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Biomedical subjects

S Amir

Publications and source records attributed to S Amir.

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

Thyrotropin-releasing hormone (TRH) blocks glucagon-induced hyperglycemia in mice: dissociation of the antihyperglycemic and pituitary actions of TRH.

Thyrotropin-releasing hormone (TRH) prevents the development of drug- or stress-induced hyperglycemia in mice through action at central sites. To study the role of the pituitary in mediating this action, we have evaluated the effect of TRH analogs lacking hypophysiotropic activity, acid-TRH and DN 1417, in blocking glucagon-induced hyperglycemia in mice. In addition, the effect of hypophysectomy on TRH antihyperglycemic action was examined. It was found that central injection of acid-TRH or DN 1417 (0.1-10 micrograms) fully mimics TRH in blocking glucagon (5 micrograms)-stimulated hyperglycemia. Moreover, TRH (1 or 10 micrograms) was fully active in blocking glucagon-induced hyperglycemia in hypophysectomized mice. These results exclude the possibility that pituitary factors play a role in the central antihyperglycemic action of TRH.

Animals↗
PubMed1988

Apparent involvement of protein kinase C in the central glucoregulatory action of insulin.

We have studied the possible involvement of the calcium- and phospholipid/diacylglycerol-dependent enzyme, protein kinase C (PKC) in mediating insulin action in the central nervous system (CNS) by testing the effect of direct activation or blockade of the CNS PKC system on the plasma glucose responses to central insulin injection in mice. Insulin (0.1-1 microgram), injected into the CNS, produced rapid transient hypoglycemia. This effect appeared to involve interaction of insulin with specific receptors, since insulin analogs exhibiting diminished receptor binding affinity and peripheral bioactivity compared to the native hormone were much less active (i.e., insulin much greater than acetyl 3 insulin greater than proinsulin greater than IGF-I) or not active at all (i.e., insulin chain A and chain B). Central injection of the specific PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.01-0.5 microgram), but not the inactive TPA analog, 4-alpha-phorbol or the unstable synthetic diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), significantly enhanced the hypoglycemic response to co-administered insulin (0.5 microgram) or the insulin derivative, acetyl 3 insulin (2.5 micrograms). Central TPA had no effect on basal glucose levels. Furthermore, central administration of the selective PKC blockers, polymyxin B (PMB, 1-25 micrograms) or 1-beta-galactosylsphingosine (psychosine, 0.5-10 micrograms) but not their respective inactive analogs, polymyxin E and sphingomyelin, strongly inhibited the hypoglycemic response to insulin (1 microgram) or acetyl 3 insulin (5 micrograms). PMB and psychosine, injected alone had no effect on basal glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

TPA (12-O-tetradecanoylphorbol-13-acetate) enhances the central hypoglycemic action of thyrotropin-releasing hormone in mice.

This study examined the effect of the calcium- and phospholipid-dependent protein kinase C (PKC) activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the plasma glucose responses to central thyrotropin-releasing hormone (TRH) injection in mice in order to evaluate the involvement of PKC in the mechanism of TRH action in the central nervous system (CNS). TRH (0.1-10 micrograms), as well as the neuroactive TRH analogs, CG 3509, CG 3703, DN 1417, RX 77368, [Nva2]-TRH, KPC-TRH, and TRH-Gly (0.1-10 micrograms), injected centrally in normoglycemic mice reduced the circulating glucose levels in a dose-dependent manner. TPA (0.1-1 microgram), administered centrally together with TRH (1 microgram) or the TRH analogs strongly enhanced the hypoglycemic response. Similar doses of TPA had no effect on plasma glucose when administered alone or together with TRH analogs devoid of central hypoglycemic action, i.e. [Glu1]-TRH, [Phe2]-TRH, and [Gly3]-TRH (1 microgram). Central injection of a TPA analog lacking PKC-stimulating activity, 4-alpha-phorbol (0.1-1 microgram) had no effect on the hypoglycemic response to coadministered TRH. These results, demonstrating a specific effect of TPA in enhancing the hypoglycemic response to central TRH or its neuroactive, though not inactive, analogs are consistent with a possible role for PKC in the mechanism of TRH action in the CNS.

Animals↗
PubMed1988

The use of post-binding agents in studying insulin action and its relation to experimental diabetes.

This review includes data related to two substances that modulate insulin mechanisms, both in vitro and in the whole animal model. It seems to us that these agents (vanadate and PMXB) will be of potential use in the next decade for basic and applied research. They may assist in characterizing the essential post-binding events involved in insulin action, which cannot presently be identified. As vanadate and PMXB modulate the effects of insulin both in vivo and in vitro, they may be of use in clinical and pathophysiological research as well. VO3- is a low molecular weight substance which permeates the intestinal tract and mimics the actions of insulin in target tissues. Studies that were summarized here may even suggest that VO3- is superior to insulin in stimulating its effects in tissues that are down-regulated or desensitized to the hormone itself. Both VO3- and PMXB may be useful in the treatment of diabetes in the future if long-range toxicity studies prove these agents to be clinically safe. PMXB has already been in use in medicine for several decades now.

Animals↗
PubMed1988

Aging blocks the thermoregulatory action of thyrotropin-releasing hormone in anaesthetized rats.

The influence of aging on the thermoregulatory effect of thyrotropin-releasing hormone (TRH) was studied in young (3-month-old) and aged (24-month-old) chloral hydrate-treated rats subjected either to normothermic (23 degrees C) or cold (4 degrees C) environment. Cerebroventricular injection of TRH (1 or 10 micrograms) or the TRH analog, CG 3509 (0.1 or 1 microgram), significantly enhanced the decline of body temperature in the young, anaesthetized rats, both in the normal and cold environments, but had no effect whatsoever on the decrease in body temperature in the chloral hydrate-treated aged animals. These results suggest that aging impairs the central mechanism(s) involved in the thermoregulatory action of TRH.

Acclimatization↗
PubMed1988

Opposite effects of restraint on morphine analgesia and naloxone-induced jumping.

It has been demonstrated that the effects of exogenous opiates like morphine could be modified by exposure of an organism to stress, but it is uncertain whether this modification is due to the action of endogenous opioid peptides released by stressful stimuli. The stress of restraint produced an antinociceptive response in mice measured by a latency to escape from a hot plate and, in addition, markedly potentiated analgesia induced by low doses of morphine. Both effects were antagonized by naloxone in a dose-dependent manner. On the other hand, restraint reduced the naloxone-precipitated jumping after single morphine injection. Morphine analgesia and a jumping response were not correlated when tested in two different strains of mice. It is suggested that the enhancement of morphine analgesia by restraint and the reduction in naloxone-induced jumping are mediated via independent mechanisms.

Analgesia↗
PubMed1988

Anaphylactic shock: catecholamine actions in the responses to opioid antagonists.

The pathophysiological consequences of endorphin release in anaphylactic shock were investigated through pharmacological studies using opiate antagonists (naloxone, naltrexone, natrexone methyl bromide) as well as agonists (morphine, beta-endorphin). These studies suggest that induction of anaphylaxis provokes the release of endogenous opioids, possibly from the hypothalamus, which contribute to the shock process by stimulating opiate receptors in the CNS. The mechanism of pathophysiologic action of endorphin in anaphylaxis involves, at least in part, inhibition of the central component of the sympatho-adrenalmedullary system. This results in reduced effectiveness of the sympathetic system to physiologically reverse the circulatory effects of the toxic mediators of anaphylaxis. Naloxone, by blocking endorphin action at CNS opiate receptors located at autonomic regulatory centers (e.g. hypothalamus), reverses the sympatho-inhibitory effect of the endorphin peptides. This results in increased central sympathetic outflow to peripheral sympathetic neuroeffector mechanisms; it affords improved sympathetic compensatory responses and increases survival. TRH and DT gamma E physiologically oppose the action of endorphins upon the autonomic system. They stimulate central sympathetic mechanisms through their own receptor systems and increase outflow to peripheral sympathetic effectors. This also results in improved circulatory function and survival.

Anaphylaxis↗
PubMed1988

Naloxone potentiates epinephrine's pressor actions in endotoxemic rats.

Naloxone's pressor effects in shock may be mediated through antagonism of endogenous opioid inhibition of sympathoadrenal catecholaminergic systems. Since circulating catecholamine levels are not further elevated by naloxone in endotoxemic animals, it is possible that naloxone acts upon opiate receptors to enhance catecholamine actions at the receptor or postreceptor level. To investigate this hypothesis, we sought to determine whether naloxone treatment would augment the pressor actions of exogenous catecholamines (epinephrine) in normal and endotoxemic rats. Naloxone (3 mg/kg intravenous [i.v.] bolus followed by 3 mg/ml/hr infusion) significantly augmented the pressor response to 10, 20, and 50 micrograms/kg of i.v. epinephrine by 69%, 48% and 14%, respectively, in endotoxin (5 mg/kg, LD20, i.v.) -treated rats but not in normal rats. Likewise, the duration of the pressor response to epinephrine was significantly increased by naloxone. These findings suggest that the coadministration of naloxone and epinephrine may be of benefit in the treatment of shock.

Animals↗
PubMed1987

Thyrotropin-releasing hormone potently reverses epinephrine-stimulated hyperglycemia in mice.

Intracerebroventricular microinjection of thyrotropin-releasing hormone (TRH) potently blocked the development of, as well as promptly reversed, epinephrine-stimulated hyperglycemia in mice. The central antihyperglycemic effect was dose-related (0.1-10 micrograms), could be reproduced by an intravenous injection of a large dose of the peptide (100 micrograms), was independent of experimental factors such as stress and age, was effective against other hyperglycemic stimuli, and appeared to be unique to TRH, as it could not be mimicked by many other centrally active peptides known to influence glucoregulation in normoglycemic animals. Moreover, the antihyperglycemic effect of TRH appeared to depend on the structural integrity of the peptide molecule but seemed to be unrelated to the peptide's hypophysiotropic actions or to interaction of the peptide with previously characterized TRH receptors, as it could be mimicked by various analogs devoid of thyrotropin- and prolactin-releasing influences or by peptides resembling TRH in amino acid composition but lacking substantial binding affinity to TRH receptors. Furthermore, the effect of TRH to reverse epinephrine-stimulated hyperglycemia appeared to be mediated by combined action of peripheral sympathetic and parasympathetic mechanisms to stimulate insulin release from the pancreas, since only complete blockade of the central autonomic outflow, but not selective perturbation of the sympathetic or parasympathetic outflow, or depletion of pancreatic insulin could substantially attenuate the antihyperglycemic action. Taken together, these results suggest a new physiologic role of TRH as a central glucoregulatory neuropeptide involved in autonomic modulation of insulin secretion and prevention of hyperglycemia.

Animals↗
PubMed1987

Vanadate ions: central nervous system action on glucoregulation.

Vanadate (VO-3), an essential trace element with insulin-mimetic actions, produces systemic hyperglycemia following central administration in mice. The hyperglycemic effect is due to specific action of vanadate or its reduced form, vanadyl (VO2+); other ions of similar atomic weight (Cr, Mn) or structure (phosphate) have no effect. The effect of central vanadate to raise circulating glucose is blocked by coadministration of 3-O-methylglucose or polymyxin B, which prevent insulin- and vanadate-stimulated glucose transport. Finally, the central hyperglycemic effect is prevented by treatments which block sympathetic outflow from the CNS or diminish the levels of circulating epinephrine. These results show that vanadate is able to influence peripheral glucoregulation by increasing sympathetic outflow from the CNS. Moreover, they suggest that this effect is linked to action of VO-3 or its reduced form, VO2+, to stimulate glucose transport into neuronal cells.

3-O-Methylglucose↗
PubMed1987

Centrally mediated hypoglycemic effect of insulin: apparent involvement of specific insulin receptors.

We have studied the involvement of central nervous system (CNS) insulin receptors in mediating the central hypoglycemic effect of insulin by using insulin derivatives modified at regions of the hormone necessary for receptor reactivity and peripheral bioactivity. Acetylation or succinylation of the 3 free amino groups of insulin at positions A1, B1 and B29 resulted in a corresponding decrease in lipogenic activity in isolated rat adipocytes, with concentrations of hormone required to produce half the maximal effect (ED50) being 0.15 ng/ml, 3 ng/ml and 50 ng/ml for native insulin, acetyl3 insulin and succinyl3 insulin, respectively. Moreover, the modified insulins exhibited diminished hypoglycemic effect following central administration in mice, with the doses needed for suppression of plasma glucose to 50% of basal levels being 1 microgram, 10 micrograms and 25 micrograms for native insulin, acetyl3 insulin and succinyl3 insulin, respectively. Because binding of insulin derivatives to CNS receptors can be predicted from their peripheral bioactivity, the present finding of parallel decrements in lipogenic activity in vitro and central hypoglycemic effect in vivo, following modification of insulin at regions implicated in receptor activation, is consistent with the view that insulin exerts its central effect on plasma glucose by interacting with specific CNS receptor sites which are closely related to the peripheral insulin receptors.

Animals↗
PubMed1987

Polymyxin B is an inhibitor of insulin-induced hypoglycemia in the whole animal model. Studies on the mode of inhibitory action.

The cyclic decapeptide, polymyxin B (PMXB), was found to inhibit hypoglycemia in mice receiving exogenous insulin (Amir, S., and Shechter, Y. (1985) Eur. J. Pharmacol. 110, 283-285). In this study, we have extended this observation to rats. Insulin-dependent hypoglycemia in rats is efficiently blocked at a 12:1 molar ratio of PMXB to insulin. This effect is highly specific, as it could not be mimicked by a variety of antibiotics or positively charged substances. Chemical modifications of PMXB have revealed that the ring structure, rather than the tail structure, is important for anti-insulin-like activity. Colistin A, which differs from PMXB by one conservative amino acid substitution in the ring structure, is devoid of this activity. Polymyxin B does not interact with insulin, nor does it alter the rate of insulin absorption and/or degradation, or the ability of insulin to bind to target tissues. This peptide inhibits hypoglycemia by blocking insulin-dependent activation of the hexose transport mechanism, as deduced by in vitro studies. The effect of insulin in stimulating hexose uptake (and subsequent glucose metabolism) in both isolated muscle tissue and adipocytes is blocked with little or no effect on the basal activities of these processes. Colistin A has no significant inhibiting effect. Other insulin-dependent activities, such as inhibition of lipolysis in adipocytes or synthesis of DNA in muscle cells, are not inhibited. It is concluded that PMXB inhibits, in a highly specific manner, the action of insulin in stimulating hexose transport and subsequent glucose metabolism, both in vitro and in the whole animal model.

Animals↗
PubMed1986

Central glucagon-induced hyperglycemia is mediated by combined activation of the adrenal medulla and sympathetic nerve endings.

Intracerebroventricular (ICV) microinjection of glucagon (0.0025-2.5 micrograms) produced significant dose-dependent hyperglycemia in mice. This hyperglycemic effect was prevented by pretreatment with the sympathetic ganglionic blocker chlorisondamine chloride or bilateral adrenalectomy plus chemical sympathectomy with 6-hydroxydopamine. Similar pretreatments had no effect on the plasma glucose responses to systemic glucagon administration. Pretreatment with somatostatin, which blocks pancreatic glucagon secretion had no effect on the hyperglycemic response to central glucagon administration. The results suggest that the increase in plasma glucose following central glucagon administration is mediated by combined action of adrenal and sympathetic amines to stimulate hepatic glucose production, or additionally to inhibit insulin release from the pancreas. The possible involvement of glucagon in the central nervous system in systemic glucoregulation is discussed.

Adrenal Medulla↗
PubMed1986

Compliance and control: issues in group training for diabetics.

When patients in treatment do not comply with medical directives, the most competent health care may go for naught and patients' well-being may be jeopardized. By focusing on the links between assertiveness and coping skills and compliant behavior, the group program described here increased compliance as well as self-confidence in diabetic group members.

Adult↗
PubMed1986

Central glucagon antagonizes morphine- and stress-induced antinociception in the mouse.

Previously, we have demonstrated that glucagon antagonizes morphine-induced antinociception in the rat (Malcolm et al. 1985). In the present studies we have shown that central injection of glucagon antagonizes morphine- and stress-induced antinociception in the mouse. Since stress-induced antinociception is mediated by the activation of endogenous opioid systems, these findings provide the first evidence for glucagon's ability to antagonize endogenous opioid actions.

Analgesia↗
PubMed1986

Endorphins contribute to the loss of glucose homeostasis in anaphylactic shock.

Central injection of naloxone attenuated the development of hyperglycemia following induction of non-fatal anaphylaxis in mice, but it failed to reverse the hyperglycemia in this model. In contrast, central TRH both blocked as well as reversed the hyperglycemic response. These results suggest a possible role for central endorphin mechanisms in the hyperglycemic response to anaphylactic shock in mice. Further, they demonstrate a novel action of TRH to block shock-induced hyperglycemia. This antihyperglycemic action of TRH is independent of opiate mechanisms.

Anaphylaxis↗