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Biomedical subjects

G Kunos

Publications and source records attributed to G Kunos.

At least 91 records · Page 5Linked to original sources
PubMed1988

Peripheral opiate receptors are not involved in the naloxone-sensitive cardiovascular effects of clonidine in rats.

The cardiovascular effects of clonidine and their inhibition by naloxone or naloxone methylbromide were tested in urethane-anesthetized, normotensive Sprague-Dawley rats. Clonidine administered intravenously (5 micrograms/kg) or directly into the nucleus tractus solitarii (NTS, 5 nmol) caused hypotension and bradycardia. The effects of intra-NTS clonidine were dose-dependently inhibited by intra-NTS administration of either antagonist, naloxone being 10 times more potent than naloxone methylbromide. The effects of i.v. clonidine were significantly inhibited by 2 mg/kg of i.v. naloxone, but were unaffected by 20 mg/kg of i.v. naloxone methylbromide. Naloxone alone had no effect on blood pressure or heart rate when given either centrally or systemically, whereas naloxone methylbromide given i.v., but not intra-NTS, caused transient hypotension and tachycardia. It is concluded that central but not peripheral opiate receptors are involved in the cardiovascular effects of clonidine.

Animals↗
PubMed1988

Endogenous opioid involvement in the cardiovascular effects of clonidine in rats: role of the parasympathetic nervous system.

The interaction between intravenously administered clonidine and naloxone on blood pressure and heart rate was studied in urethane-anesthetized, normotensive Sprague-Dawley rats. In rats pretreated with propranolol, 1 mg/kg i.v., to eliminate sympathetic tone in the heart clonidine, 5 micrograms/kg i.v. produced hypotension and bradycardia which were inhibited by naloxone, 2 mg/kg i.v. These effects were similar to effects observed in earlier studies in the absence of propranolol. In contrast, in rats pretreated with atropine, 5 mg/kg i.v., to eliminate the effects of changes in vagal tone, the hypotensive and bradycardic effects of clonidine were not influenced by naloxone. These findings are interpreted to indicate that an endogenous opioid is involved in the clonidine-induced increase in parasympathetic outflow to the myocardium.

Animals↗
PubMed1987

Opiate receptors and the endorphin-mediated cardiovascular effects of clonidine in rats: evidence for hypertension-induced mu-subtype to delta-subtype changes.

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.

Animals↗
PubMed1987

Time dependent conversion from alpha 1- to beta-adrenoceptor-mediated glycogenolysis in isolated rat hepatocytes: role of membrane phospholipase A2 and protein kinase C.

1. Incubation of isolated rat liver cells in a serum-free buffer leads to the reduction of the glycogenolytic effect of phenylephrine and the simultaneous emergence of the response to isoprenaline within 4 h. 2. Inhibitors of phospholipase A2 reverse the adrenergic activation of phosphorylase alpha from a beta- to an alpha 1-receptor-mediated event. Conversely activators of phospholipase A2 enhance the conversion. 3. In vitro incubation of hepatocytes leads to a translocation of protein kinase C from the cytosol to the membrane which can be mimicked by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. PMA is also associated with transformation from alpha 1- to beta-adrenoceptor-mediated glycogenolysis. 4. It is proposed that coupling of hepatic alpha 1- and beta-adrenoceptors to postreceptor pathways are regulated by changes in membrane phospholipase A2 and protein kinase C activity.

Animals↗
PubMed1987

Endorphinergic mechanism in the central cardiovascular and analgesic effects of clonidine.

In urethane-anesthetized male rats, injection of 5 nmol clonidine into the nucleus of the solitary tract (NTS) causes hypotension and bradycardia. These effects are greater in spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley (SD) rats than in normotensive Wistar-Kyoto (WKY) rats. The effects of clonidine are stereoselectively inhibited by 100 ng intra-NTS naloxone in SHR and SD but not in WKY rats. In SHR, the effects of clonidine are also inhibited by intra-NTS administration of ICI 174864 (a delta-receptor antagonist) but not by beta-funaltrexamine (a mu-receptor antagonist), while in SD rats only the mu- and not the delta-antagonist was effective. Neonatal treatment of SHR with monosodium glutamate (MSG) reduced the beta-endorphin content of the arcuate nucleus and the NTS, reduced the cardiovascular effects of clonidine, and abolished their naloxone sensitivity. MSG treatment of newborn WKY reduced the beta-endorphin content of the arcuate nucleus but not the NTS and did not affect the responses to clonidine. Measurement of pain sensitivity by the formalin test indicated that clonidine was more potent as an analgesic in SHR and SD than in WKY rats, and its effect was inhibited by naloxone (2 mg/kg i.p.) in the former two strains but not in WKY. It is proposed that a naloxone-sensitive component of the cardiovascular effects of clonidine is due to release of a beta-endorphin-like opioid from the NTS, and that this mechanism is present in SHR and SD but not in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1987

Adrenergic regulation of beta-endorphin secretion from anterior pituitary in conscious rats: effects of thyroid state.

In conscious, chronically cannulated, unrestrained rats, systemic administration of catecholamines increases the plasma levels of beta-endorphin-like immunoreactivity (beta Ei). In euthyroid rats, this effect is mediated by both alpha 1 and beta-adrenergic receptors; the rise in plasma beta Ei caused by isoproterenol is blocked by 1 mg/kg propranolol, and the similar effects of norepinephrine and phenylephrine are blocked by 0.1 mg/kg prazosin. Both types of responses are completely suppressed by a 4-h pretreatment of rats with 0.1 mg/kg dexamethasone, indicating the anterior pituitary origin of the beta Ei released. Prior sectioning of the pituitary stalk does not significantly reduce the response to either phenylephrine or isoproterenol, suggesting that both agents act directly on the pituitary. Hypothyroidism induced by surgical thyroidectomy does not influence the beta Ei response to isoproterenol, which remains sensitive to block by propranolol or suppression by dexamethasone. However, neither norepinephrine nor phenylephrine is able to increase plasma beta Ei in the hypothyroid animals. Both isoproterenol and phenylephrine remain fully effective in rats made hyperthyroid by daily injections of 40 micrograms/kg T3 for 4 days. We propose that in unstressed rats catecholamines increase plasma beta Ei by a direct action on the anterior pituitary via either alpha 1- or beta-adrenergic receptors, and that expression of the alpha 1-, but not the beta-adrenergic response is regulated by thyroid hormones.

Animals↗
PubMed1986

Isolation and characterization of lipocortin (lipomodulin).

Lipocortin is a phospholipase inhibitory protein whose synthesis is induced in various cells by glucocorticoids. At least three species with molecular weights of 40,000, 30,000, and 15,000 are presently known. This protein mimics the anti-inflammatory action of glucocorticoids in vitro as well as in vivo. The synthesis of the protein appears to be associated with the MHC genes.

Animals↗
PubMed1986

An arachidonate metabolite is involved in the conversion from alpha 1- to beta-adrenergic glycogenolysis in isolated rat liver cells.

In vitro incubation of isolated rat liver cells in a serum-free buffer leads to the suppression of the glycogenolytic effect of phenylephrine and the simultaneous emergence of a glycogenolytic response to isoproterenol within 4 hr. This time-dependent conversion of the adrenergic receptor response from alpha 1 to beta type is prevented by the presence in the incubation medium of 0.5% fatty-acid-free, but not regular, bovine serum albumin. A 20-min exposure of freshly isolated liver cells to arachidonic acid (10 micrograms/ml), but not to stearic or palmitic acid, causes an acute shift in the receptor response from alpha 1 to mixed alpha 1/beta type, similar in direction to that seen after prolonged incubation of the cells. This effect of arachidonic acid is prevented by 0.2 microM ibuprofen but not by the same concentration of nordihydroguaiaretic acid. Ibuprofen (1 microM) or indomethacin (1 microM) also inhibits the time-dependent shift in the receptor response. Actinomycin D inhibits the change in receptor response that is caused by prolonged incubation but not the change that is caused by exogenous arachidonic acid. It is proposed that the time-dependent conversion from alpha 1- to beta-adrenergic receptor-mediated glycogenolysis in isolated rat liver cells is related to a parallel increase in the phospholipase-mediated release of arachidonic acid and the subsequent formation of a key cyclooxygenase metabolite. A protein factor appears to be involved in the regulation of the release of arachidonic acid but not in the action of its metabolite. A possible mechanism by which this metabolite may regulate inverse changes in the coupling of alpha 1- and beta-receptors to postreceptor pathways is discussed.

Animals↗
PubMed1986

Opioid-mediated cardiovascular effects of clonidine in spontaneously hypertensive rats: elimination by neonatal treatment with monosodium glutamate.

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.

Animals↗
PubMed1985

Naloxone reverses the antinociceptive action of clonidine in spontaneously hypertensive rats.

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.

Analgesia↗
PubMed1985

Adrenergic receptors: possible mechanism of inverse regulation of alpha- and beta-receptors.

Many physiologic and pathologic conditions, including bronchial asthma, are associated with inverse changes in alpha- and beta-receptor-mediated responses in various tissues. The direction of the change elicited by a given stimulus is tissue specific, as exemplified by the actions of thyroid hormones: In the rat heart, hypothyroidism reduces beta- and increases alpha-receptor responses, whereas in the rat liver it has the opposite effects. A similar increase in beta- and decrease in alpha-receptor responses in the rat liver is triggered by a number of different conditions, including glucocorticoid deficiency, that appear to represent lower levels of cellular differentiation. Among these, incubation of isolated hepatocytes in a serum-free buffer triggers the conversion of the receptor response in vitro within 4 hours, without parallel changes in the density or affinity of receptor binding sites. This change can be acutely reversed by an endogenous inhibitor of membrane phospholipase A2, or accelerated by an activator of phospholipase A2, suggesting that changes in the activity of this enzyme are involved in the conversion of the hepatic adrenoceptor response. The glucocorticoid-induced increase in beta-receptors in cultured human lung adenocarcinoma cells also appears to be mediated indirectly through the induction of an endogenous inhibitor (lipomodulin) of membrane phospholipase A2. The possible relevance of altered membrane phospholipid metabolism in the pathomechanism of asthma and in the associated glucocorticoid-sensitive changes in adrenergic receptor mechanisms is discussed.

Animals↗
PubMed1985

Molecular mechanism of inverse regulation of hepatic alpha-1 and beta-2-adrenergic receptors.

The adrenergic activation of glycogenolysis in the rat liver is converted from an alpha-1 to a beta-2-receptor mediated event in various conditions associated with cellular dedifferentiation. Short-term incubation of isolated hepatocytes in a serum-free medium results in a similar conversion of the adrenoceptor response, without concomitant changes in the density or affinity of alpha-1 or beta-receptor binding sites. This time-dependent conversion can be prevented or reversed by inhibitors of protein synthesis, by an endogenous inhibitor of phospholipase A2 (lipomodulin), or by removal of fatty acids from the medium through a lipid-trap. Conversely, activation of phospholipase A2 or addition of exogenous arachidonic acid to freshly isolated rat liver cells induces an acute conversion from alpha-1 to beta-type response, and the effect of the latter is prevented by the cyclooxygenase inhibitor, ibuprofen. It is proposed that reciprocal changes in alpha-1 and beta-2 receptor activity in rat liver cells are triggered by inverse changes in the coupling of the two receptors to their respective post-receptor pathways. These changes are mediated by a cyclooxygenase product generated through increased phospholipase A2 activity.

Animals↗
PubMed1985

Inverse reciprocal regulation of alpha 1- and beta 2-adrenoceptors in the rat liver: possible mechanism.

Reciprocal changes in alpha- and beta-receptor responses occur in a number of in vivo as well as in vitro conditions. Incubation of isolated rat liver cells in a serum-free buffer results in the conversion of the adrenergic activation of glycogenolysis from an alpha 1 to a beta-receptor mediated response within 4 h. The decrease in the alpha 1-adrenergic response and the simultaneous emergence of a beta-adrenergic response are selective with regards to the effects of other glycogenolytic hormones and are not accompanied by changes in the density or affinity of alpha 1 or beta-receptor binding sites. Lipomodulin, an endogenous inhibitor of membrane phospholipase A2, reverses the receptor response in 4 h cells from beta to alpha, whereas lipomodulin antibody, or melittin, a phospholipase A2 activator, have opposite effects in freshly isolated cells. The time-dependent conversion of the adrenoceptor response is prevented by the presence of indomethacin or inhibitors of protein or mRNA synthesis, and is accelerated by a serine protease inhibitor. These findings are interpreted to indicate that changes in membrane phospholipase A2 activity are involved in the conversion of the adrenergic receptor response in isolated rat liver cells, by influencing the coupling of alpha 1 and beta-receptors to postreceptor pathways in an inverse, reciprocal manner. The activation of this mechanism requires a protein factor(s), whose cellular levels are controlled by a balance between protein synthetic and proteolytic activities. The possibility that this phospholipase effect is mediated by a cyclooxygenase product is under study.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1985

beta-Endorphin and essential hypertension: importance of the clonidine-naloxone interaction.

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.

Adult↗
PubMed1984

Beta-endorphin contributes to the antihypertensive effect of clonidine in a subset of patients with essential hypertension.

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.

Adult↗
PubMed1984

Time-dependent conversion of alpha 1- to beta-adrenoceptor-mediated glycogenolysis in isolated rat liver cells: role of membrane phospholipase A2.

Incubation of isolated rat liver cells in a serum-free buffer leads to the reduction of the glycogenolytic effect of phenylephrine and the simultaneous emergence of a glycogenolytic response to isoproterenol within 4 hr. This conversion of the adrenergic activation of phosphorylase from an alpha 1- to a beta-adrenoceptor-mediated response is associated with no change in the glycogenolytic response to the calcium-linked activator vasopressin, and a reduction of the glycogenolytic response to the cAMP-linked activator glucagon. In vitro incubation of hepatocytes does not influence the density of affinity of [3H]prazosin-labeled alpha 1-receptors and [3H]CGP-12177-labeled beta-receptors. In cells preincubated for 4 hr, a further 30-min incubation with 50 nM lipomodulin, an endogenous inhibitor of membrane phospholipase A2 (EC 3.1.1.4), reverses the adrenergic activation of phosphorylase from a beta- to an alpha 1-receptor-mediated event, whereas in freshly isolated cells lipomodulin does not affect the predominant alpha-receptor response. Conversely, exposure of freshly isolated cells to a monoclonal antibody to lipomodulin in the presence of 10 microM phenylephrine, or to melittin, an activator of phospholipase A2, at 2 micrograms/ml, results in the suppression of the effect of phenylephrine and the emergence of a response to isoproterenol within 30 min. It is proposed that coupling of hepatic alpha 1- and beta-adrenoceptors to postreceptor pathways is regulated in an inverse reciprocal manner by changes in membrane phospholipase A2 activity.

Animals↗
PubMed1984

Reversal by naloxone of the antihypertensive action of clonidine: involvement of the sympathetic nervous system.

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.

Adult↗