally, together with either naloxone or 0.9% saline vehicle (placebo) given intravenously, in a double-blind crossover study. Naloxone did not appear to modify the circulatory effects of captopril in these patients, in contrast to earlier findings after acute captopril administration in normotensives. The results do not support an important endogenous opioid role in the chronic antihypertensive effect of captopril, but provide evidence that different mechanisms may contribute to the early short term falls in blood pressure, compared to the later long term effects.

Topics: Adult; Aged; Blood Pressure; Captopril; Clinical Trials as Topic; Double-Blind Method; Drug Interactions; Endorphins; Female; Humans; Hypertension; Male; Middle Aged; Naloxone; Random Allocation

Naloxone, a competitive antagonist of opioid receptors, and placebo (dextrose 5% in water (D5W) were administered on separate days to healthy normotensive (NT) male volunteers and to male patients with essential hypertension (HT). A single-blind, placebo-controlled, cross-over design was employed. Increasing doses of naloxone (0.4, 1.2, 3.6, 10.8, 32.4, 97.2 mg) were given every 30 min as slow i.v. boluses. On a separate day, i.v. boluses of D5W were given according to a similar protocol. Naloxone failed to significantly modify systolic and diastolic blood pressure (BP), heart rate (HR), respiratory rate, oral temperature or plasma catecholamines. No adverse reactions or behavioral effects were seen with naloxone. Naloxone produced a dose-dependent increase in plasma cortisol, whereas plasma cortisol showed a gradual decline on the placebo day (circadian variation). HT and NT showed similar maximal increases in plasma cortisol. Hypertensives responded to lower doses of naloxone with greater increases in plasma cortisol. The results were significantly different only if corrected by using the baseline values obtained on the placebo day. The study suggests that in awake, resting men, endogenous opioids play no role in regulating BP, HR, respiration, temperature or the activity of the sympathetic nervous system. It also suggests that the sustained elevation of BP in HT is not due to endogenous opioid substances. However, endogenous opioid substances produce a tonic inhibitory effect on the release of cortisol. This tonic inhibition seems to be greater in hypertensives than in normotensives.

Topics: Adult; Blood Pressure; Cardiovascular System; Catecholamines; Endocrine Glands; Endorphins; Heart Rate; Humans; Hypertension; Male; Middle Aged; Naloxone; Respiration

It has been reported that endogenous opioid antagonism through naloxone (NAL) blunts the hypotensive effect of captopril (CAP) in normal man. For this reason a study was carried out to determine whether NAL interacts with the antihypertensive effect of CAP in patients with mild-to-moderate essential hypertension (n = 6; age 22-43 years). Patients received, according to a randomized code, placebo (PL) during saline infusion, CAP (25 mg orally) during saline infusion, PL + NAL (0.4 mg as a bolus followed by a continuous infusion of 4.0 mg/h for 2 h) and CAP + NAL at the same doses. Three-day intervals elapsed between each phase of the study. Blood pressure (BP) and heart rate (HR) were recorded before (-20 to 0 min) and every 15 min for the next 2 h after drug administration. Blood samples for plasma renin activity (PRA), noradrenaline (NA) and aldosterone (ALD) were collected before (time 0) and 120 min after drug administration. Neither PL nor NAL changed any of the parameters examined, while CAP alone reduced mean BP to a highly significant extent. Naloxone did not change the hypotensive effect of CAP to any significant extent. Captropril, either alone or associated with NAL, tended to reduce plasma ALD and increase PRA (P less than 0.05) without changing HR or plasma NA. These data indicate that, at least under the experimental conditions used, endogenous opioid antagonism does not interfere with the haemodynamic and humoral effect of CAP in essential hypertensive man. This suggests that endogenous opioids do not mediate the pharmacological actions of CAP.

Topics: Adult; Blood Pressure; Captopril; Drug Interactions; Humans; Hypertension; Male; Naloxone; Receptors, Opioid

Studies in animals and man indicate a functional interaction between the adrenergic and the opiate systems. In the present study the effect of the opiate receptor blocker naloxone on the increase in plasma GH induced by clonidine was investigated in eight patients with essential hypertension. In a randomized order the patients received a bolus dose of naloxone (10 micrograms/kg) or physiological saline followed by a slow infusion of naloxone (5 micrograms/kg X h) or saline, respectively. Fifteen minutes after the bolus dose of saline or naloxone, clonidine (3 micrograms/kg) was infused for 10 min. Clonidine induced a significant increase in plasma GH. Naloxone pretreatment resulted in a significantly reduced GH increase after the clonidine infusion. These results indicate that the clonidine-induced increase in plasma GH in hypertensive man is partly mediated via activation of opiate receptors which can be blocked by naloxone.

Topics: Clonidine; Female; Growth Hormone; Humans; Hypertension; Male; Naloxone; Receptors, Opioid

The effects of clonidine, naloxone, and their combination on arterial blood pressure (BP), heart rate (HR), and hemodynamic and biochemical parameters were examined in 29 patients with essential hypertension. Treatment for 3 days with 0.3 mg/day clonidine reduced BP and HR, and these effects were quickly reversed by a single injection of 0.4 mg iv naloxone in 17 of the patients (responders), but not in the remaining 12 (nonresponders). Responders had higher control values for cardiac output, stroke index, plasma renin activity (PRA), and plasma epinephrine levels than did nonresponders. Basal BP was similar in the two groups, but clonidine decreased BP, PRA, and plasma epinephrine more in responders than in nonresponders. Naloxone given during placebo treatment had no significant effects. During clonidine treatment naloxone increased BP, HR, total peripheral resistance, PRA, and plasma epinephrine and norepinephrine, and decreased stroke volume in responders, whereas in nonresponders its only effect was a small increase in HR. It is concluded that in a subset of hyperadrenergic, hypertensive patients the antihypertensive effect of clonidine involves a naloxone-reversible inhibition of central sympathetic outflow, probably mediated by the release of an endogenous opioid.

Topics: Adult; Blood Pressure; Clonidine; Drug Therapy, Combination; Epinephrine; Heart Rate; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Middle Aged; Naloxone; Norepinephrine; Renin; Stroke Volume; Sympathetic Nervous System

Daily doses of 0.3 mg clonidine and 3 mg guanfacine were equiactive in decreasing blood pressure and heart rate in 17 subjects with essential hypertension. Clonidine decreased cardiac output and guanfacine decreased total peripheral resistance, while clonidine had no effect on stroke volume but guanfacine increased it. Both clonidine and guanfacine decreased plasma renin activity. Naloxone, 0.4 mg iv, reversed the antihypertensive effect of clonidine but was ineffective even at higher doses (1.6 mg iv) when subjects were treated with placebo or guanfacine. It is suggested that the hemodynamic differences between the two centrally acting alpha 2-adrenoceptor agonist antihypertensive drugs may at least in part result from the involvement of opioid mechanisms only in the action of clonidine.

Topics: Adult; Blood Pressure; Cardiac Output; Clonidine; Guanfacine; Guanidines; Heart Rate; Humans; Hypertension; Indium; Injections, Intravenous; Middle Aged; Naloxone; Phenylacetates; Radioisotopes; Renin

Reports on spontaneously hypertensive rats suggested that naloxone blocked the antihypertensive effects of clonidine. We compared the effects of an 8-hr intravenous naloxone infusion (6 micrograms/kg/hr) or 5% dextrose in water (D5/W) begun 2 hr before single oral doses of clonidine (0.3 mg) in six men with mild to moderate essential hypertension (EHT). Supine and standing (after 5 min) blood pressure (BP) and heart rate (HR) were measured every 20 min. Initial treatment with naloxone or placebo (D5/W) infusion was randomly allocated, with the alternate treatment given 1 wk later. Naloxone did not modify either supine or standing BP or HR. Clonidine induced a gradual, sustained reduction in both supine and standing systolic and diastolic BP and in supine HR, and there was an increase in standing HR. Naloxone did not modify the onset, maximal effect, or recovery of the hypotensive and HR effects of clonidine in both the supine and standing positions. Our data indicate that hypotensive and bradycardiac effects of clonidine in EHT are not mediated by naloxone-sensitive opioid receptors. They also suggest that opioid receptors play no role in the maintenance of hypertension nor in the BP and HR adjustments induced by postural changes in EHT.

Topics: Adult; Blood Pressure; Clonidine; Double-Blind Method; Heart Rate; Humans; Hypertension; Male; Naloxone; Posture; Random Allocation; Receptors, Opioid

Studies in animals and man indicate a functional interaction between the adrenergic and the opiate systems. In the present study the effect of the opiate receptor blocker naloxone on the reduction of blood pressure and plasma noradrenaline induced by the alpha 2-agonist clonidine was investigated in nine patients with essential hypertension. In a randomised manner the patients received a bolus dose of naloxone (10 micrograms/kg) or physiological saline followed by a slow infusion of naloxone (5 micrograms/kg/h) or saline, respectively. Fifteen minutes after the respective bolus dose, clonidine (3 micrograms/kg) was infused over 10 minutes. Naloxone had no effect on the clonidine induced hypotension and reduction of plasma noradrenaline. Accordingly, there is no evidence that the clonidine induced reduction of blood pressure and plasma noradrenaline involves opiate receptors that can be blocked by naloxone. Plasma adrenaline increased significantly during the early phase of naloxone infusion.

Topics: Adult; Blood Pressure; Clonidine; Female; Humans; Hypertension; Male; Middle Aged; Naloxone; Norepinephrine; Receptors, Opioid; Sodium Chloride

Topics: Blood Pressure; Clinical Trials as Topic; Clonidine; Drug Antagonism; Female; Hemodynamics; Humans; Hypertension; Male; Naloxone

The effect of naloxone on the hypotensive and bradycardiac action of clonidine was studied in 27 hospitalized patients with uncomplicated mild-to-moderate essential hypertension. In a double-blind, crossover study, clonidine, 0.3 mg/day orally for 3 days, significantly reduced systolic and diastolic blood pressure and heart rate, whereas placebo was ineffective. Naloxone, 0.4 mg given intravenously on the third day of clonidine treatment, caused a rapid increase in blood pressure and heart rate in 14 patients (reacting group), but was ineffective in the remaining 13 patients (nonreacting group). Naloxone given during the placebo period was ineffective in all patients. Both the clonidine-induced hypotension and the rebound increase in blood pressure after cessation of clonidine were significantly greater in the reacting than in the nonreacting group. These observations suggest that release of an endogenous opioid contributes to the antihypertensive action of clonidine; this mechanism may be also involved in the discontinuation syndrome after cessation of clonidine.

Topics: Adult; Blood Pressure; Clonidine; Drug Interactions; Heart Rate; Humans; Hypertension; Middle Aged; Naloxone; Placebos; Receptors, Opioid

Moderate exercise reduces arterial pressure (AP) and heart rate (HR) in spontaneously hypertensive rats (SHR) and changes neurotransmission in medullary areas involved in cardiovascular regulation. We investigated if regularly swimming exercise (SW) affects the cardiovascular adjustments mediated by opioidergic neuromodulation in the RVLM in SHR and Wistar-Kyoto (WKY) rats. Rats were submitted to 6 wks of SW. The day after the last exercise bout, α-chloralose-anesthetized rats underwent a cannulation of the femoral artery for AP and HR recordings, and Doppler flow probes were placed around the lower abdominal aorta and superior mesenteric artery. Bilateral injection of endomorphin-2 (EM-2, 0.4 mmol/L, 60 nL) into the RVLM increased MAP in SW-SHR (20 ± 4 mmHg, N = 6), which was lower than in sedentary (SED)-SHR (35 ± 4 mmHg, N = 6). The increase in MAP in SW-SHR induced by EM-2 into the RVLM was similar in SED- and SW-WKY. Naloxone (0.5 mmol/L, 60 nL) injected into the RVLM evoked an enhanced hypotension in SW-SHR (-66 ± 8 mmHg, N = 6) compared to SED-SHR (-25 ± 3 mmHg, N = 6), which was similar in SED- and SW-WKY. No significant changes were observed in HR after EM-2 or naloxone injections into the RVLM. Changes in hindquarter and mesenteric conductances evoked by EM-2 or naloxone injections into the RVLM in SW- or SED-SHR were not different. Mu Opioid Receptor expression by Western blotting was reduced in SW-SHR than in SED-SHR and SW-WKY. Therefore, regularly SW alters the opioidergic neuromodulation in the RVLM in SHR and modifies the mu opioid receptor expression in this medullary area.

Topics: Analgesics, Opioid; Animals; Arterial Pressure; Heart Rate; Hypertension; Medulla Oblongata; Naloxone; Narcotic Antagonists; Neurons; Oligopeptides; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid, mu; Swimming

Large doses of intramuscular (IM) naloxone are commonly used in out-of-hospital settings to reverse opioid toxicity; however, they are used less commonly in hospitals because of concerns about opioid withdrawal, particularly agitation. We aimed to determine the frequency of severe agitation following a single 1.6 mg IM naloxone dose.. We undertook a prospective study of adult (>15 years) patients treated by an Australian state ambulance service with 1.6 mg IM administration of naloxone for respiratory depression (respiratory rate <11 breaths/min and/or oxygen saturation <93% in room air) caused by presumed opioid poisoning. The primary outcome was the proportion of presentations with severe agitation (Sedation Assessment Tool score >1) within 1 hour of naloxone administration. Secondary outcomes were the proportion of presentations with acute opioid withdrawal (tachycardia [pulse rate >100 beats/min], hypertension [systolic >140 mm Hg], vomiting, agitation, seizure, myocardial infarction, arrhythmia, or pulmonary edema), and reversal of respiratory depression (respiratory rate >10 breaths/min and saturation >92% or Glasgow Coma Scale score 15).. From October 2019 to July 2021, there were 197 presentations in 171 patients, with a median age of 41 years (range, 18 to 80 years); of the total patients, 119 were men (70%). The most common opioids were heroin (131 [66%]), oxycodone (14 [7%]), and morphine (11 [6%]). Severe agitation occurred in 14 (7% [95% confidence interval {CI} 4% to 12%]) presentations. Opioid withdrawal occurred in 76 presentations (39% [95% CI 32% to 46%]), most commonly in the form of tachycardia (18%), mild agitation/anxiety (18%) and hypertension (14%). Three presentations (1.5%) received chemical sedation for severe agitation within 1 hour of naloxone administration. A single 1.6 mg dose of naloxone reversed respiratory depression in 192 (97% [95% CI: 94% to 99%]) presentations.. Severe agitation was uncommon following the administration of 1.6 mg IM naloxone and rarely required chemical sedation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Australia; Drug Overdose; Female; Hospitals; Humans; Hypertension; Male; Middle Aged; Naloxone; Narcotic Antagonists; Narcotics; Prospective Studies; Respiratory Insufficiency; Substance Withdrawal Syndrome; Young Adult

While our recent studies have suggested that effective acupoints display neurogenic inflammation and can be identified as neurogenic spots (Neuro-Sps), the optimal stimulation conditions and the underlying mechanisms remain uncharacterized. We developed a combined mechano-electrical acupuncture device (MEA) and examined the effects of acupuncture at Neuro-Sps on systolic blood pressure (BP) in a rat model of immobilization-induced hypertension (IMH) and the mediation of endogenous opioid systems in its effect. Cutaneous neurogenic spots were found mostly in the forelimb. Electrical and mechanical acupuncture of Neuro-Sps increased 22-kHz ultrasonic vocalizations (USVs), c-Fos expression and cell excitability in the midbrain and synergistically alleviated the development of hypertension following immobilization stress, which was prevented by administration of the opioid antagonist naloxone into the rostral ventrolateral medulla (rVLM). These findings suggest that mechanical and electrical stimulation at Neuro-Sps suppresses the development of hypertension via mediation of the endogenous opioid system.

Topics: Acupuncture Points; Acupuncture Therapy; Analgesics, Opioid; Animals; Blood Pressure; Electric Stimulation; Hypertension; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley

Surgical stress and pain are potential provoking factors for postoperative myasthenic crisis (POMC). We report the occurrence of early POMC and late deep vein thrombosis (DVT) in a man with myasthenia gravis (MG) undergoing thymectomy, addressing possible link between reversal of opioid overdose with naloxone and the triggering of POMC.. A 71-year-old man with impaired renal function (ie, estimated glomerular filtration rate [egfr]: 49.1 mL/min/1.73 m) with diagnosis of MG made 2 months ago was scheduled for thymectomy. After uncomplicated surgery, he experienced opioid overdose that was treated with naloxone. Hyperlactatemia then developed with a concomitant episode of hypertension. Three hours after reversal, he suffered from myasthenic crisis presenting with respiratory failure and difficult weaning from mechanical ventilation.. Stress-induced hyperlactatemia and subsequent myasthenic crisis INTERVENTIONS:: Pyridostigmine and immunosuppressive therapy with prednisolone were initiated. Hyperlactatemia subsided on postoperative day (POD) 5. Tracheal extubation was performed successfully on POD 6.. During the course of hospitalization, his eGFR (ie, 88.9 mL/min/1.73 m) was found to improve postoperatively. After discharge from hospital, he developed DVT in the left femoral and popliteal veins on POD 24 when he was readmitted for immediate treatment with low-molecular-weight heparin. He was discharged without sequelae on POD 31. There was no recurrence of myasthenic crisis or DVT at 3-month follow-up.. Following naloxone administration, hyperlactatemia may be an indicator of pain-related stress response, which is a potential provoking factor for myasthenic crisis. Additionally, patients with MG may have an increased risk of DVT possibly attributable to immune-mediated inflammation. These findings highlight the importance of perioperative avoidance of provoking factors including monitoring of stress-induced elevations in serum lactate concentration, close postoperative surveying for myasthenic crisis, and early recognition of possible thromboembolic complications in this patient population.

Topics: Aged; Anticoagulants; Cholinesterase Inhibitors; Heparin, Low-Molecular-Weight; Humans; Hyperlactatemia; Hypertension; Immunosuppressive Agents; Male; Myasthenia Gravis; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Patient Readmission; Postoperative Complications; Prednisolone; Pyridostigmine Bromide; Respiration, Artificial; Respiratory Insufficiency; Thymectomy; Treatment Outcome; Venous Thrombosis

Apelin receptors (APJ) cross-talk with other G-protein-coupled receptors. However, the role of APJ interaction with opioid receptors (OPR) on the cardiovascular effects of apelin in hypertension is not clear. Renovascular hypertension was induced by placing a Plexiglas clip on the left kidney of rats. After 16 weeks, F13A (an APJ antagonist), naloxone (a general OPR inhibitor), and nor-binaltorphimine dihydrochloride (nor-BNI; a selective inhibitor of KOR) were given prior to injections of apelin at doses of 40 and 60 μg/kg. The arterial systolic/diastolic blood pressure and left ventricular contractility responses were then evaluated. The arterial systolic/diastolic blood pressure in sham and 2K1C rats was 110/71 mm Hg and 171/124 mm Hg, respectively. The hypotensive effects of apelin at both doses were inhibited by F13A and naloxone. Nor-BNI completely inhibited the effects of apelin 40 on arterial pressure, and decreased the effects of 60 μg/kg. KOR inhibition also prevented the compensation for the decrease in the left ventricle +dp/dt max and -dp/dt max caused by apelin 60. The simultaneous inhibition of OPR and APJ reduced arterial pressure and increased cardiac contractility. Findings showed that the OPR, particularly KOR, mediate the inotropic, lusitropic, and depressor effects of apelin. The interaction of the OPR and APJ augments the inotropic and vasodepressor effects of apelin. This interaction may have potential clinical applications in cardiac failure since opioids are currently used in the treatment of myocardial infarction and stroke, and apelin has been introduced as a potential therapeutic agent in cardiovascular complications.

Topics: Animals; Apelin; Blood Pressure; Gene Expression Regulation; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Male; Myocardial Contraction; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Catalase; Cultured Milk Products; Diet; Glutathione Peroxidase; Hypertension; Lactococcus lactis; Lipid Peroxidation; Male; Malondialdehyde; Naloxone; Narcotic Antagonists; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred SHR; Receptors, Opioid; Superoxide Dismutase

Following clonidine ingestion, naloxone is seldom administered as it is considered ineffective in reversing somnolence, bradycardia, or hypotension. However, this conclusion has been based on administration of small doses (2 mg or less) of naloxone. The somnolence is frequently treated with endotracheal intubation (ETI), a procedure with significant morbidity.. We aimed to determine if naloxone administration reversed the effects of clonidine or caused any adverse effects.. We performed a retrospective descriptive cohort (IRB approved) of hospital medical records for pediatric patients (6 months-16 years) with clonidine exposure. Demographics, history, co-ingestants, clinical data, treatments, and outcome were recorded in a de-identified database.. The most common clinical findings in the 52 patients were sedation (n = 51), bradycardia (n = 44), and hypotension (n = 11). Of 51 somnolent patients, naloxone administration awoke 40 patients, five of which had co-ingestants. Nine patients experienced recurrent sedation that resolved with a repeat bolus of naloxone. Twenty somnolent bradycardic patients (11 less than 3 years old) received 10 mg naloxone via intravenous bolus. Thirteen awoke; bradycardia persisted in six of the awake patients. Of the remaining 31 patients, 22 awoke following 6 mg or less of naloxone. Naloxone reversed hypotension in 7 of 11 hypotensive patients. Only one hypotensive patient (with a coingestion) received vasopressors for hypotension. Three awake normotensive patients received vasopressors for bradycardia. Seven patients awoke and had normal vital signs following naloxone administration, but were chemically sedated and intubated for transport. There were no adverse events following the administration of any dose of naloxone.. Administration of naloxone to somnolent pediatric patients with clonidine toxicity awoke the majority (40/51) and resolved bradycardia and hypotension in some. Persistent bradycardia was benign. Hypotension was rare and clinically insignificant. No adverse effects occurred in any patient including the 21 patients who received 10 mg naloxone. Morbidity in this overdose may be due to ETI, a procedure that could be prevented if high-dose naloxone (10 mg) were administered. Administration of high-dose naloxone should be considered in all children with clonidine toxicity.

Topics: Adolescent; Antidotes; Antihypertensive Agents; Child; Child, Preschool; Clonidine; Cohort Studies; Dose-Response Relationship, Drug; Drug Overdose; Female; Humans; Hypertension; Infant; Male; Naloxone; Retrospective Studies

The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [noradrenergic activity, induction of the hypothalamic-pituitary-adrenocortical (HPA) axis and activation of heat shock proteins (Hsps)]. Corticotropin-releasing factor (CRF) pathways are important mediators in the negative symptoms of opioid withdrawal. We performed a series of experiments to characterize the role of the CRF₁ receptor in the response of stress systems to morphine withdrawal and its effect in the heart using genetically engineered mice lacking functional CRF₁ receptors.. Wild-type and CRF₁ receptor-knockout mice were treated with increasing doses of morphine. Precipitated withdrawal was induced by naloxone. Plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, the expression of myocardial Hsp27, Hsp27 phosphorylated at Ser⁸², membrane (MB)- COMT, soluble (S)-COMT protein and NA turnover were evaluated by RIA, immunoblotting and HPLC.. During morphine withdrawal we observed an enhancement of NA turnover in parallel with an increase in mean arterial blood pressure (MAP) and heart rate (HR) in wild-type mice. In addition, naloxone-precipitated morphine withdrawal induced an activation of HPA axis and Hsp27. The principal finding of the present study was that plasma ACTH and corticosterone levels, MB-COMT, S-COMT, NA turnover, and Hsp27 expression and activation observed during morphine withdrawal were significantly inhibited in the CRF₁ receptor-knockout mice.. Our results demonstrate that CRF/CRF₁ receptor activation may contribute to stress-induced cardiovascular dysfunction after naloxone-precipitated morphine withdrawal and suggest that CRF/CRF₁ receptor pathways could contribute to cardiovascular disease associated with opioid addiction.

Topics: Adrenergic Neurons; Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Heart Ventricles; HSP27 Heat-Shock Proteins; Hypertension; Hypothalamo-Hypophyseal System; Male; Mice; Mice, 129 Strain; Mice, Knockout; Morphine Dependence; Naloxone; Nerve Tissue Proteins; Phosphorylation; Pituitary-Adrenal System; Protein Processing, Post-Translational; Receptors, Corticotropin-Releasing Hormone; Signal Transduction; Tachycardia

An Asian multiparous woman weighing 47 kg, who suffered from a rare myopathy, congenital fibre type disproportion, was given morphine 10 mg intramuscularly for labour analgesia. After delivery, she had diastolic hypertension and proteinuria and was prescribed magnesium sulphate. Some hours later she became unresponsive with little respiratory effort. Blood gas analysis revealed a respiratory acidosis. Naloxone administration reversed the symptoms. Further doses were required as the respiratory depression recurred. Opioid-related narcosis is the most likely diagnosis in this case. Other possible differential diagnoses were magnesium overdose or a post-ictal state. The presence of a myopathy could render this patient susceptible to the respiratory effects of opioids. Other explanations for an exaggerated and delayed response to opioids include co-administration of other respiratory depressant drugs such as magnesium sulphate, co-morbidity such as renal impairment and genetic variability in the metabolism of morphine. Robust guidelines and highlighting patients with risk factors are required to prevent this complication from recurring.

Topics: Acidosis, Respiratory; Adult; Analgesia, Obstetrical; Analgesics, Opioid; Anticonvulsants; Blood Gas Analysis; Diagnosis, Differential; Female; Humans; Hypertension; Magnesium Sulfate; Morphine; Myopathies, Structural, Congenital; Naloxone; Narcotic Antagonists; Pre-Eclampsia; Pregnancy; Proteinuria; Risk Factors; Stupor

Topics: Aged; Analgesia, Epidural; Analgesics, Opioid; Anesthetics, Local; Antihypertensive Agents; Bupivacaine; Carcinoma; Cardiotonic Agents; Dobutamine; Enalapril; Female; Humans; Hypertension; Hypotension; Liver Neoplasms; Metoprolol; Morphine; Naloxone; Narcotic Antagonists; Norepinephrine; Thoracic Vertebrae; Time Factors; Vasoconstrictor Agents

Our study aimed at elucidating the effects of acute central hypervolemia induced by water immersion (WI) on renal hemodynamics, hormonal responses and on cardiovascular control in hypertensive patients, as well as at evaluating the possible role of the opioidergic system (OS) in determining these effects. Thirteen essential hypertensives were studied for 2 h before and for 2 h during WI. This was done twice, without and with i.v. injection of the OS antagonist naloxone. Before and during WI alone, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial pressure (MAP), pulse interval (PI), spontaneous baroreflex sensitivity (BRS), Low frequency to High frequency (LF/HF) ratio in PI spectra, hematocrit, urinary sodium excretion, plasma renin activity (PRA) and aldosterone (PA) were assessed. Based on their response to WI, hypertensives were subdivided into two groups: ERPF+ (n = 7) in whom WI increased ERPF, and ERPF- (n = 6) in whom WI reduced ERPF. ERPF+ displayed a higher BRS than ERPF- at baseline and during WI. A suppression of PRA and PA and an increase in MAP and urinary sodium excretion were found in both groups. In ERPF+ naloxone caused RVR and MAP to increase during WI and this response was associated with a blockade of the increase in ERPF in this group, while BRS and natriuresis were unchanged. In ERPF- naloxone did not affect WI-induced MAP, ERPF, RVR and BRS changes, while it blunted sodium excretion. Our data provide the first evidence of a differentiate renal hemodynamic response to WI in hypertension; they also suggest that while OS may significantly potentiate the renal vasodilatory response to WI in ERPF+, it does not affect the natriuretic response nor the changes in systemic cardiovascular regulation induced by central hypervolemia.

Topics: Adult; Blood Volume; Hemodynamics; Humans; Hypertension; Immersion; Kidney; Male; Middle Aged; Naloxone; Narcotic Antagonists; Renal Plasma Flow, Effective; Water

Safe, effective, and reversible immobilization protocols are essential for the management of free-ranging red wolves (Canis rufus). Combinations using an alpha2-adrenoceptor agonist and ketamine have been shown to be effective for immobilization but are not reversible and can produce severe hypertension and prolonged or rough recoveries. To minimize hypertension and provide reversibility, 24 red wolves were immobilized using three medetomidine-butorphanol (MB) combinations without the use of ketamine in the initial injection. All wolves were administered medetomidine (0.04 mg/kg i.m.) and butorphanol (0.4 mg/kg i.m.). Seven wolves received no other immobilization agents (MB wolves), nine received diazepam (0.2 mg/kg i.v.) at the time they were instrumented (MBD wolves), and eight received ketamine (1 mg/kg i.v.) 30 min after instrumentation (MBK30 wolves). Physiologic parameters were monitored during immobilization. The heart rate was similar among the three groups for the first 30 min, and marked bradycardia was noted in one wolf from each group. Hypertension was observed initially in all three groups but was resolved within 10-30 min. The MBK30 wolves had significant elevations in heart rate and transient hypertension after intravenous ketamine administration. Most wolves had mild to moderate metabolic acidemia. Immobilizing drugs were antagonized in all wolves with atipamezole (0.2 mg/kg i.m.) and naloxone (0.02 mg/kg i.m.). The medetomidine-butorphanol-diazepam wolves were also given flumazenil (0.04 mg/kg i.v.). All wolves were standing within 12 min and were fully recovered within 17 min. Medetomamine-butorphanol and MBD combinations provided effective and reversible immobilization of red wolves without the sustained hypertension associated with the use of alpha2-adrenoceptor agonist-ketamine combinations. Delaying the administration of ketamine reduced its hypertensive effects.

Topics: Adrenergic alpha-Antagonists; Anesthetics, Dissociative; Animals; Animals, Zoo; Blood Pressure; Body Temperature; Butorphanol; Diazepam; Drug Combinations; Female; Flumazenil; GABA Modulators; Heart Rate; Hypertension; Hypnotics and Sedatives; Imidazoles; Immobilization; Ketamine; Male; Medetomidine; Muscle Relaxation; Naloxone; Narcotic Antagonists; Narcotics; Respiration; Wolves

Cardiovascular effects of subcutaneous administration of synthetic alpha-lactorphin, a tetrapeptide (Tyr-Gly-Leu-Phe) originally derived from milk alpha-lactalbumin, were studied in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY) with continuous radiotelemetric monitoring. Alpha-lactorphin dose-dependently lowered blood pressure (BP) without affecting heart rate in SHR and WKY. The lowest dose which reduced BP was 10 microg/kg, and the maximal reductions in systolic and diastolic BP (by 23+/-4 and 17+/-4 mm Hg, respectively) were observed at 100 microg/kg dose in SHR. No further reductions were obtained at a higher dose of 1 mg/kg. There were no significant differences in the BP responses to alpha-lactorphin between SHR and WKY. Naloxone (1 and 3 mg/kg s.c.), a specific opioid receptor antagonist, abolished the alpha-lactorphin-induced reduction in BP and reversed it into a pressor response, which provides evidence for an involvement of opioid receptors in the depressor action of the tetrapeptide.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Captopril; Dose-Response Relationship, Drug; Hypertension; Male; Naloxone; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Neuropeptide FF (NPFF), a morphine modulatory peptide, is localized within discrete autonomic regions including the brainstem nucleus tractus solitarius (NTS) and the parabrachial nucleus (PBN). We investigated the activation of NPFF neurons in the NTS of rats induced by cardiovascular challenge and centrally generated opiate withdrawal. For hypotensive stimulation, we used systemic infusions of sodium nitroprusside (NP) or hemorrhage (HEM), and hypertension was achieved by intravenous phenylephrine (PHENYL) or angiotensin II (AII). In rats that received continuous intracerebroventricular injections of morphine, intraperitoneal injections of naloxone precipitated behavioural signs of opioid withdrawal. Activated NTS neurons were identified by using a combined immunohistochemistry for Fos and NPFF, and neurons projecting to the PBN were determined with a retrograde tracer. HEM, administration of vasoactive drugs, and opiate withdrawal produced a very robust activation of NTS neurons. In NP and HEM groups, 25.6+/-3.2% and 7.6+/-1.3% of NPFF neurons were activated, respectively. Lesser numbers of NPFF neurons were activated in the PHENYL (4.6+/-1.6%) and AII (2.4+/-0.8%) groups. However, following opiate withdrawal, virtually no Fos expression was observed in NPFF neurons. NPFF neurons activated during NP infusion constituted the largest number of cells projecting to the PBN. This study shows that NPFF neurons in NTS that project to the PBN respond selectively to NP as opposed to other cardiovascular challenges or opiate withdrawal. These data support an emerging and important role for NPFF in the context of central cardiovascular regulation.

Topics: Angiotensin II; Animals; Hemodynamics; Hypertension; Hypotension; Male; Morphine; Morphine Dependence; Naloxone; Neurons; Nitroprusside; Oligopeptides; Phenylephrine; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Solitary Nucleus; Substance Withdrawal Syndrome

Topics: Adult; Asthma; Codeine; Humans; Hypertension; Male; Naloxone; Narcotic Antagonists; Travel

To highlight the increase in the number of cases of clonidine overdose admitted to a specialist paediatric hospital, with particular reference to the clinical features, clinical course and circumstances surrounding the incident.. Cases of clonidine overdose were identified by review of the emergency department attendance register, the intensive care unit database and inpatient statistics collection. Case notes were reviewed to determine the clinical features, history and clinical course in each case.. Fifteen patients experienced 16 overdoses during the period 1990-97 inclusive. Only one case occurred before 1994. Depressed level of consciousness and bradycardia were the most common clinical manifestations, and were observed in 75 and 88% of cases respectively. There were no fatalities. Five patients received naloxone. Other treatment modalities included gastrointestinal decontamination, atropine, ventilation and inotropic support. Fourteen cases occurred in association with medication prescribed for attention-deficit hyperactivity disorder (ADHD).. Clonidine overdose is a potentially serious condition, often requiring intensive care management. Our experience suggests that it is a growing problem, related in part to its increased use in the treatment of ADHD. Preventive strategies, including raising the level of awareness of risks, changes to packaging and appropriate selection of patients for treatment, need consideration if further overdoses are to be prevented.

Topics: Adrenergic alpha-Agonists; Attention Deficit Disorder with Hyperactivity; Bradycardia; Child; Child, Preschool; Clonidine; Drug Overdose; Drug Therapy, Combination; Drug Utilization; Female; Humans; Hypertension; Infant; Male; Naloxone; Narcotic Antagonists; Sleep Stages; Sympatholytics

To investigate the involvement of endogenous opioids in acute increases in blood pressure and their functional relationship with atrial natriuretic factor and endothelin-1, we assessed plasma levels of beta-endorphin, met-enkephalin, dynorphin B, catecholamines, atrial natriuretic factor, and endothelin-1 before and after administration of the opioid antagonist naloxone hydrochloride (8 mg i.v.) in 28 hypertensive patients with a stress-induced acute increase in blood pressure. Ten patients with established mild or moderate essential hypertension and 10 normotensive subjects served as control groups. Opioids, atrial natriuretic factor, and endothelin-I were radioimmunoassayed after chromatographic preextraction; catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Patients with an acute increase in blood pressure (systolic, 203.2 +/- 2.2 mm Hg; diastolic, 108.4 +/- 1.3) had plasma opioid, catecholamine, and atrial natriuretic factor levels significantly (P < .01) higher than hypertensive control patients (systolic pressure, 176.4 +/- 1.0 mm Hg; diastolic, 100.0 +/- 1.4), who had a hormonal pattern similar to that of normotensive subjects (systolic pressure, 123.2 +/- 1.5 mm Hg; diastolic, 75.0 +/- 2.0). Endothelin-1 did not differ in any group. In patients with an acute increase in blood pressure, naloxone significantly (P < .01) reduced blood pressure, heart rate, opioids, catecholamines, and atrial natriuretic factor 10 minutes after administration. Naloxone effects on blood pressure, heart rate, opioids, and catecholamines wore off within 20 minutes. In control groups, naloxone failed to modify any of the considered parameters. Our findings suggest that pressor effects of opioid peptides mediated by the autonomic nervous system during stress-induced acute episodes of blood pressure increase in hypertensive patients.

Topics: Atrial Natriuretic Factor; beta-Endorphin; Blood Pressure; Dynorphins; Endorphins; Endothelin-1; Enkephalin, Methionine; Female; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Opioid Peptides; Stress, Physiological; Stress, Psychological

Brief (7-14 days) social deprivation stress has been found to increase blood pressure in Wistar rats, an effect dependent on activation of opioid function. The role of central opioids in this and other responses to stress has been repeatedly determined, but the possible involvement of modifications of peripheral opioid mechanisms is poorly understood. To further increase this knowledge, we have examined the opioid sensitivity of tail arteries taken from social deprived Wistar rats by studying the effect of beta-endorphin and DADLE "in vitro". Both opioids inhibited the electrically-induced constriction of the preparations in a dose-dependent manner, but these actions were significantly attenuated after 7-14 days of social deprivation. When the rats were isolated for 30-35 days, the hypertensive response was still present but the arteries from group-housed and isolated animals no longer showed differential sensitivity to opioids. This difference with respect to 7-14 days of isolation could be related to age-dependent changes of opioid function, which were observed among group-housed animals. The results suggest that social deprivation stress induces an adaptation of the tail arteries to the opioid effects on contractility. It is suggested that this endogenous adaptation could be contributing to the hypertensive response observed after social deprivation.

Topics: Adaptation, Physiological; Animals; beta-Endorphin; Dose-Response Relationship, Drug; Enkephalin, Leucine-2-Alanine; Hypertension; Male; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Wistar; Receptors, Opioid; Social Isolation; Stress, Physiological; Tail; Vasoconstriction

The influence of naloxone-induced general opiate receptor blockade on hypothalamic blood flow autoregulation was investigated in anaesthetized, artificially ventilated, temperature controlled cats. In order to study the changes of the hypothalamic blood flow (H2-gas clearance technique) at the lower limit of autoregulation systemic arterial pressure was reduced in a stepwise manner to 100, 80, 60 and 40 mmHg, by haemorrhage. Autoregulatory mechanisms of the hypothalamic vessels remained effective and hypothalamic blood flow showed no significant reduction until the arterial pressure was reduced to 60 mmHg in the vehicle-treated control cats. General opiate receptor blockade by 1 mg kg-1 mL-1 i.v. injected naloxone resulted in a significant reduction of the autoregulatory capacity of the hypothalamic vessels: the blood flow followed passively the arterial pressure fall already from 100 mmHg mean arterial pressure. The effect of opiate receptor blockade on the upper limit of the autoregulation was studied during acute arterial hypertension, induced by angiotensin-II infusion (25 micrograms 0.1 mL-1 min-1 i.v.). Hypothalamic blood flow remained remarkably steady following angiotensin-II infusion in the saline-treated control animals. Naloxone pretreatment (1 mg kg-1 mL-1 i.v.), however, induced a significant downward shift of the upper limit of the autoregulation, and hypothalamic blood flow started to increase in the 125-145 mmHg arterial pressure range. The narrowing of the autoregulatory range following general opiate receptor blockade suggests an important role of endogenous opioid peptides in hypothalamic blood flow autoregulatory mechanisms both in hypotensive and in hypertensive conditions.

Topics: Angiotensin II; Animals; Carbon Dioxide; Cats; Central Venous Pressure; Cerebrovascular Circulation; Female; Hemorrhage; Homeostasis; Hypertension; Hypotension; Hypothalamus; Male; Naloxone; Narcotic Antagonists; Receptors, Opioid

1. The central cardiovascular effects of several opioid receptor selective agonists and the nonselective opioid antagonist, naloxone, were studied in anesthetized normotensive control rats, in spontaneously hypertensive rats (SHR), and in foot-shock-stressed rats. 2. Receptor-selective agonists injected into the rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), and dorsal hippocampus (dHip) were DAGO (mu), DADLE (delta), and U50,488H (kappa). 3. DAGO and DADLE (3 nM) decreased arterial pressure and heart rate in RVLM and PVN of all rat strains, while U-50,488H (9 nM) had only minimal effects in these areas. 4. In dHip, only DADLE (3 nM) had depressor and bradycardic effects, and then, only in SHR, with DAGO and U50,488H being ineffective in any strain, even at 9 nM. 5. Prior injection of naloxone (10 nM) into the RVLM, PVN and dHip blocked and postinjection reversed the cardiovascular effects of the agonists. Naloxone alone increased blood pressure and heart rate in all three areas, in all rat strains except SHR, suggesting a tonic depressor effect of endogenous opioids. 6. Lack of significant quantitative differences in opioid agonist and antagonist effects between normotensive and hypertensive or stressed rats argues against a role for endogenous brain opioids in experimental hypertension.

Topics: Animals; Blood Pressure; Heart Rate; Hippocampus; Hypertension; Medulla Oblongata; Microinjections; Naloxone; Narcotic Antagonists; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stress, Psychological

Carfentanil citrate, the only opioid approved in the United States for immobilizing large exotic animals, increasingly has been used to chemically restrain exotic horses, such as Prezwalski's horses (Equus przewalskii) and wild horses (E caballus). Because carfentanil's duration of action is long and renarcotization may develop 2 to 24 hours after administration of antagonists, a study was designed to compare the physiologic effects of opioid antagonists, using domestic horses chemically restrained with xylazine hydrochloride and carfentanil. The study was terminated after the initial 3 horses developed severe tachycardia and hypertension, which resulted in the death of 1 horse from pulmonary edema. Although it was possible that the clinical findings in these horses may have resulted from use of an inadequate dosage of carfentanil or xylazine, or both, analysis of the results more likely indicated that domestic and exotic horses may respond differently to carfentanil, and domestic horses may not be a good model for use in studies of carfentanil.

Topics: Analgesics, Opioid; Animals; Animals, Domestic; Fentanyl; Horse Diseases; Horses; Hypertension; Immobilization; Naloxone; Naltrexone; Pulmonary Edema; Tachycardia; Xylazine

In order to investigate the changes of endogenous opiate systems in hypertension and their possible role in the pathogenesis in hypertension, we measured plasma concentrations of beta-endorphin, leucine-enkephalin, neurotension, arginine vasopressin, plasma renin activity and angiotensin II by radioimmunoassay in 60 normal persons and 120 patients with essential hypertension. The results showed that the patient group had lower levels of beta-endorphin and leucine enkephalin (P < 0.001), higher levels of arginine vasopressin, plasma renin activity and angiotensin II (P < 0.01, P < 0.05 and P < 0.05, respectively), and normal level of neurotensin, as compared with those in normal group. Plasma levels of leucine-enkephalin was correlated negatively to the mean artery pressure (r = -0.196, P < 0.05). Plasma level of arginine vasopressin was correlated to the duration of the hypertension (r = 0.216, P < 0.05). After 150 min and 14 days of treatment with clonidine, plasma levels of beta-endorphin, leucine-enkephalin increased significantly (< 0.01) and correlated negatively with the decrease of the mean artery pressure (r = -0.340 and r = -0.436 at 150 min, r = -0.369 and r = -0.441 on the 14th day, respectively, P < 0.01). Plasma renin activity and angiotensin II decreased significantly (P < 0.05 and P < 0.01). Arginine vasopressin and neurotensin did not change significantly. After intravenous administration of opiate antagonist-naloxone, the blood pressure and heart rate increased significantly (P < 0.01). The results suggested that the changes of endogenous opioids may be involved in the pathogenesis of hypertension and in the antihypertensive action of clonidine.

Topics: Angiotensin II; Antihypertensive Agents; Arginine Vasopressin; beta-Endorphin; Blood Pressure; Clonidine; Enkephalin, Leucine; Female; Heart Rate; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged; Naloxone; Narcotic Antagonists; Neurotensin; Renin; Time Factors

Background and noxious heat-evoked responses of wide-dynamic-range (WDR) and high-threshold (HT) lumbosacral spinal dorsal horn neurons were recorded in spontaneously hypertensive rats (SHRs), Wistar-Kyoto normotensive rats (WKYs), lifetime captopril-treated SHRs, SHRs with bilateral cervical vagotomy, SHRs with bilateral sino-aortic deafferentation (SAD), and SHRs with either a single or repeated administration of naloxone methobromide (NMB). Stimulus-response functions (SRFs) were generated for neurons using 15 sec of heating of the foot at temperatures ranging from 38 to 52 degrees C. Comparisons were made of neuronal response thresholds, slopes of the SRFs, mean discharge frequency during heat stimulation, arterial blood pressure (ABP), and heart rate (HR). The primary finding was that group mean SRFs for both WDR and HT neurons were shifted in a parallel, rightward fashion in SHRs compared to WKYs. Heat-evoked response thresholds were increased and asymptotic discharge frequencies were decreased in WDR and HT neurons of SHRs compared to WKYs. Analyses of group mean SRFs for WDR and HT neurons of SHRs receiving lifetime captopril treatment indicated they were normalized to the SRFs of WKYs, but detailed comparisons using discharge frequency during heat stimulation revealed that this was due to a statistical averaging effect. Specifically, lifetime captopril-treated SHRs not only showed enhanced neuronal responses to the onset of noxious heat but also enhanced adaptation of neuronal responses with continued heating compared to WKYs. Bilateral SAD in SHRs significantly increased the total discharge frequency of WDR neurons to heat stimuli between 44 and 52 degrees C, but produced no change in the response threshold for heat-evoked activation of these neurons. A similar effect of SAD was observed in HT neurons of SHRs, but the greater response thresholds of HT neurons precluded detection of any significant effect. Bilateral cervical vagotomy did not affect response thresholds, slopes, or total discharge frequencies of SHRs, although only WDR neurons were studied. SRFs of WDR and HT neurons in SHRs obtained pre- and post-administration of a single dose of NMB did not differ. However, repeated administration of NMB in SHRs resulted in a parallel, leftward shift in SRFs of both WDR and HT neurons. In all strains and treatments studied, there were no significant differences in background activities of these neurons that might contribute to the observed outco

Topics: Animals; Captopril; Female; Hemodynamics; Hot Temperature; Hypertension; Male; Microelectrodes; Muscle Denervation; Naloxone; Nociceptors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spinal Cord; Stereotaxic Techniques; Synaptic Transmission; Vagotomy

In order to study the role of opioid receptors in two models of experimental hypertension the binding of 3H-naloxone to membranes prepared from discrete brain regions and spinal cord was determined. Renal hypertensive rats (RHR) were found to have a greater density of 3H-naloxone binding sites in the hippocampus and hypothalamus when compared to spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NR). The apparent dissociation constant (Kd) for 3H-naloxone binding did not differ between groups.

Topics: Analysis of Variance; Animals; Brain; Hypertension; Hypertension, Renal; Male; Naloxone; Rats; Rats, Inbred SHR; Reference Values; Tissue Distribution; Tritium

It has been previously shown that endogenous opioid peptides suppress human ACTH and gonadotropins secretion via hypothalamic mechanism. Since the angiotensin converting enzyme can participate in the metabolism of opioid peptides, this study examined the action of Captopril, an angiotensin converting enzyme inhibitor, on corticotropin and gonadotropin (LH and FSH) release induced by the opiate antagonist naloxone in man. Seven male hypertensive volunteers (aged 30-52) were treated with A) saline; B) naloxone 8 mg iv as a bolus followed by an iv infusion of 4 mg/h; C) naloxone as above after pretreatment with captopril 150 mg/day for 15 days; D) captopril alone. Naloxone significantly stimulated ACTH and LH secretion when compared with the saline infusion. This stimulating effect was taken as an indirect evidence for a tonic opioid inhibition on pituitary hormones release. The pre-medication with captopril significantly enhanced the ACTH and LH response to the opiate antagonist naloxone, but captopril alone did not modify ACTH and LH values when compared to saline. The results would suggest that captopril interferes with the opioid regulation of human ACTH and LH secretion probably by blocking the proteolytic degradation of opioid peptides.

Topics: Adrenocorticotropic Hormone; Adult; Captopril; Follicle Stimulating Hormone; Humans; Hydrocortisone; Hypertension; Luteinizing Hormone; Male; Middle Aged; Naloxone; Peptidyl-Dipeptidase A

As preliminary evidence for the implication of opioids in the increase in blood pressure due to the stress of brief social deprivation, hypertension has been shown to be antagonized by acute administration of opiate receptor blockers. As a further evidence of involvement of opioids in the hypertensive response to this type of stress, cross-tolerance ought to be capable of being demonstrated in isolated animals, treated with an opiate. When rats were treated subchronically with morphine in the drinking water throughout the isolation period (1-15 days), readings of blood pressure did not show any variation, as compared to group-housed control rats. However, 7 days after withdrawal of morphine readings of arterial pressure in the isolated rats increased above the levels of the group-housed control animals. These findings support the idea that an endogenous opioid system is implicated in the induction of readings of high blood pressure due to the stress of social deprivation.

Topics: Animals; Blood Pressure; Body Weight; Drug Tolerance; Hypertension; Male; Morphine; Naloxone; Rats; Rats, Wistar; Self Administration; Social Isolation; Stress, Psychological; Substance Withdrawal Syndrome

Experimental and clinical studies seem to prove that both endogenous opioids and atrial natriuretic peptide (ANP) are involved in blood pressure regulation. This raised the question, whether these two factors are functionally interrelated to each other. We tried to answer this question by assessing plasma ANP levels in 15 patients with II degrees essential hypertension and in 15 healthy subjects under water immersion (WI) conditions. In all subjects two WI tests were performed--one without pretreatment with naloxone, and a second one after blockade of opioid receptors by this opioid receptor antagonist. Parallel to ANP, plasma renin activity (PRA), aldosterone (ALD) and vasopressin (AVP) were assessed. In hypertensive patients significantly higher basal plasma ANP levels were found than in control subjects. WI induced a significant increase of plasma ANP in both examined groups which became markedly reduced after blockade of opioid receptors by naloxone. Naloxone did not influence the WI induced decrease of PRA, ALD and AVP respectively. From results presented in this study we conclude, that a.) opioid receptors seem to influence regulation of ANP secretion both in healthy normotensive subjects and patients with essential hypertension, and b.) that WI induced alterations of ANP on the one side and of PRA, ALD and AVP on the other side are not interrelated.

Topics: Adult; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Immersion; Male; Naloxone; Receptors, Opioid; Renin; Renin-Angiotensin System

Effects of intracerebroventricular (third ventricle) injection of N-methyl-D-aspartate (NMDA) on arterial blood pressure, on heart rate, on arginine vasopressin (AVP) and levels of catecholamines in plasma and on the behaviour of normotensive freely-moving rats have been evaluated. N-Methyl-D-aspartate significantly (P less than 0.01) increased arterial blood pressure and levels of catecholamines and AVP in plasma. With 0.1-1.0 micrograms/rat all animals presented psychomotor agitation, stereotyped movements, hyperexcitability, exophthalmus, dyspnoea, jumping, rearing and teething. The selective antagonist for NMDA receptors, 2-APV injected in the third ventricle, significantly (P less than 0.01) antagonized the hypertension, the increase in levels of catecholamines and AVP in plasma and behavioural effects. An antagonist of alpha 1 adrenergic receptors, prazosin (i.v.), an agonist of alpha 2 adrenergic receptors, clonidine (i.c.v.) and a relatively selective antagonist of V1 subtype of receptor of AVP, CGP 25838 (i.c.v. and i.v.), 15 min before NMDA, significantly (P less than 0.01) decreased the effects induced by the injections of NMDA. On the contrary, an antagonist of opiate receptors, naloxone (i.v.), 15 min before NMDA, significantly (P less than 0.01) increased the NMDA-induced modifications. Pretreatment with the antagonists at these doses, did not significantly modify the basal values of arterial blood pressure and behaviour. Only 2-APV sometimes induced ataxia, lasting about 5 min. This study points out an increase in the central sympathetic efferent activity and in release of AVP involved in the NMDA-induced cardiovascular and behavioural effects.

Topics: 2-Amino-5-phosphonovalerate; Animals; Arginine Vasopressin; Blood Pressure; Cerebral Ventricles; Clonidine; Dose-Response Relationship, Drug; Epinephrine; Heart Rate; Hypertension; Injections, Intravenous; Injections, Intraventricular; Male; N-Methylaspartate; Naloxone; Norepinephrine; Prazosin; Rats; Rats, Inbred Strains

Experiments were conducted to test the hypothesis that chronic administration of an opioid receptor antagonist, naloxone, would affect the outcome of the developmental phase of hypertension in Dahl salt-sensitive (S/JR strain) rats. Accordingly, S/JR rats were maintained on either a low-salt (0.45% NaCl) or a high-salt (7% NaCl) diet for 4 wk. Half of the animals of each dietary group were treated with naloxone (100-130 micrograms/h) by osmotic minipump. Food and water intakes of the high-salt animals were measured for the first 25 days, and blood pressure was measured at the end of the 4 wk via an indwelling femoral arterial catheter. Naloxone treatment slightly but significantly reduced the level of hypertension attained in the high-salt animals (158 +/- 2 mmHg in naloxone-treated animals vs. 168 +/- 3 mmHg in control animals; P less than 0.05) and also attenuated food (and hence salt) and water intakes. Naloxone did not affect the blood pressure of the low-salt animals. To determine whether the slight attenuation of hypertension might be secondary to a reduction of salt intake, a group of control S/JR animals were fed a moderately high-salt diet (2% NaCl), and naloxone-treated S/JR animals were salt-intake matched to this group by daily adjustment of the dietary salt content. Blood pressures after 4 wk of treatment were not different between these two groups. Finally, acute administration of 1 and 30 mg/kg of naloxone failed to lower blood pressure of animals with established hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Body Weight; Diet; Drinking; Eating; Hypertension; Male; Morphine; Naloxone; Rats; Rats, Mutant Strains; Sodium Chloride

Stress is an important risk factor in cardiovascular diseases, including hypertension. Endogenous opioids are known to be elevated in stress and in various models of hypertension with differing etiologies. Blockade of endogenous opioids with naloxone has been demonstrated to attenuate or reverse the elevation in blood pressure in both renovascular and spontaneous hypertension. In the current study, increased blood pressure was induced using a model of psychosocial stress. During the first week of stress, systolic blood pressure rose rapidly to reach a level that was sustained throughout the remaining period of stress. Chronic infusion of the opiate antagonist, naloxone, both prevented and completely reversed the elevated blood pressure due to psychosocial stress. These data demonstrate that elevated endogenous opioids are important factors in cardiovascular regulation and are likely to influence both the development and maintenance of stress-induced hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endorphins; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains; Stress, Psychological

The effect of adrenalectomy on the hypotensive response induced by social deprivation was studied in a line of Wistar-derived rats. Prior removal of the adrenal gland by surgery was found to prevent the elevation in systolic or diastolic blood pressure observed in sham-operated isolated rats. The social deprivation-induced hypertensive response ran parallel with an increase in the levels of plasma corticosterone. Supplementation therapy with this glucocorticoid in previously adrenalectomized animals restored the levels of plasma corticosterone to normal and made the rats able to respond to social deprivation with an elevation in arterial pressure. Thus, corticosterone plays a "permissive" role in the elevation of blood pressure due to isolation. Apparently, this effect is dependent upon genetic, maturational and environmental factors since it is only evident in some lines of Wistar rats.

Topics: Adrenalectomy; Animals; Blood Pressure; Corticosterone; Hypertension; Male; Naloxone; Psychosocial Deprivation; Rats; Rats, Inbred Strains; Stress, Physiological

The effects of naloxone on the development of hypertension were studied in unilaterally nephrectomized rats implanted with deoxycorticosterone acetate (DOCA; 200 mg/kg) and given saline to drink. Intraperitoneal (i.p.) infusion of naloxone at 150 micrograms/hr significantly lowered systolic blood pressure (SBP) compared to rats not receiving naloxone, (135 +/- 4.4 vs 158 +/- 5.9 mmHg on day 16). IP infusion of naloxone at 300 micrograms/hr produced the same reductions of SBP as that at 150 micrograms/hr in DOCA-salt treated rats. In other experiments intracerebroventricular (i.c.v.) infusion of naloxone at 7 micrograms/hr also significantly attenuated the DOCA-salt hypertension. The same dose given i.p. had no effect on the development of hypertension. Naloxone had no effect on plasma renin activity (PRA), plasma atrial natriuretic peptide (ANP), or concentrations of Na+ and K+ in plasma. The present data demonstrate that naloxone significantly attenuates the development of hypertension in rats given DOCA and fed a high salt diet. The attenuation of blood pressure could not be associated with the changes in PRA or plasma ANP. These results imply that the central opiate receptors play an important role in the pathogenesis of this model of hypertension.

Topics: Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Heart Rate; Hypertension; Naloxone; Rats; Rats, Inbred Strains; Sodium Chloride

We studied the roles of the sympathoadrenal system and endogenous opiate in the antihypertensive effects of supplementation of dietary taurine, a sulfur amino acid, in deoxycorticosterone acetate (DOCA)-salt rats. Supplementation of 1% taurine in drinking water for 2 weeks was found to prevent the increase in systolic blood pressure of DOCA-salt rats (116 +/- 2 vs 138 +/- 2 mmHg, p less than 0.01), but failed to effect the systolic blood pressure of vehicle-treated control rats (115 +/- 2 vs 112 +/- 3 mmHg), taurine supplementation restored to normal increased plasma norepinephrine (326 +/- 32 vs 531 +/- 67 pg/ml, p less than 0.01) and epinephrine (204 +/- 19 vs 304 +/- 43 pg/ml, p less than 0.05) concentrations in DOCA-salt rats, but had no effect on norepinephrine (346 +/- 23 vs 338 +/- 33 pg/ml) or epinephrine (198 +/- 17 vs 224 +/- 26 pg/ml) concentrations in control rats. Accordingly, the increased epinephrine content in the adrenals of DOCA-salt rats was normalized with the supplementation of taurine, associated with a markedly increased adrenal taurine content. In conscious rats, moreover, intraperitoneal injection of naloxone (2 mg/kg), a specific opiate antagonist, increased systolic blood pressure only in taurine-supplemented DOCA-salt rats. Evidence presented suggests, therefore, that both the suppression of the increased sympathoadrenal activity and the activation of endogenous opiate might contribute to the antihypertensive effect of taurine in DOCA-salt rats.

Topics: Adrenal Glands; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Heart Rate; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains; Sodium Chloride; Sympathetic Nervous System; Taurine

We have previously shown that prolonged low-frequency muscle stimulation, inducing contractions of the gastrocnemius muscle, in conscious spontaneously hypertensive rats leads to an opioid-mediated post-stimulatory reduction in blood pressure and analgesia. In the present study we investigated whether muscle stimulation would also induce a post-stimulatory reduction in behavioural activity in the spontaneously hypertensive rats. Selective opioid receptor antagonists were used to analyse the involvement of endogenous opioids. Muscle stimulation, lasting 60 min, induced a post-stimulatory sedation that outlasted the stimulation for hours. Sniffing, locomotor activity and total behavioural activity were significantly reduced. The post-stimulatory reduction in activity was reversed back to control levels by a high dose of naloxone (15 mg kg-1 i.v.). The selective mu-receptor antagonist beta-funaltrexamine, given intracerebroventricularly before stimulation, did not influence the development of the post-stimulatory drop in activity. The delta-receptor antagonist ICI 154,129 had no effect at all on the already developed sedation, whereas MR 2266 BS, a kappa-receptor antagonist (3 mg kg-1 i.v.), completely reversed the drop in activity. These results show that muscle stimulation gives rise to an opioid-mediated post-stimulatory reduction in activity in spontaneously hypertensive rats. The results also indicate the involvement of the opioid kappa-receptor in the behavioural response.

Topics: Animals; Benzomorphans; Electric Stimulation; Hypertension; Male; Motor Activity; Muscles; Naloxone; Naltrexone; Rats; Rats, Inbred SHR; Receptors, Opioid

Naloxone enantiomorphs were given intracerebroventricularly (i.c.v.) to rats socially deprived for a brief period of time (7-14 days) in order to ascertain the mediation of central opiate receptors in the reversal effect of opiate antagonists on the high systolic blood pressure induced by this type of stress. While the active enantiomorph ((-)-naloxone, 20 nmol per rat) lowered the elevated blood pressure, the (+)-enantiomorph (which shows a 10,000-fold lower affinity for opiate receptors) had no effect. Additionally, the antihypertensive effect induced by i.c.v. administration of an antagonist of the mu-opiate receptor (beta-funaltrexamine, 20 nmol per rat), but not of the delta-opiate receptor (ICI 174,864, 15 nmol per rat) pointed to the involvement of mu-opiate receptors as the endogenous component of the hypertensive response of rats to stress.

Topics: Animals; Blood Pressure; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Social Isolation; Stereoisomerism; Stress, Psychological

We have studied the effect of acute hypertensive episodes on the renal sympathetic baroreceptor reflex in conscious rabbits and the role played by cardiac afferents and endogenous opiate mechanisms. Renal sympathetic nerve activity was recorded during brief perivascular balloon-induced ramp changes in mean arterial pressure before and during 40-minute elevations in resting pressure. Methoxamine infusion was adjusted to increase pressure by +30 and +45 mm Hg in the presence of autonomic blockade of the heart with atenolol and methscopolamine. Experiments were repeated in other rabbits after blocking cardiac afferents with 5% intrapericardial procaine or during intravenous naloxone (4-6 mg/kg, then 0.12 mg/kg/min). We found a progressively severe attenuation of the renal sympathetic baroreceptor reflex during increasing elevations in resting pressure. The upper plateau and range of the reflex curve were both reduced by one third and two thirds during moderate and severe hypertension, respectively. The average gain fell by 64% and 87%, and the range-independent gain and hypotensive reversal response were also reduced. There was no resetting of the reflex to higher pressures as would be expected. One third of the reflex inhibition was prevented by blocking cardiac afferents; none of it was affected by intravenous naloxone, which had previously been shown to reverse the renal baroreceptor reflex depression elicited by hemorrhagic hypotension. Factors possibly responsible for the remaining two thirds of the hypertension-induced sympathoinhibition are suggested to be either central depression of sympathetic tone after elevation of arterial baroreceptor discharge during the hypertensive episode or additional inhibitory afferent input arising from the pulmonary circulation.

Topics: Acute Disease; Animals; Heart; Hypertension; Kidney; Naloxone; Pressoreceptors; Rabbits; Reflex; Sympathetic Nervous System; Vasoconstriction

The present study was carried out to investigate the effects of enkephalins (methionine-enkephalin: Met-Enk, leucine-enkephalin: Leu-Enk) on the adrenergic neurotransmission in hypertension. Perfused mesenteric vasculatures were prepared in spontaneously hypertensive rats (SHR, Okamoto and Aoki strain, 7-10 weeks old) and age-matched Wistar Kyoto rats (WKY), and the effects of these peptides on vascular responsiveness as well as norepinephrine release from the sympathetic nerve endings were examined. Pressor responses to electrical nerve stimulation were inhibited in a dose-dependent manner by Met-Enk and Leu-Enk, and the inhibition was antagonized by naloxone. Norepinephrine release during electrical nerve stimulation was also suppressed by these peptides. In SHR, stimulation-evoked pressor responses and norepinephrine release were significantly enhanced compared to those in WKY, while the suppressive magnitudes of the responses by Met-Enk and Leu-Enk were smaller in SHR than in WKY. These results demonstrate that Met-Enk and Leu-Enk affected presynaptic sites of blood vessels and caused a decrease in electrically-stimulated norepinephrine release from the sympathetic nerve endings. The lower reduction in norepinephrine release and vascular responsiveness by Met-Enk and Leu-Enk in SHR suggests an insufficient regulation of the vascular adrenergic neurotransmission by the opioid peptides in this model of hypertension.

Topics: Animals; Blood Pressure; Electric Stimulation; Enkephalin, Leucine; Enkephalin, Methionine; Hypertension; Male; Mesenteric Arteries; Naloxone; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Sympathetic Nervous System; Synaptic Transmission

Endogenous opioid regulation of blood pressure is altered during stress in young adults at risk for hypertension. We studied the effects of the opioid antagonist naloxone on the secretion of corticotropin and beta-endorphin during psychological stress in young adults with mildly elevated casual arterial pressures. Naloxone-induced secretion of both corticotropin and beta-endorphin was significantly diminished in persons at enhanced risk for hypertension compared with the low blood pressure control group. Results suggest that opioidergic inhibition of anterior pituitary function is altered in hypertension development.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; beta-Endorphin; Blood Pressure; Epinephrine; Humans; Hydrocortisone; Hypertension; Male; Naloxone; Stress, Psychological

1. In conscious rabbits intracerebroventricular (i.c.v.) morphine (10 and 50 micrograms kg-1) caused a dose-related increase in plasma noradrenaline and adrenaline, respiratory depression and sedation. The increase in sympatho-adrenal outflow resulted in hypertension accompanied by bradycardia and the increase in adrenaline secretion caused hyperglycaemia. Morphine (1 microgram kg-1 i.c.v.) and i.c.v. saline had no effect. 2. The same doses of morphine given intracisternally (i.c.) caused bradycardia and a similar degree of respiratory depression to i.c.v. morphine, but no significant increase in blood pressure and only a small, gradual rise in plasma adrenaline. 3. Intravenous naloxone (1 mg kg-1) did not block the hypertension, hyperglycaemia or increase in plasma catecholamines that followed i.c.v. morphine, but prevented the respiratory depression and sedation. 4. Ganglionic blockade with pentolinium prevented the rise in plasma catecholamines, blood pressure and plasma glucose induced by i.c.v. morphine. 5. These findings demonstrate that the increased sympathoadrenal outflow following i.c.v. morphine results from an action on periventricular structures. The resultant increase in plasma catecholamines, which is largely naloxone resistant, accounts for the hypertension and hyperglycaemia. The bradycardia is probably partly baroflex mediated and partly due to an increase in vagal tone as a result of stimulation of brainstem opioid receptors. The respiratory depression is probably due to an action of morphine on brainstem opioid receptors.

Topics: Animals; Behavior, Animal; Blood Glucose; Blood Pressure; Catecholamines; Cisterna Magna; Ganglionic Blockers; Heart Rate; Hypertension; Injections; Injections, Intraventricular; Male; Morphine; Naloxone; Oxygen Consumption; Rabbits; Receptors, Opioid

1. In conscious rabbits, intravenous morphine caused hypertension, bradycardia, hyperglycaemia and increased plasma adrenaline and noradrenaline. These effects were prevented by ganglionic blockade with pentolinium. 2. The cardiovascular responses to morphine were not altered by pretreatment with a vasopressin V1-receptor antagonist. 3. After bilateral adrenalectomy morphine caused a similar rise in noradrenaline but no increase in adrenaline. The rise in blood pressure was attenuated and the hyperglycaemia was abolished. 4. Adrenaline infused intravenously to mimic the levels that occurred after morphine caused a similar degree of hyperglycaemia but only a small increase in blood pressure. 5. Pretreatment with intracerebroventricular naloxone prevented the morphine-induced hypertension, hyperglycaemia, increase in plasma catecholamines, respiratory depression and sedation. 6. These results demonstrate that, in conscious rabbits, intravenous morphine causes hypertension by increasing sympathetic vasoconstrictor nerve activity and elevating plasma adrenaline levels; the latter alone produces the hyperglycaemia. Vasopressin release is not involved in the hypertensive response to morphine. The effects of morphine appear to result from stimulation of central opiate receptors leading to enhanced sympathoadrenal outflow.

Topics: Adrenalectomy; Animals; Arginine Vasopressin; Blood Pressure; Epinephrine; Heart Rate; Hypertension; Infusions, Intravenous; Injections, Intraventricular; Male; Morphine; Naloxone; Norepinephrine; Pentolinium Tartrate; Rabbits; Sympathetic Nervous System

Endogenous opioid peptides have been implicated in the regulation of cardiovascular and renal function. We tested this hypothesis by examining whether the opioid antagonist naloxone alters the cardiovascular or renal responses produced by environmental stress (air stress) in conscious spontaneously hypertensive rats (SHR). Before naloxone administration, air stress produced significant increases in heart rate, mean arterial pressure, and renal sympathetic nerve activity, and it caused a decrease in urinary sodium excretion. After intravenous and intracerebroventricular administration of naloxone, the air stress-induced pressor and antinatriuretic responses were inhibited. Subsequent studies with a different opioid antagonist, the quaternary compound naltrexone methylbromide, also showed inhibition of the air stress-induced pressor and antinatriuretic responses and demonstrated opioid receptor specificity of this inhibition. Furthermore, since only intracerebroventricular and not intravenous administration of naltrexone methylbromide inhibited the pressor and antinatriuretic responses to air stress, a central nervous system site of action was established. The opioid antagonists caused inhibition of the pressor and antinatriuretic responses to air stress without affecting the air stress-induced increase in renal sympathetic nerve activity. Our investigations indicate that central endogenous opioid peptides contribute to the pressor and antinatriuretic responses that occur in conscious SHR during acute environmental stress.

Topics: Animals; Blood Pressure; Consciousness; Endorphins; Hemodynamics; Hypertension; Kidney; Male; Naloxone; Naltrexone; Narcotic Antagonists; Natriuresis; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Stress, Physiological

The effect of adenosine triphosphate (ATP) on the expression of opiate withdrawal was examined using a chronic model of morphine-dependence. ATP was studied for its ability to modify or block jumping in morphine-abstinent mice. In mice administered 2 mg/kg ATP intravenously, the naloxone ED50 for withdrawal jumping increased by 11-fold in comparison to saline-treated mice. Nalaxone-precipitated morphine-withdrawal in the rats, has been shown to induce a specific pattern of intestinal hypermyoelectric activity and to increase the arterial blood pressure. Administration of ATP at dose of 1 and 2 mg/kg intravenously inhibited the induction of hypermyoelectric activity pattern in 80 and 100% of animals tested respectively. ATP also blocked the increase in mean arterial blood pressure seen during withdrawal in a dose-dependent fashion. Investigations were carried out to determine if blocking of the alpha 2-adrenoreceptors with yohimbine would result in an alteration in antiwithdrawal action of ATP. Yohimbine reversed the effect of ATP in blocking naloxone-precipitated withdrawal on the myoelectric activity of jejunum and colon, however, it failed to antagonize the effect of ATP on withdrawal jumping and to block the effect of ATP on the pressor response produced by naloxone in morphine-dependent animals.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Electric Conductivity; Hypertension; Intestines; Mice; Motor Activity; Naloxone; Narcotics; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Experimental evidence that supports or rejects an involvement of opioid receptors in the cardiovascular effects of clonidine was sought. In anesthetized rabbits, clonidine decreased blood pressure and heart rate. These effects were related to the clonidine dose. High doses of clonidine produced a biphasic response in blood pressure without resulting in a significant baroreflex. However, it was not difficult to produce hypotensive action of clonidine without the biphasic action using low doses of clonidine. A pretreatment of the animals with naloxone (1 mg/1 kg) prevented the hypotensive action of clonidine at low dose. This antagonistic action of naloxone against clonidine was also evident in other cardiac parameters such as heart rate and efferent sympathetic renal nerve activity. The antagonistic action was not demonstrably significant with the high doses of clonidine. The present study in normotensive anesthetized rabbits suggests that specific central interactions between opioid and adrenergic receptors can be demonstrated under defined conditions, although such interactions were reported in pathophysiologic conditions such as essential hypertension.

Topics: Animals; Blood Pressure; Bradycardia; Clonidine; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Naloxone; Receptors, Opioid; Time Factors

We studied the role of endogenous opiate activation in the hypotensive action of taurine, a sulphur amino acid, in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Previous work had shown that supplementation with 1% taurine reduced blood pressure when given after DOCA-salt hypertension had been established. In the present study, in conscious rats, intraperitoneal injection of naloxone, an opiate antagonist, increased blood pressure in taurine-supplemented DOCA-salt rats, but not in DOCA-salt rats or vehicle-treated control rats. These results suggest that activation of an endogenous opiate might contribute to the hypotensive action of taurine in DOCA-salt hypertensive rats.

Topics: Animals; Desoxycorticosterone; Endorphins; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains; Taurine

Topics: Clonidine; Humans; Hypertension; Naloxone

The purpose of this study was to evaluate the effect of clonidine--an alpha 2-adrenergic agonist--and naloxone--an opiate antagonist--on pituitary hormone release. The study involved 43 women: 20 menopausal women, 9 untreated women with ACTH-dependent Cushing's disease, and 14 healthy women. Serum GH, ACTH, LH, FSH, TSH, cortisol, and plasma beta-endorphin concentrations were measured with RIA methods. A significant increase in GH and a significant decrease in ACTH and in cortisol was observed after clonidine injection in healthy women. Clonidine caused a significant decrease in LH concentration in the luteal phase of the menstrual cycle. However, naloxone induced the opposite effect on pituitary hormone release. In Cushing's disease, ACTH significantly decreased in response to clonidine. In postmenopausal women with hypertension a decrease in blood pressure, a marked decrease in the number of hot flashes, as well as a diminution in amplitude and frequency of LH pulsatility was found. Conclusions are as follows: (1) Clonidine may be useful in the treatment of hypertensive menopausal women; and (2) a diminution in ACTH, beta-endorphin, and cortisol release in response to clonidine was observed in Cushing's disease.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; Clonidine; Cushing Syndrome; Female; Growth Hormone; Humans; Hydrocortisone; Hypertension; Luteinizing Hormone; Menopause; Middle Aged; Naloxone; Pituitary Gland, Anterior; Pituitary Hormones, Anterior

Effects of opiate receptor antagonists on centrally mediated cardiovascular responses to clonidine and beta-endorphin were studied in urethane-anesthetized spontaneously hypertensive Okamoto-Aoki rats (SHR), normotensive Sprague-Dawley rats, and Sprague-Dawley rats made hypertensive with deoxycorticosterone pivalate/salt. Microinjection of 270 pmol of naloxone into the nucleus tractus solitarii (NTS) significantly inhibited the hypotensive and bradycardic response to 5 nmol of similarly administered clonidine in both SHR and normotensive Sprague-Dawley rats. In SHR, a similar inhibition was observed after the delta-opiate receptor antagonist ICI 174864, but not after the mu-receptor antagonist beta-funaltrexamine (both at 270 pmol, intra-NTS), whereas in normotensive Sprague-Dawley rats, beta-funaltrexamine, but not ICI 174864, was an effective inhibitor. The same pattern of differential inhibition was seen when clonidine was given i.v. and the opiate antagonists were given intracisternally in SHR and Sprague-Dawley rats. Intra-NTS microinjection of 280 fmol of beta-endorphin caused hypotension and bradycardia, and these effects were similarly inhibited by ICI 174864 in SHR and by beta-funaltrexamine in Sprague-Dawley rats. In Sprague-Dawley rats made hypertensive by chronic administration of deoxycorticosterone pivalate and salt, the hypotensive and bradycardic effects of intra-NTS clonidine were inhibited by ICI 174864, but not by beta-funaltrexamine, a pattern similar to that in SHR, but different from that in normotensive Sprague-Dawley rats. These results support the hypothesis that beta-endorphin release and subsequent stimulation of opiate receptors in the NTS are involved in the cardiovascular effects of clonidine in rats. These results further suggest, however, that hypertension regulates the subtype of opiate receptors mediating these effects.

Topics: Animals; Blood Pressure; Clonidine; Endorphins; Enkephalin, Leucine; Heart Rate; Hypertension; Male; Naloxone; Naltrexone; Rats; Rats, Inbred SHR; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

The relationship between the centrally mediated hypotensive and bradycardic effects of clonidine to central alpha-2 adrenergic receptor activation, brain beta-endorphin (BE) release and opiate receptor activation was studied in chloralose-anesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats, using a cerebroventricular perfusion system. Prior treatment of SHRs with i.v. naloxone (2 or 4 mg/kg) or i.c.v. yohimbine (10 or 20 micrograms/kg) reduced the hypotension and bradycardia induced by i.c.v. clonidine, but in Wistar-Kyoto rats naloxone had no similar blocking effects. Prazosin (20 micrograms/kg i.c.v.) reduced the clonidine bradycardia but not the hypotension in SHRs. Hypotension in the SHRs due to i.c.v. alpha-methylnorepinephrine (20 micrograms/kg) was reduced by both naloxone and yohimbine whereas alpha-methylnorepinephrine bradycardia was reduced by yohimbine but not by naloxone. Prior hypothalamic lesions in the SHRs reduced clonidine hypotension, but not bradycardia, and interfered with naloxone blockade of the residual clonidine hypotensive effect. Clonidine lowered immunoreactive BE levels in SHR hypothalamus, medulla and pituitary but did not change BE levels in the i.c.v. perfusate. The findings support the idea that in the SHRs, clonidine hypotension results from alpha-2 adrenergic stimulation of brain, causing BE release and central opiate receptor activation, and they suggest that the hypothalamus is involved in these interactions. Also, clonidine hypotension and bradycardia appear to involve different mechanisms in brain.

Topics: Animals; beta-Endorphin; Blood Pressure; Brain; Clonidine; Endorphins; Heart Rate; Hypertension; Hypothalamus; Male; Naloxone; Prazosin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, alpha; Receptors, Opioid; Yohimbine

Behavioral and autonomic signs of the morphine withdrawal syndrome were measured in dependent rats injected with the opiate antagonist naloxone. The purpose of this study was to determine whether spinal cholinergic pathways play a role in the expression of spinally mediated withdrawal symptoms. Intrathecal (i.t.) administration of 1 microgram carbachol or 5 micrograms neostigmine resulted in increases in mean arterial pressure (MAP) of 32 and 45 mm Hg, respectively, in conscious, freely moving rats. The pressor response to carbachol began almost immediately after injection, but that to neostigmine was delayed in onset. Both responses were completely abolished following i.v. injection of 2 mg/kg atropine. However, in spinal-transected (C-1), ventilated rats, i.t. injection of carbachol or neostigmine resulted in only small, transient increases in MAP. Intraarterial (i.a.) injection of 0.5 mg/kg naloxone to morphine-dependent rats resulted in an immediate increase in MAP (to 33 mm Hg) that lasted at least 1 hr. This was accompanied by classical behavioral signs of withdrawal. Pretreatment of dependent rats with i.t. injection of atropine or hemicholinium-3 (HC-3) significantly reduced the pressor and several behavioral responses elicited by naloxone. In contrast, when morphine-dependent, spinal-transected rats were pretreated with i.t. injection of cholinergic antagonists, i.a. injection of naloxone resulted in an enhanced MAP response. Finally, in intact dependent rats, i.t. injection of naloxone (6 micrograms) produced a 14 mm Hg increase in MAP that was significantly augmented (21 mm Hg) following i.t. pretreatment with HC-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Cardiovascular System; Decerebrate State; Hemicholinium 3; Hypertension; Injections, Spinal; Male; Morphine; Naloxone; Parasympathetic Nervous System; Parasympathomimetics; Rats; Rats, Inbred Strains; Spinal Cord; Substance Withdrawal Syndrome

Hypertension due to pheochromocytoma is generally considered to be a straightforward, direct consequence of the elevated concentrations of circulating catecholamines. However, clonidine, a centrally acting antihypertensive drug, has been reported to lower blood pressure in patients with pheochromocytoma, suggesting the possibility that the sympathetic nervous system is involved in the maintenance of hypertension in this disease. We have investigated this possibility in New England Deaconess Hospital rats harboring a transplantable pheochromocytoma that secretes norepinephrine and dopamine. Both clonidine and chlorisondamine, a ganglionic blocker, markedly decreased blood pressure in tumor-bearing rats. However, in other rats made acutely hypertensive with a norepinephrine infusion, neither clonidine nor chlorisondamine decreased blood pressure. This result indicates that in an acute model of hypertension, where baroreflex mechanisms have likely withdrawn sympathetic tone, neither clonidine nor chlorisondamine had nonspecific antihypertensive effects. A central nervous system site of action for the antihypertensive effect of clonidine in the rats harboring pheochromocytoma was suggested by the observation that the opiate antagonist naloxone both reversed and prevented clonidine's effect on blood pressure. Prazosin and yohimbine were utilized to determine the respective contributions of alpha-1 and alpha-2 adrenergic receptors in the maintenance of hypertension in rats harboring pheochromocytoma. Both drugs markedly lowered blood pressure in these rats. Our data suggest that both the sympathetic nervous system and circulating catecholamines are involved in the maintenance of hypertension due to pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Animals; Chlorisondamine; Clonidine; Hypertension; Naloxone; Pheochromocytoma; Rats; Sympathetic Nervous System

In spontaneously hypertensive rats (SHR) a diminished responsiveness for nociceptive stimuli is present, which might be associated with alterations in endogenous opioid peptide and receptor systems. In SHR, normotensive Wistar-Kyoto controls (WKY) and in Wistar rats the effects of acute morphine administration on pain sensitivity and body temperature have been investigated. Morphine potency decreases significantly in the rank order Wistar, SHR, WKY. Concerning body temperature, a low dose (2.5 mg/kg i.p) results in an initial and transient decrease in body temperature in SHR, which is not elicited in Wistar rats and WKY. After higher doses (10 and 20 mg/kg. i.p) in Wistar rats profound hypothermia occurs whilst SHR and WKY show a modest increase in body temperature. These differential effects in the three strains could not be explained by altered morphine concentrations in subcortical brain tissue.

Topics: Animals; Body Temperature; Brain; Hypertension; In Vitro Techniques; Male; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Pain; Pain Measurement; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Sensory Thresholds; Species Specificity

A naloxone-reversible enhancement of systolic blood pressure (BP) was induced in rats by application of three different types of stressor, i.e. intense light and sound, cold and foot-shock. In the case of labile high BP provoked by short-term isolation, the opiate antagonist naloxone (1 mg/Kg, i.p.) was also found to reverse hypertension. Naltrexone (2.5 mg/Kg, i.p.) also diminished high BP readings of briefly isolated rats. Conversely, blockade of the opiate receptor with naloxone did not alter elevated BP in cases of established hypertension (spontaneously hypertensive rats, deoxycorticosterone (DOCA)-salt rats and long-term isolated rats). These data can be taken as an evidence of opioid involvement at the onset of high BP readings induced by stress. However, once hypertension becomes established, the opioid system appears to recover its silent features.

Topics: Acoustic Stimulation; Animals; Blood Pressure; Cold Temperature; Electroshock; Hypertension; Male; Naloxone; Naltrexone; Photic Stimulation; Rats; Rats, Inbred Strains; Social Isolation; Stress, Physiological; Stress, Psychological

A case of severe hypertension during labor after Naloxone injection is described in a patient with previous mild hypertension. The interaction of andogenous opioids and opiate antagonists, and their role in the control of blood pressure is discussed. Opiate antagonists should be given with caution to obstetric patients with mild to moderate hypertension.

Topics: Adult; Female; Humans; Hypertension; Naloxone; Obstetric Labor Complications; Pregnancy

In anesthetized, normotensive beta-blocked rats, the alpha 1-adrenoceptor blocking drug, AR-C 239 (300 micrograms/kg, i.v.) induced a bradycardic effect related to a central increase in the vagal tone. This bradycardia was inhibited by previous administration of naloxone, intravenously (1 mg/kg) or centrally (100 micrograms/kg, i.c.) injected. Naloxone, by itself did not change the heart rate. In brainstem membranes from normotensive rats, AR-C 239 did not influence the stereoselective binding of [3H]naloxone. In spontaneously hypertensive (SH) rats, naloxone peripherally or centrally administered did not influence the activation of the vagal tone induced by AR-C 239, in beta-blocked animals. These results suggest the possible involvement of opiate release in the AR-C 239-induced vagal bradycardia, in normotensive rats. They also afford new arguments for the existence of close interactions between central alpha-adrenergic and opiate systems in the cardiovascular regulation. The possible participation of kappa-receptors in this effect is discussed. In addition, such an opiate mechanism triggered by central alpha 1-adrenoceptor blockade seems to be either absent or inactive in SH rats.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Bradycardia; Brain Stem; Hypertension; Isoquinolines; Male; Naloxone; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Opioid; Vagotomy; Vagus Nerve

The interaction between clonidine and opiate receptor antagonists on arterial blood pressure (BP) and heart rate were examined in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). In conscious SHR, the hypotension and bradycardia caused by clonidine, 5 micrograms/kg iv, were significantly attenuated by naltrexone, 2 mg/kg ip. In urethane-anesthetized SHR, the reduction in mean BP and heart rate in response to 5 nmol clonidine microinjected into the nucleus of the solitary tract (NTS), were similarly inhibited after intra-NTS microinjection of 100 ng DL-naloxone but not after the same dose of D-naloxone. Neonatal treatment of SHR by monosodium glutamate (MSG) markedly reduced the beta-endorphin (BE) but not the leucin-enkephalin content of the arcuate nucleus and the NTS. MSG treatment did not affect the basal BP of these animals, but significantly reduced the hypotensive effect of clonidine and eliminated its susceptibility to opiate antagonists in both conscious and anesthetized SHR. In conscious and anesthetized WKY, the cardiovascular effects of clonidine were smaller than in SHR and were unaffected by naloxone or naltrexone. Neonatal treatment of WKY with MSG reduced the BE content of the arcuate nucleus but not of the NTS. MSG treatment of WKY did not influence either basal BP or the cardiovascular effects of clonidine, and the latter remained unaffected by opiate antagonists. These findings support the hypothesis that in SHR, but not in WKY, the centrally mediated cardiovascular effects of clonidine are partially mediated by the release of a BE-like opioid. They also strongly suggest that the site of both the release and the action of this opioid is in the NTS.

Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Blood Pressure; Clonidine; Endorphins; Enkephalin, Leucine; Glutamates; Heart Rate; Hemodynamics; Hypertension; Medulla Oblongata; Naloxone; Naltrexone; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Glutamate

The involvement of endogenous opioid peptides in the antihypertensive action of acutely administered clonidine, a centrally acting adrenergic agonist, was studied in humans. Eight hypertensive subjects received clonidine 0.2 mg orally, naloxone 8 mg i.v. followed by a 0.13 mg/min infusion, and both drugs together on separate days. Clonidine resulted in a significant decrease in mean blood pressure, which was not affected by concomitant treatment with naloxone. Naloxone alone or with clonidine caused significant elevations in plasma aldosterone, not mediated by increased plasma renin activity. Plasma beta-endorphin was not increased after clonidine administration. In humans, the antihypertensive effects of acute clonidine administration do not appear to be mediated by the release or action of endogenous opioids.

Topics: Adult; Aged; Aldosterone; beta-Endorphin; Blood Pressure; Clonidine; Endorphins; Humans; Hypertension; Male; Middle Aged; Naloxone; Renin

The effects of continuous intravenous infusion of naloxone or vehicle on the blood pressure and vasopressin responses to step-wise hemorrhage were examined in conscious, age-matched spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY). Step-wise hemorrhage progressively lowered blood pressure and increased plasma vasopressin levels in both SHR and WKY. The WKY were relatively resistant to the hypotensive effect of hemorrhage. No significant differences were noted in blood pressure responses between naloxone-treated and vehicle-treated SHR while naloxone treatment attenuated hypotension only slightly in WKY. Plasma vasopressin levels were also elevated by naloxone treatment in SHR following a nonhypotensive hemorrhage equivalent to 0.5% of body weight. However, no differences were observed between plasma vasopressin levels in naloxone-treated and vehicle-treated SHR at greater degrees of hemorrhage. In addition, plasma vasopressin levels were similar at all times in hemorrhaged WKY, regardless of treatment. Plasma vasopressin levels were increased by naloxone in both time-control SHR and WKY. The data demonstrate that naloxone-sensitive systems exert only minimal effects on the immediate cardiovascular responses to hypovolemia in normotensive rats and no measurable effects in SHR. It does appear that naloxone-sensitive mechanisms contribute a small, but significant, tonic inhibitory influence over vasopressin secretion in both normotensive and hypertensive rats under basal conditions and in SHR in response to a small reduction in blood volume.

Topics: Animals; Blood; Blood Pressure; Heart Rate; Hemorrhage; Hypertension; Male; Naloxone; Osmolar Concentration; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid; Vasopressins

Pressor responses to successive doubling doses of clonidine were examined in anaesthetised normotensive (NT) and spontaneously hypertensive rats (SHR). The slope of the dose-response curves was similar in both strains of rat, but the average response to the same concentrations of clonidine was less in the SHR. Naloxone (2 mg/kg i.v.) did not alter the dose-response curve in either strain. However, in NT and SHR made morphine-dependent (3 X 75 mg morphine pellets s.c.) and in hypophysectomised rats the increase in blood pressure was significantly reduced compared to the untreated or sham operated control groups, with a decrease in both the slope of the dose-response curve and a decrease in the average response. These results suggest that opioid peptide systems can modify vascular reactivity although not via circulating peptides. The specificity of the effects remains to be established.

Topics: Animals; Blood Pressure; Clonidine; Dose-Response Relationship, Drug; Hypertension; Hypophysectomy; Male; Morphine Dependence; Naloxone; Rats; Rats, Inbred SHR

Clonidine is a centrally acting antihypertensive agent used in the management of essential hypertension. Oral clonidine loading is now used frequently in the management of hypertensive urgencies (ie, increases in arterial pressure not associated with acute, life-threatening end-organ injury). We report the case of a patient with an acute inferior myocardial infarction associated with blunt chest trauma who developed an abrupt and unexplained increase in arterial pressure 24 hours after admission and who was treated with oral clonidine (0.5 mg in divided doses over two hours). Drug therapy was followed by prolonged (four hours) systemic arterial hypotension (mean arterial pressure less than 70 mm Hg). Four milligrams of naloxone in two divided doses was given. Each naloxone bolus was followed by a 15-mm-Hg increase in mean arterial pressure and a return to values that were normal for this patient. Naloxone may be of value in reversing clonidine toxicity when clonidine is given to treat an acute rise in arterial pressure.

Topics: Accidents, Traffic; Aged; Clonidine; Female; Humans; Hypertension; Hypotension; Myocardial Infarction; Naloxone; Wounds, Nonpenetrating

The adrenal medulla provides one of the most convenient preparations for studying the mechanism and control of neurosecretion. It has been suggested that neuropeptides including opioid peptides control the catecholamine secretion from adrenals and may play an important role in the maintenance of hypertension. In the present study the basal outflow of 3H-noradrenaline (3H-NA) from adrenal gland slices of normotensive and spontaneously hypertensive (SH) rats in the presence and without naloxone was examined. The amount of the basal 3H-NA outflow from adrenal gland slices of SH-rats was significantly higher compared with WKY-rats, whereas the outflow on slices of Wistar-rats was significantly lower compared with WKY-rats. Naloxone reduced the elevation of the basal 3H-NA outflow in a concentration-dependent manner, both in SH- and WKY-rats, but the absolute reduction was dependent from the level of elevation. These data suggest a functional interaction between opioid peptides and the basal catecholamine outflow during maintenance of hypertension.

Topics: Adrenal Glands; Animals; Hypertension; In Vitro Techniques; Kinetics; Male; Naloxone; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Tritium

The tissue contents of catecholamines (CAs) and methionine-enkephalin-like immunoreactivity (Met-enk) were examined in 8 patients with phaeochromocytomas (Phs). In 6, Ph cells were cultured, and the modes of secretion of CAs and Met-enk were examined. Tissue contents of CAs and Met-enk varied from patient to patient, but larger amounts of Met-enk were found in medullary Phs than extramedullary ones, regardless of the secreting CA type. Three patients with extramedullary Phs had clinically showed a sustained hypertension, whereas five with medullary Phs were normotensive or had occasional paroxysmal hypertension. Nicotine (10(-7) M to 10(-4) M) stimulated simultaneous secretion of CAs and Met-enk from the cultured human Ph cells. Met-enk, however, was not secreted in proportion to either epinephrine (E), norepinephrine (NE) or total CAs (E + NE). Met-enk, FK33-824 (FK) (Met-enkephalin analogue), and dynorphin 1-13 (Dyn) significantly suppressed the secretion of CA evoked by 10(-5) M nicotine. The 50% inhibitory concentrations (IC50) of Met-enk, FK, and Dyn were 5 X 10(-6) M, 9.9 X 10(-5) M, and 9.0 X 10(-8) M, respectively, in one patient and 9.0 X 10(-6) M, 1.5 X 10(-7) M, and 1.4 X 10(-7) M in another. In one patient, 10(-5) M naloxone inhibited the CA secretion evoked by 10(-5) M nicotine and did not reverse the 10(-5) M FK-induced suppression of CA secretion in the presence of 10(-5) M nicotine. These results suggest that human Phs may be heterogeneous with regard to storage and secretion of CAs and opioid peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Cells, Cultured; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Enkephalin, Methionine; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Naloxone; Nicotine; Norepinephrine; Pheochromocytoma

To evaluate the role of endogenous opioid peptides in regulating the blood pressure of hypertensive individuals, we administered the opiate antagonist, naloxone. One individual developed a severe hypertensive response, mean arterial pressure rising from a baseline of 107 mmHg to 147 mmHg 145 min after naloxone injection and infusion. After stopping naloxone, his blood pressure rapidly returned to baseline. Re-challenge with naloxone and clonidine resulted in a modest reduction of blood pressure in contrast to the profound hypotension induced by clonidine alone during a third session. Thus, endogenous opioids appear to regulate blood pressure in some hypertensive patients and opiate antagonists must be administered with caution to these individuals.

Topics: beta-Endorphin; Blood Pressure; Clonidine; Endorphins; Humans; Hypertension; Male; Middle Aged; Naloxone

The effect of 100 mM sodium chloride on the binding of [3H]-naltrexone to rat brain opiate receptors in spontaneously hypertensive (SHR) and normotensive (WKY) rats was studied. The percentage increase in binding in the presence of sodium chloride did not vary with age in WKY rats. Brain homogenates from 4 week old SHR rats incubated with 100 mM sodium chloride exhibited a similar increase in binding compared to age matched WKY rats. In contrast, brain preparations from 6, 14 and 20 week old SHR rats were more sensitive to sodium chloride, and the increase in binding of [3H]-naltrexone was significantly greater in these animals than in corresponding normotensive ones. Since blood pressure is increased in SHR rats compared to WKY rats at these ages, these results suggest that elevated blood pressure may be correlated with an increase in opiate receptor sensitivity to sodium chloride. The effect of in vivo sodium chloride was examined by feeding the animals a diet containing 4% salt. This concentration of salt did not significantly alter the binding of [3H]-naltrexone to rat brain homogenates prepared from 8 week old SHR rats. These results suggest that higher levels of sodium chloride and longer exposure to the diet may be required to observe the salt sensitivity produced by 100 mM salt in the in vitro radioreceptor assay.

Topics: Animals; Blood Pressure; Brain; Drug Implants; Female; Hypertension; Male; Naloxone; Naltrexone; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid; Sodium Chloride

The possibility that some of the cardiovascular, sedative or neurohormonal effects of clonidine are mediated by opiate receptors was investigated in normotensive and hypertensive subjects. In normal subjects intravenous (i.v.) clonidine lowered blood pressure, increased sedation and raised levels of plasma renin activity and growth hormone. Levels of other anterior pituitary hormones (prolactin, luteinizing hormone and follicle stimulating hormone) and of arginine vasopressin were unchanged. The effects of clonidine were similar after the administration of naloxone. In patients with essential hypertension clonidine lowered blood pressure, increased sedation and reduced plasma noradrenaline levels. There was an insignificant fall in levels of plasma renin activity. Prior administration of naloxone did not influence the effects of clonidine. It is concluded that the cardiovascular, sedative and neurohormonal effects of acutely administered clonidine are not dependent on opiate receptor activation in either normal or hypertensive man.

Topics: Adult; Blood Pressure; Clonidine; Double-Blind Method; Hemodynamics; Hormones; Humans; Hypertension; Hypnotics and Sedatives; Male; Middle Aged; Naloxone; Norepinephrine; Pituitary Hormones; Random Allocation; Receptors, Opioid; Renin

Analysis of the effect of naloxone (0.4 mg iv.) on clonidine hypotension in 80 patients with essential hypertension revealed that two groups could be separated. In the responding group (43 pts) naloxone increased blood pressure and heart rate in clonidine-treated patients while in the non-responding group (37 pts) it has no such effect. Patients in the responding group had higher cardiac output, stroke volume, plasma renin activity, plasma adrenaline and beta-endorphin levels and lower total peripheral resistance, shorter history of hypertension and lesser body weight than those in the non-responding group. The pressor effect of naloxone in four responding patients treated with clonidine for 29 months tended to be smaller compared to the response obtained after a 3-day clonidine therapy. Results favour the hypothesis of the existence of two (responding, non-responding) groups of patients with essential hypertension. Further work will clarify whether these groups represent different pathogenesis or they indicate only a different stage of hypertension.

Topics: Adult; beta-Endorphin; Blood Pressure; Clonidine; Endorphins; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Naloxone; Random Allocation

Earlier studies have shown that the antihypertensive action of clonidine is reversed by naloxone in hypertensive (SHR), but not in normotensive rats (WKY). We investigated the effects of clonidine and naloxone on pain sensitivity of SHR and WKY by using the formalin test (FT) and the tail-flick test (TFT). Using the FT, basal pain sensitivity was similar in SHR and WKY. Clonidine produced dose-dependent analgesia (0.03-0.15 mg/kg i.p.), and it was more potent in SHR than in WKY. The effect of clonidine was partially antagonized by naloxone (2 mg/kg i.p.) in SHR, but not in WKY. Naloxone alone caused moderate analgesia in SHR and no effect in WKY. Using the TFT, SHR displayed a naloxone-reversible decrease in basal pain sensitivity, when compared to WKY. Clonidine was ineffective (WKY) or caused moderate hyperalgesia (SHR). These results indicate that the two pain tests activate different pain controlling mechanisms, with different sensitivity to the antinociceptive action of clonidine. In SHR, this action seems to involve the release of endogenous opioids.

Topics: Analgesia; Animals; Clonidine; Dose-Response Relationship, Drug; Drug Interactions; Hypertension; Male; Naloxone; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The hypothalamo-neurohypophysial system is altered in the spontaneously hypertensive rat (SHR). We hypothesized that an aberrant regulation of vasopressin (VP) and oxytocin (OT) release by endogenous opioid peptides alters this neuroendocrine system in the SHR. Concentrations of the neurohypophysial hormones in plasma and the pituitary were measured in 17-week-old SHRs and two strains of normotensive controls. Wistar Kyoto (WKY) and Sprague-Dawley rats. Animals were decapitated 20 min after s.c. injection of saline (1 ml/kg) or naloxone hydrochloride (1 or 10 mg/kg). In addition, neurohypophysial hormones excreted during the day (08.00-17.30 h) and night (17.30-08.00 h) were determined in urine from 16-week-old animals kept in metabolic cages for 5 days. VP at extrahypothalamic sites was also measured as [VP] in acid extracts of the subfornical organ area, hippocampal commissure-fornix and choroid plexus. Hormones were quantified by radioimmunoassay. The pituitary content, plasma concentration, and urinary excretion of OT were reduced (P less than 0.05) in SHRs, whereas VP content was increased (P less than 0.05) in the pituitary and plasma, but unchanged in urine, of hypertensive animals. In extrahypothalamic tissues, [VP] in the hippocampal commissure-fornix was increased in the SHR. Naloxone elevated (P less than 0.05) the plasma concentration of OT in WKY animals and VP in SHRs. Neither [VP] nor [OT] in plasma was changed by naloxone in Sprague-Dawley rats. Pituitary stores of the neurohypophysial hormones were not altered by naloxone in either hypertensive or normotensive rats. In conclusion, endogenous opioid peptides tonically inhibit OT release in WKY rats, whereas VP release is decreased by opioid peptides in SHRs, 16-17 weeks of age. The neuromodulatory role of opioid peptides in the release of neurohypophysial hormones appears to be altered in the SHR such that VP release is suppressed and OT release is augmented.

Topics: Animals; Endorphins; Hypertension; Hypothalamo-Hypophyseal System; Male; Naloxone; Oxytocin; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Vasopressins; Water-Electrolyte Balance

By isolating young rats (90-100 g) a state of hypertension and tachycardia was induced after 7 days or a longer period of social deprivation. Clonidine, a drug used to treat hypertension in man, readily reversed the high blood pressure and heart rate in this experimental model of hypertension. In two different tests, an elevated nociceptive threshold was shown to be present in isolated animals as compared to group-housed rats. Naloxone was found to reverse this hypoalgesic state. The opiate antagonist also diminished the high blood pressure in the socially-deprived animals. Moreover, after 7 days of isolation, 24 hr of housing the rats in groups of five made the level of blood pressure and the sensitivity to pain return to control values. In this experimental model, in which hypertension was linked to stressful housing conditions, the data suggest that high blood pressure and hypoalgesia are closely associated.

Topics: Animals; Clonidine; Disease Models, Animal; Heart Rate; Hypertension; Male; Naloxone; Pain; Rats; Rats, Inbred Strains; Sensory Thresholds; Social Isolation

Intravenous naloxone or naltrexone produced transient, dose-related reductions in the mean arterial pressure (MAP) and heart rate (HR) of urethane-anesthetized spontaneously hypertensive rats (SHRs). Yet these same doses of narcotic antagonists reduced HR but not MAP of normotensive Wistar-Kyoto rats (WKYs). Such effects were not observed upon administration to SHRs of increasing doses of methylnaltrexone, which possesses no central activity. (+)-Naloxone, which does not block opiate receptors, reduced HR but not MAP of both SHRs and WKYs. These findings indicate that SHRs and WKYs differ in their MAP and HR responses to narcotic antagonists. The high doses required for effect plus the brevity of the responses suggest that these drug effects are perhaps not mu-opiate receptor-mediated; however, the methylnaltrexone and (+)-naloxone findings clearly implicate a central specificity of action. We conclude that narcotic antagonist-induced changes in MAP and HR in SHRs are possibly specific and central in origin yet not mediated by mu-opiate receptors.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Male; Naloxone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stereoisomerism

The influence of naloxone on the blood pressure response to tilting was studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). At the age of 5 weeks there were no significant differences in baseline blood pressure or the blood pressure response to tilting between both strains. After pretreatment with naloxone (0.4 mg/kg) there was a significantly higher increase of blood pressure due to tilting in SHR than in WKY rats. At the age of 26 weeks when in SHR the hypertension was fully developed the blood pressure response to tilting was significantly different from that in WKY rats and pretreatment with naloxone had no longer any influence. These results suggest a possible role of endogenous opiates in the development of hypertension.

Topics: Age Factors; Animals; Blood Pressure; Endorphins; Hypertension; Male; Naloxone; Posture; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Naloxone [0.4 mg iv.] increased blood pressure and heart rate of 13 clonidine-treated [0.3 mg per os for 3 days] patients with essential hypertension [reacting group] while it has no such effect in 11 clonidine-treated patients [non-reacting gr.] Clonidine increased plasma beta-endorphin concentration of the reacting patients by 17.53 +/- 1.68 pM/1 and in the non-reacting ones by 5.91 +/- 0.88 pM/1. Significant linear correlation was found between the clonidine-induced increase in plasma beta-endorphin level and the naloxone-induced change in mean blood pressure [r = 0.9572, n:24, p less than 0.001]. In another group of 8 patients clonidine [0.15 mg iv.] decreased mean blood pressure but naloxone, 30 min after the clonidine injection, did not reverse the clonidine hypotension. We suggest that beta-endorphin, released by chr. clonidine therapy, contributes to the anti-hypertensive effect only in the reacting group.

Topics: Adult; beta-Endorphin; Blood Pressure; Clonidine; Drug Interactions; Endorphins; Heart Rate; Humans; Hypertension; Middle Aged; Naloxone

The effect of tibalosine (CP 804 S) on systolic blood pressure and heart rate of unanaesthetized normotensive, spontaneously hypertensive (SHR) and DOCA-salt and Goldblatt hypertensive rats has been examined. After a single oral dose, tibalosine (1.9 to 15 mg/kg) elicited dose-dependent reductions in blood pressure in the four models tested. These reductions are accompanied by a tachycardia except in the SHR where no variation in heart rate is observed. The same result is obtained in SHR after oral, i.v. or i.c.v. administration. After repeated treatment (9 to 14 weeks), the blood pressure lowering effect of tibalosine (10 mg/kg, p.o.) is observed only in hypertensive rats. No variation in heart rate is observed in normotensive, DOCA-salt and Goldblatt rats. A significant bradycardia is observed in the SHR. The antihypertensive effect of tibalosine in SHR is suppressed by naloxone, like that of clonidine and unlike that of prazosin. The present study suggests that the antihypertensive activity of tibalosine is at least partly centrally mediated.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Clonidine; Desoxycorticosterone; Female; Heart Rate; Hypertension; Injections, Intravenous; Injections, Intraventricular; Male; Naloxone; Prazosin; Propanolamines; Rats; Rats, Inbred Strains

Although a possible role for endogenous opioids in the regulation of feeding behavior has been proposed, little direct information is available concerning the impact of long term opiate antagonist treatment on body weight. Therefore, the effect of chronic exposure to naloxone on body weight was examined in WKY and SHR rats. Since the affinity of opiate antagonists for the receptor is increased by the presence of sodium ions, body weight was also determined in animals receiving a diet containing either 0.48% or 4% sodium chloride. Naloxone does not affect body weight in either strain of animals fed a normal (0.48% NaCl, Purina) diet. However, WKY rats fed the diet elevated in sodium chloride showed an increase in body weight which is blocked by treatment with naloxone. In contrast, SHR rats fed this diet weighed less than control animals receiving the normal diet, and naloxone did not decrease their weights further. These results suggest that naloxone may impact on mechanisms which regulate body weight, but is not capable of decreasing weight below a set point in either WKY or SHR rats.

Topics: Animals; Body Weight; Diet; Drug Interactions; Female; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains; Sodium Chloride

In this study, 12 dogs were anesthetized with sodium pentobarbital, and blood flows were determined using the radioactive microsphere technique. Ten dogs were first made acutely hypertensive by the infusion of norepinephrine and demonstrated preserved cerebral autoregulation. The administration of naloxone, 10 mg/kg i.v., in these animals produced a significant increase in cerebral blood flow and a proportional drop in cerebrovascular resistance with no change in the cerebral metabolic rate of oxygen or the electroencephalogram. Two additional spontaneously hypertensive dogs demonstrated a similar response to naloxone. These results suggest that high dose naloxone produces cerebrovasodilation either directly or through the inhibition of cerebral autoregulation.

Topics: Animals; Blood Pressure; Cerebral Arteries; Cerebrovascular Circulation; Dogs; Electroencephalography; Homeostasis; Hypertension; Naloxone; Norepinephrine; Vascular Resistance; Vasodilation

Topics: Adrenalectomy; Animals; Clonidine; Endorphins; Humans; Hypertension; Male; Naloxone; Naltrexone; Psychophysiologic Disorders; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Social Isolation

Chronic administration of naloxone by means of miniosmotic pumps retarded the development of hypertension in young spontaneously hypertensive rats (SHRs) in a dose-related manner. Abrupt termination of naloxone treatment resulted in acceleration in the rate of the blood pressure increase, while increasing the naloxone concentration further slowed the development of hypertension in SHRs. The heart rates of SHRs undergoing chronic naloxone treatment were generally lower than those of control SHRs. Naloxone had no influence upon the mean systolic blood pressures or heart rates of normotensive Wistar-Kyoto control rats. These findings indicate that chronic naloxone treatment can alter the development of hypertension in the SHR.

Topics: Aging; Animals; Blood Pressure; Female; Heart Rate; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains

Spontaneously hypertensive (SH), Wistar Kyoto (WKY) or Sprague-Dawley (SD) rats were tested for their responsiveness to noxious mechanical pressure before and after a subplantar yeast injection to the right rear paw. Prior to the yeast injection, hypertensive animals were less responsive to pain relative to normotensive animals, as seen in the significantly greater pre-yeast latencies of SH compared to WKY or SD rats. Subplantar yeast injection produced hyperreactivity in the inflamed paws of WKY or SD rats, with no effect on the contralateral non-injected paw. However, identical subplantar yeast injections to hypertensive animals produced a robust, long-lasting antinociceptive effect in both rear paws of SH rats. This effect was not reversed by naloxone (opiate antagonist), labetalol (beta-blocker/vasodilator antihypertensive), or hydralazine (peripheral vasodilator antihypertensive); the antinociception was not potentiated by thiorphan (enkephalinase inhibitor). However, the alpha 2-receptor antagonist yohimbine (0.1-5 mg/kg s.c.), produced a dose-related reversal of the yeast-induced antinociception in SH rats. These results suggest that the subplantar yeast injection is triggering descending noradrenergic pain inhibitory pathways in SH rats.

Topics: Animals; Endorphins; Hypertension; Male; Naloxone; Norepinephrine; Pain; Rats; Rats, Inbred Strains; Reaction Time; Yeast, Dried; Yohimbine

Beta-endorphin and related opioid peptides are neuropeptides which appear to play a role in cardiovascular regulation which is supported by altered nociceptive responsiveness in hypertensive animals. In spontaneously hypertensive rats the pain threshold for electric stimulation is elevated; these rats show increased response latency time in a hot plate test. The opiate antagonist naloxone reverses these values to that of the normotensive controls. In other forms of experimental hypertension, eg, renal hypertension (one-clip, two-kidney model), no change in pain sensitivity is apparent. Sinoaortic baroreceptor denervation causes a labile hypertension without changes in hot plate response. Administration of beta-endorphin into the nucleus of the solitary tract (NTS) gradually decreases blood pressure and heart rate without affecting respiratory frequency. These cardiovascular effects are blocked by naloxone as well as by an antibody to beta-endorphin. In contrast to the effects of beta-endorphin, microinjection of enkephalins into the NTS increases blood pressure and heart rate. The data suggest the existence of two separate endorphin systems at the level of the NTS, one a depressor and another a pressor system. The depressor influence of beta-endorphin may play a role in the mechanism of action of antihypertensive agents such as methyldopa and clonidine. Our data support a role of endorphins as neuropeptides involved in cardiovascular regulation, exerting a dual influence at the level of the NTS.

Topics: Animals; beta-Endorphin; Blood Pressure; Brain; Endorphins; Enkephalins; Heart Rate; Hypertension; Male; Medulla Oblongata; Naloxone; Nociceptors; Pain; Rats; Sensory Thresholds

We investigated the in vitro action of naloxone (1 X 10(-6) M) on the content and 32P incorporation into di-and triphosphoinositides of erythrocytes from spontaneously hypertensive rats (SHR) and WKY controls (both 10 weeks of age). We found that the content of diphosphoinositides was decreased and the specific activity of their phosphate groups was increased after incubation with naloxone for 1 min in both rat strains. The effect was faster in SHR than in WKY rats.

Topics: Animals; Erythrocytes; Hypertension; Naloxone; Phosphatidylinositol Phosphates; Phosphatidylinositols; Rats; Rats, Mutant Strains

Topics: Clonidine; Drug Interactions; Humans; Hypertension; Naloxone; Renin

Injection of leukotriene D4 (LTD4, 20 micrograms/kg, i.a.) to conscious spontaneous hypertensive (SHR) rats produces a short-lasting pressor and tachycardic response followed by prolonged hypotension and bradycardia. Plasma norepinephrine and epinephrine were elevated at the peak pressor/tachycardic phase as well as at the hypotensive phase. Injection of thyrotropin-releasing hormone (TRH, 2 or 5 mg/kg) at the peak of the LTD4-induced hypotension resulted in prompt reversal of the hypotension and bradycardia in a dose-related manner. Naloxone (5 mg/kg) had no effect on blood pressure and heart rate of LTD4-treated SHR rats. Pretreatment with TRH (5 mg/kg) did not prevent the depressor effect of LTD4, but attenuated the bradycardic effect of this leukotriene. In addition, TRH had no effect on LTD4-induced hypotension in the pithed SHR rat. These results suggest that TRH might exert beneficial effects in hypotensive states mediated by leukotrienes or other mediators of anaphylactic reactions.

Topics: Animals; Blood Pressure; Drug Resistance; Epinephrine; Heart Rate; Hypertension; Male; Naloxone; Norepinephrine; Rats; Rats, Inbred Strains; SRS-A; Thyrotropin-Releasing Hormone

Topics: Aged; Anesthetics; Atropine; Cardiovascular System; Colectomy; Droperidol; Drug Combinations; Female; Fentanyl; Gastrectomy; Humans; Hypertension; Male; Middle Aged; Naloxone; Neuroleptanalgesia; Preanesthetic Medication; Pulmonary Edema; Respiratory Insufficiency; Thyroidectomy

The effect on systolic blood pressure and heart rate of the acute and chronic intraperitoneal (i.p.) administration of d- and dl-propranolol was investigated on unanesthetised spontaneously hypertensive rats. The effect of naloxone on the propranolol induced hypotension was also studied to test the hypothesis that the antihypertensive effect of propranolol involves the release of an endogenous opiate. On i.p. administration, 3 mg/kg d-propranolol was inactive; 3 and 30 mg/kg dl-propranolol decreased blood pressure and heart rate in a dose-dependent manner. When the rats were pretreated with 2 mg/kg naloxone i.p., the effect of propranolol on the blood pressure was nearly completely abolished, while that on the heart rate was only partially blocked. Chronic administration of dl-propranolol (30 mg/kg b.i.d.) to spontaneously hypertensive rats from the age of 6 weeks (prehypertensive phase) for 29 days prevented the development of hypertension while the rats treated with physiological saline for 29 days (control group) developed hypertension. Naloxone (2 mg/kg i.p.) administered on the 29th day to chronically treated rats induced a reversal of the propranolol action on systolic blood pressure and heart rate, i.e., blood pressure and heart rate increased. Naloxone had no such effect in the control group. We suggest that the release of an endogenous opioid contributes to the acute and chronic antihypertensive action of i.p. propranolol in spontaneously hypertensive rats and that the secretion of endogenous opioids participating in the control of cardiovascular functions is influenced by adrenergic mechanisms.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Endorphins; Heart Rate; Hypertension; Male; Naloxone; Propranolol; Rats; Rats, Inbred Strains

Zomepirac sodium inhibited the reflex hypertension caused by an injection of bradykinin into the splenic artery of anaesthetized dogs, but not that by injection of bradykinin plus PGE1. In the rat acetic acid writhing test, the potency ratio of intraperitoneal (ED50 = 0.41 microgram/kg) to intravenous (ED50 = 33.5 micrograms/kg) anti-writhing activity of zomepirac sodium was 79.2 (37.1-173), though the ratio of codeine phosphate (373 micrograms/kg, i.p., 352 micrograms/kg, i.v.) was 0.934. When equipotent doses of zomepirac sodium were administered to rats receiving intraperitoneally acetic acid, the plasma zomepirac level after i.v. administration was more than 200 times that after i.p. administration, while the peritoneal exudate zomepirac contents were nearly equal after administration by both routes. Zomepirac sodium (5 micrograms/kg) did not produce significant anti-writhing activity after intracerebroventricular administration. From these results, it was suggested that zomepirac sodium produced analgesic action through a strong blockade of the hyperalgesia in the peripheral system.

Topics: Alprostadil; Analgesics; Animals; Ascitic Fluid; Bradykinin; Dogs; Hypertension; Injections, Intraventricular; Male; Naloxone; Pain; Prostaglandins E; Pyrroles; Rats; Rats, Inbred Strains; Tolmetin

Blood pressure responses to tilting were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at different ages. The increase in blood pressure due to tilting was significantly higher in SHR with a developed hypertension (26 week-old) than in WKY rats of the same age, whereas the increase was not significantly different in SHR with a still developing hypertension (10 week-old), compared to WKY rats. Yet, even in 10 week-old SHR, there was a significantly higher increase after treatment with naloxone (0.4 mg/kg) then in WKY rats. Obviously, there are differences in the endogenous opiates between the 10 week-old SHR and WKY rats.

Topics: Aging; Animals; Blood Pressure; Hypertension; Male; Naloxone; Posture; Rats; Rats, Inbred Strains

The effect of fusaric acid (FA) on the body temperature of age-matched spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY) was investigated at an ambient temperature of 4 degrees C. During a 7 h period of cold exposure the body temperature decreased by 6.5 degrees C in WKY (p less than 0.01) and by 5.4 degrees C in SR (p less than 0.05) after administration of 100 mg/kg FA, with the effects occurring faster in WKY. At 50 mg/kg the effect was lower. Naloxone completely abolished the temperature effect of FA in both rat strains. The naloxone antagonism may point to an opiate involvement in the thermoregulation after FA. A possible contribution of vasopressin and tetrahydroisoquinoline alkaloids to the maintenance of body temperature is also discussed.

Topics: Animals; Body Temperature; Cold Temperature; Fusaric Acid; Hypertension; Male; Naloxone; Picolinic Acids; Rats; Rats, Inbred Strains

Recent studies have demonstrated a hypoalgesia in hypertensive subjects. This study reports and evaluates factors responsible for the expression of the hypoalgesic behavior demonstrated by genetically hypertensive rats of the Okamoto-Aoki strain (SHR) as compared to normotensive age-matched Wistar-Kyoto rats (WKY). Analgesiometric assays were conducted by the hot plate method. SHR's hypoalgesic behavior was reversed by subcutaneously administered naloxone. The intravenous administration of naloxone did not alter arterial pressure or heart rate in either SHR or WKY. Subcutaneous administration of the peripherally acting ganglionic blocker hexamethonium bromide at a dose which lowered mean arterial blood pressure and thus decreased tonic baroreceptor stimulation, concomitantly reversed the SHR hypoalgesic behavior and induced a hyperalgesia in WKY. Denervation of the sino-aortic baroreceptors failed to alter the hypoalgesic behavior demonstrated by SHR. Denervation of the right vagal nerve trunk with associated cardiopulmonary baroreceptor afferents resulted in a reduction of the SHR hypoalgesic behavior and produced a hyperalgesic behavior in WKY as compared to age-matched sham operated controls over a 4 week period. These data suggest a possible physiological role for vagal afferent systems in the concomitant regulation of resting arterial blood pressure and responsiveness to aversive environmental stimuli. A discussion of the interaction between blood pressure and pain regulatory systems as potential substrates associated with the onset and maintenance of hypertension is provided.

Topics: Animals; Blood Pressure; Heart Rate; Hexamethonium; Hexamethonium Compounds; Hypertension; Male; Muscle Denervation; Naloxone; Nociceptors; Pain; Rats; Rats, Inbred Strains; Vagotomy

Various peptides have been shown to alter body temperature. Intraperitoneal administration of substance P (SP) in doses of 25 and 250 micrograms/kg produces a significant hypothermic response in normotensive rats under cold exposure at 4 degrees C, whereas a dose of 2.5 micrograms/kg causes an increase in body temperature. Pretreatment with naloxone (4 mg/kg, 30 min before SP) suppresses the hypothermic effect. In spontaneously hypertensive rats (SHR), however, SP does not alter the body temperature. This result points to an altered thermoregulation in SHR based on changes in endorphin systems.

Topics: Animals; Body Temperature Regulation; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains; Substance P

A naloxone-reversible long-lasting depressor response induced by a prolonged low frequency stimulation of the sciatic nerve in conscious spontaneously hypertensive rats (SHRs) was reported in a previous paper. In the present study pharmacological tools were used to further investigate the neurotransmitters involved in this phenomenon. Naloxone infusion (20--25 mg/kg/h following a bolus dose of 10 mg/kg i.v.) attenuated significantly the depressor response, while dexamethasone pretreatment had no such effect, suggesting an important role of the brain endorphin system, but not of the pituitary beta-endorphin, in this depressor response. Since the concomitant increase in pain threshold produced by the sciatic stimulation exhibited a different time course of development and naloxone reversibility, it is suggested that the depressor response and the hypalgesic effect produced by the same stimulation are mediated via different types of opiate receptors in the brain. On the other hand, PCPA abolished the post-stimulatory depressor response whereas 5-HTP and zimelidine had additive effects on the sciatic stimulation-induced depressor response, suggesting the involvement of central serotonin systems in the mechanism of the response. The interaction between the central endorphin and the serotonin systems in the mediation of the post-stimulatory depressor response is discussed.

Topics: 5-Hydroxytryptophan; Animals; Blood Pressure; Brompheniramine; Dexamethasone; Electric Stimulation; Endorphins; Heart; Heart Rate; Hypertension; Naloxone; Neural Inhibition; Nociceptors; Rats; Rats, Inbred Strains; Sciatic Nerve; Serotonin; Synaptic Transmission; Zimeldine

[D-ala2]-met-enkephalinamide injected intracisternally in anaesthetized rats induced a centrally-mediated increase in blood pressure. The pressor response appeared to be due to activation of opiate receptors and mediated through the sympathetic nervous system. The hypotension observed with high doses may be induced by the respiratory depression. The intracisternal injection of an antagonist of opioid compounds (diprenorphine) caused a similar blood pressure decrease in spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto rats (WKY). Our data suggest a central pressor effect of enkephalins in anaesthetized rats. This represents an important argument concerning a role of endogenous opioids in blood pressure control but suggests that brain stem endogenous opioids may not be involved in the mechanism of hypertension.

Topics: Animals; Autonomic Nervous System; Blood Pressure; Diprenorphine; Endorphins; Enkephalin, Methionine; Enkephalins; Heart Rate; Hypertension; Injections, Spinal; Naloxone; Oxygen; Rats; Rats, Inbred Strains; Respiration

Rats were trained to run spontaneously, without stress, in running wheels. The running activity increased gradually and could reach a plateau of 7 km/night after 3-4 weeks. During the first hour of running in the dark phase the squeak threshold increased significantly and remained high in the morning. The degree of increased threshold was correlated to the amount of running activity. The squeak threshold declined during the following 6 hours of inactivity. A rapid decrease in threshold occurred after naloxone (1-2 mg/kg i.p.). It is suggested that long-lasting muscle exercise (e.g. jogging), acupuncture, and low frequency electrical stimulation of afferent nerve fibres produce discharges in muscle afferents which influence central endorphin mechanisms giving analgetic effects.

Topics: Animals; Endorphins; Hypertension; Male; Naloxone; Pain; Physical Exertion; Rats; Rats, Inbred Strains; Sensory Thresholds; Species Specificity

Topics: Animals; Blood Pressure; Female; Heart Rate; Hypertension; Male; Naloxone; Pregnancy; Prenatal Exposure Delayed Effects; Rats

Topics: Anesthesia; Animals; Blood Pressure; Carotid Sinus; Denervation; Dogs; Female; Heart Rate; Hypertension; Male; Naloxone

Topics: Animals; Cats; Clonidine; Enkephalins; Hemodynamics; Hypertension; Naloxone; Rats; Rats, Inbred Strains

The effect of chronic administration of the opiate antagonist naltrexone on the genesis and development of hypertension and correlated changes in central norepinephrine levels was evaluated in spontaneously hypertensive rats and Wistar-Kyoto controls. Capsules of poly-epsilon-caprolactone containing naltrexone in ethyl oleate or ethyl oleate alone were implanted in 4 week old SHR and WKY rats. Naltrexone failed to alter the genesis or magnitude of hypertension developed by the SHR and did not alter heart rates. Blood pressure and heart rate of WKY rats were also unaffected. A significant decrease in midbrain and hippocampal NE levels was observed in SHRs but not in WKYs following naltrexone.

Topics: Animals; Blood Pressure; Brain Chemistry; Catecholamines; Heart Rate; Hypertension; Male; Naloxone; Naltrexone; Norepinephrine; Rats; Rats, Inbred Strains; Time Factors

The hemodynamic and catecholamine response to intravenously administered naloxone, 0.2 mg and 0.4 mg, were determined in one group of surgical patients and one group of volunteers. Naloxone, 0.2 mg, was administered 30 minutes before the 0.4-mg dose. Group I consisted of six normotensive (IA) (aged 18 to 64, mean 35.7 years) and six hypertensive surgical patients (IB) (aged 35 to 67, mean 49.1 years) who were receiving a nitrous oxide, oxygen, and halothane anesthetic. Group II consisted of six normotensive (IIA) (aged 27 to 38, mean 36.1 years) and five hypertensive (IIB) unanesthetized volunteers (aged 41 to 60, mean 51.4 years). Mean arterial pressure, heart rate, plasma norepinephrine, epinephrine, and dopamine levels were compared before and after intravenous naloxone. Changes in mean arterial pressure, heart rate, plasma norepinephrine, epinephrine, and dopamine levels were not statistically significant in any group. This study suggests that intravenous naloxone, per se, alters neither mean arterial pressure, heart rate, or plasma catecholamine levels in normotensive or hypertensive humans.

Topics: Adolescent; Adult; Aged; Catecholamines; Hemodynamics; Humans; Hypertension; Middle Aged; Naloxone

The influence of a prolonged low frequency electrical stimulation of the somatic afferents on cardiovascular and sympathetic nerve activities was investigated in unanaesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto normotensive rats (WKRs). In SHR, an elevation of blood pressure, heart rate and splanchnic nerve outflow was elicited during a 30-min period of sciatic nerve stimulation. Following the cessation of the stimulation, depressor response and bradycardia slowly developed and lasted up to 12 h. Activation of the group III or A-delta afferent fibers was essential for this post-stimulatory response. The progressive depressor response and a parallelled reduction of the splanchnic nerve activity, reached their maxima at about 1 h after the termination of the sciatic stimulation. The magnitude of the post-stimulatory depressor response was correlated with the prestimulatory control blood pressure level. There were also behavioural changes accompanying the depressor response. The cardiovascular and the behavioural depression were immediately reversed by naloxone (10-15 mg/kg, i.v.). The post-stimulatory depressor response was still present after bilateral sino-aortic denervation, but was absent in animals anaesthetized with chloralose and urethane. Emotional stress produced by air-blowing on the animal resulted in pressor response and tachycardia during the period of the stressful stimulation, but there was no depressor response following the termination of air-blowing. These findings indicate a sympathetic and cardiovascular depression induced by a prolonged stimulation of the somatic group III or A-delta afferent fibers; its long duration and naloxone reversibility suggest the involvement of endorphins in the mechanism of this response. The physiological significance of the effects of the prolonged somatic afferent stimulation and its possible relations with acupuncture are discussed.

Topics: Acupuncture Therapy; Animals; Behavior, Animal; Cardiovascular Diseases; Chronic Disease; Consciousness; Electric Stimulation; Humans; Hypertension; Male; Naloxone; Rats; Rats, Mutant Strains; Sciatic Nerve; Splanchnic Nerves; Stress, Psychological

Clonidine and L-alpha-methylnoradrenaline (but not D-alpha-methylnoradrenaline) increase the release of a substance with beta-endorphin immunoreactivity from slices of brainstem of spontaneously hypertensive rats, but not that of normotensive rats. It was reported earlier that opiate antagonists inhibit the hypotensive action of clonidine and alpha-methyldopa in spontaneously hypertensive but not in normotensive rats and that beta-endorphin has hypotensive effects of its own. Together, these findings indicate that release of beta-endorphin by central alpha-receptor agonists may contribute to the antihypertensive action of these drugs.

Topics: Adrenergic alpha-Agonists; Animals; Brain Stem; Clonidine; Disease Models, Animal; Endorphins; Hypertension; Immunoassay; Male; Naloxone; Nordefrin; Rats

Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Electric Stimulation; Heart Rate; Hypertension; Male; Naloxone; Neurons, Afferent; Rats; Sciatic Nerve; Sympathetic Nervous System

Topics: Animals; Humans; Hypertension; In Vitro Techniques; Intestines; Male; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotics; Rats; Rats, Inbred Strains

Topics: Female; Humans; Hypertension; Intracranial Aneurysm; Naloxone; Rupture, Spontaneous

Topics: Aging; Animals; Atropine; Blood Pressure; Disease Models, Animal; Hypertension; Naloxone; Pain; Rats; Rats, Inbred Strains

Topics: Animals; Hypertension; Male; Naloxone; Pain; Propranolol; Rats; Rats, Inbred Strains; Sensory Thresholds

Antagonism between cardiovascular effects of clonidin (10-30 micrograms/kg) and naloxon (0.15-1.0 mg/kg) was studied on anesthetized spontaneously hypertensive rats (SHR) as compared to Wistar Kyoto (WKY) rats and on awake cats. Naloxon was shown to completely block the clonidin hypotensive effect in SHR and cats and to partially block it in WKY rats. In some experiments, naloxon was administered after the blockade of peripheral M-cholinoreceptors by metacin (2 mg/kg). In these experiments naloxon evoked elevation of blood pressure, cardiac output and heart rate (in cats). It is concluded that the opioid link participates in the development of clonidin-evoked bradycardia and hypotension both in hypertensive and in normotensive animals.

Topics: Animals; Blood Pressure; Cats; Clonidine; Hypertension; Naloxone; Rats

Pain sensitivity was studied in renal and DOCA-salt hypertensive rats, and in two strains of rats derived from the same parental strain for their sensitivity (H) or immunity (N) to hypertension induced by DOCA-salt treatment. Experimentally hypertensive rats, and H and N rats were less sensitive to painful stimuli than their appropriate controls, as assessed in the hot-plate and paw pinch tests. Naloxone reversed this hypoalgesia in both experimentally and genetically hypertensive rats while it did not affect blood pressure in any rat-type tested. Opioid activity was measured with the radioreceptor assay in several brain regions and pituitary gland of both experimentally and genetically hypertensive rats. Experimentally hypertensive rats had a 45% higher level of opioid activity in the spinal cord compared to control. Rats of the H and N strains both exhibited higher levels of opioid activity in the spinal cord, hypothalamus and pituitary. It is suggested that control systems for blood pressure and pain sensitivity are closely associated in the rat.

Topics: Animals; Blood Pressure; Brain; Desoxycorticosterone; Enkephalins; Hypertension; Hypertension, Renal; Male; Naloxone; Pain; Pituitary Gland; Rats; Receptors, Opioid; Spinal Cord

In unanesthetized sponatneously hypertensive rats (SHR), naloxone (0.5--2 mg/kg ip.) or naltrexone (2 mg/kg) inhibited the hypotension and bradycardia produced by clonidine (5--20 micrograms/kg iv.). Chronic treatment of SHR with clonidine (3 x 20 micrograms/kg/day orally for 12 days) reduced blood pressure and heart rate and these effects were acutely reversed by a single injection of naloxone. Naloxone also reversed the hypotension produced by a single injection of alpha-methyldopa (50--300 mg/kg ip.). In pentobarbital-anesthetized SHR, the hypotension and bradycardia produced by 5 micrograms/kg of clonidine were inhibited either by naloxone (2 mg/kg) or by yohimbine (1 mg/kg ip.). Morphine (0.33 mg/kg iv.) also reduced blood pressure and heart rate in these animals but these effects were only antagonized by naloxone and not by yohimbine. In conscious and anesthetized normotensive Wistar Kyoto rats, the reduction in blood pressure and heart rate by clonidine or alpha-methyldopa were smaller than in SHR, and these effects were not influenced by naloxone. These results confirm and extend earlier observations and suggest the existence of an "opioidergic" component in the antihypertensive action of central alpha adrenoceptor stimulants in SHR. They also show that a similar mechanism is either absent or inactive in the normotensive Wistar Kyoto rats.

Topics: Anesthesia; Animals; Blood Pressure; Clonidine; Dose-Response Relationship, Drug; Drug Interactions; Endorphins; Heart Rate; Hypertension; Male; Methyldopa; Morphine; Naloxone; Naltrexone; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Opioid; Time Factors; Yohimbine

Topics: Humans; Hypertension; Naloxone; Physostigmine

Topics: Humans; Hypertension; Naloxone

1. The cardiovascular effects of an enkephalin analogue were examined in spontaneously hypertensive and normotensive Wistar-Kyoto rats. (D-Ala2)-methionine enkephalin caused a biphasic increase in blood pressure and an increase in heart rate after intracerebroventricular injection. 2. The initial pressor response to (D-Ala2)-methionine enkephalin was greater in hypertensive than in normotensive rats. No difference was noted between groups during the secondary pressor response. Heart rate increases paralleled the secondary increase in blood pressure. 3. Naloxone pretreatment abolished the secondary increase in blood pressure and the tachycardia, but did not blunt the initial pressor response in female Wistar-Kyoto rats. 4. Plasma levels of arginine vasopressin were depressed during the plateau phase of the pressor response in hypertensive rats given intracerebroventricular (D-Ala2)-methionine enkephalin. 5. The results suggest that the cardiovascular effects of central enkephalin are not due to vasopressin, but may involve activation of the sympathetic nervous system.

Topics: Animals; Arginine Vasopressin; Blood Pressure; Endorphins; Enkephalins; Female; Heart Rate; Hypertension; Injections, Intraventricular; Male; Naloxone; Rats; Stimulation, Chemical

In 70 patients (maxillo-facial-, neurosurgical-, abdominal- and gynaecological operations) the technique of "analgetic anaesthesia" using high doses of fentanyl (0.025 mg/kg body weight) and naloxone as its antagonist (0.02 mg/kg body weight) has been employed. All patients were artificially ventilated with N2O/O2 in a 3:1 ratio. Muscle relaxation was achieved with pancuronium-bromide (0.08 mg/kg). The patients had no apparent heart or lung disease. The youngest patient was 4 years of age, the oldest 82 years of age (average age 48.9). The necessity for a reinjection of fentanyl (half the initial dose) was determined by continously monitoring heart rate. This variable appeared to be the most subtle index indicating a reduction in analgesia. Sufficient analgesia was maintained once the heart rate stayed 20% below preanaesthetic levels. At the end of the operation naloxone reversed the respiratory depression. There was no evidence indicating postoperative pain, which may have required administration of additional analgesics. If deep analgesia was maintained up to the last surgical procedures no emesis appeared in the post operative period. The incidence of emesis was higher 10% compared to the classical neuroleptanalgesia with droperidol this was often noted in cases where blood accumulated in the stomach (maxillo-facial operations) (70%). In 3% of all cases psychomotor agitation with delirium appeared right after the injection of naloxone. This lasted for about 15 minutes. We suspect that due to the sudden and powerful effect of naxolone, in replacing fentanyl from its receptor site, acute withdrawal symptoms may be precipitated.

Topics: Adolescent; Adult; Aged; Analgesia; Autonomic Nervous System; Child; Child, Preschool; Female; Fentanyl; Genital Diseases, Female; Humans; Hypertension; Hypotension; Male; Maxilla; Middle Aged; Naloxone; Nausea; Neurosurgery; Tachycardia; Vomiting

Topics: Acute Disease; Blood Pressure; Humans; Hypertension; Male; Middle Aged; Naloxone