Genichi Watanabe

Increase in insulin release from rat pancreatic islets by quinolone antibiotics

1 The present study was undertaken to elucidate the mechanism(s) of hypoglycaemia caused by quinolone antibiotics. We investigated the effects of various quinolone antibiotics on insulin release in rat pancreatic islets. 2 At a non‐stimulatory concentration of 3 mM glucose, lomefloxacin (LFLX) or sparfloxacin at 1 mM and pipemidic acid (0.1‐1 mM) induced slight insulin release but tosufloxacin or enoxacin up to 100 μm did not. 3 At the stimulatory concentration of 10 mM glucose, all quinolones augmented insulin release in a dose‐dependent manner. LFLX (100 μm) shifted the dose‐response curve of glucose‐induced insulin release to the left without altering the maximal response. 4 At 10 mM glucose, LFLX (100 μm) increased insulin release augmented by forskolin (5 μm) or 12‐0‐tetradecanoyl phorbol‐13‐acetate (100 nM) but not by raising the K+ concentration from 6 to 25 mM. 5 Verapamil (50 μm) or diazoxide (50–400 μm) antagonized the insulinotropic effect of LFLX. 6 These data suggest that quinolone antibiotics may cause hypoglycaemia by increasing insulin release via blockade of ATP‐sensitive K+ channels.

Intrahypothalamic, but not hippocampal, administration of muscimol suppresses hyperglycemia induced by hippocampal neostigmine in anesthetized rats

We investigated the effects of intrahypothalamic or hippocampal injection of GABA receptor agonists on hyperglycemia induced by hippocampal neostigmine. Prior to the injection of neostigmine (50 nmol) into the hippocampus (HPC), muscimol (0.01-1 nmol) or baclofen (1 nmol) was injected into the bilateral ventromedial hypothalamus (VMH). Muscimol suppressed the hyperglycemia in a dose-dependent manner, but baclofen affected it only minimally. In contrast, neither hippocampal muscimol (1 or 2.5 nmol) nor baclofen (1 nmol) suppressed the hippocampal neostigmine-dependent hyperglycemia. Intrahypothalamic muscimol (1 nmol) also decreased the changes in hepatic venous plasma glucagon and epinephrine significantly. These results indicate that intrahypothalamic muscimol suppresses hyperglycemia caused by cholinergic neurons originating from the HPC, indicating existence of the location specificity.

Role of brain histamine H1- and H2-receptors in neostigmine-induced hyperglycemia in rats

We previously reported that when neostigmine, an inhibitor of acetylcholine esterase, was injected into the third cerebral ventricle, the concentration of hepatic venous plasma glucose was increased via central muscarinic receptors in anesthetized rats. To determine whether brain histamine receptors are involved in cholinergic system transmission with regard to central nervous system (CNS)-mediated glucoregulation, we examined the effects of the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine on neostigmine-induced hyperglycemia in anesthetized rats. The injection of pyrilamine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle suppressed hyperglycemia induced by intraventricular injection of neostigmine (1 x 10(-9) mol) in a dose-dependent manner. Injection of ranitidine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle did not suppress the hyperglycemia induced by neostigmine, but enhanced it in a dose-dependent manner. These findings suggest that neostigmine-induced CNS-mediated hyperglycemia is transmitted by not only brain cholinergic muscarinic receptors but also in part by histamine H1 receptors.

Activation of GABAA receptors in hypothalamus modulates PGF2α- or PGE2-induced catecholamine secretion in rats

We previously reported that injection of PGF2 alpha into the third cerebral ventricle produces hyperglycemia and hyperthermia associated with catecholamine secretion in anesthetized rats. We have also studied the potency of catecholamine secretion induced by injecting PGE2 or PGF2 alpha into the third cerebral ventricle and the effect of the GABA-selective agonist, muscimol, on the catecholamine secretion induced by PGE2 or PGF2 alpha. Administration of 50 micrograms of PGE2 into the third cerebral ventricle increased norepinephrine secretion to a greater extent than the same dose of PGF2 alpha, whereas the latter increased epinephrine secretion to a greater degree. These effects paralleled the potencies of the hyperglycemic and hyperthermic effects of PGF2 alpha and PGE2, respectively. Simultaneous injection of 2.5 nmol of muscimol into the third cerebral ventricle with 50 micrograms of PGF2 alpha or PGE2 completely suppressed epinephrine and norepinephrine secretion induced by PGF2 alpha or PGE2. These findings suggest that central PGF2 alpha and PGE2 stimulate epinephrine and norepinephrine secretion with different potencies, and that brain GABAA receptors suppress catecholamine secretion induced by PGF2 alpha or PGE2.

CNS regulation of blood lactate concentration in anesthetized rats

This study evaluated the effect of stimulating the central nervous system (CNS) with neostigmine, an inhibitor of acetylcholinesterase, on the blood lactate concentration in fed rats and in rats fasted for 48 hours. After the rat was anesthetized with pentobarbital, neostigmine was stereotaxically injected into the third cerebral ventricle. In fed rats, the central injection of neostigmine significantly increased the blood lactate level, while concomitantly increasing plasma glucagon, epinephrine and norepinephrine concentrations. Constant infusion of somatostatin throughout the experiments, to inhibit glucagon secretion from the pancreas, did not affect alterations in blood lactate by central injection of neostigmine. In adreno-medullated rats, CNS-stimulation by neostigmine still increased plasma norepinephrine significantly, however, the alteration in blood lactate was only one-third of that in intact rats. Intraperitoneal propranolol, but not phentolamine, prevented the rise in lactate. Neostigmine increased lactate in fasted rats as well as in fed rats. We conclude that in anesthetized rats, stimulation of the CNS by neostigmine increases blood lactate mainly through circulating epinephrine and partially through circulating norepinephrine or direct sympathetic nervous stimulation; glucagon does not appear to be involved in the increase in blood lactate.

Histamine-induced, central nervous system-mediated hyperglycemia is suppressed by atropine in the brain.

We investigated the relationship between histamine and muscarinic cholinergic neurons in central nervous system (CNS)-mediated glucose regulation in anesthetized fed rats. The injection of pyrilamine (5 x 10(-7) mol) into the third cerebral ventricle suppressed the hyperglycemia induced by intraventricular injection of histamine (5 x 10(-7) mol). Ranitidine (5 x 10(-7) mol), however, did not suppress this hyperglycemia. The injection of atropine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle suppressed the histamine-induced hyperglycemia in a dose-dependent manner. These findings suggest that histamine induction of CNS-mediated hyperglycemia involves neuronal transmission not only via H1 receptors but also, at least in part, by muscarinic cholinergic neurons.

Activation of GABAA receptor in the brain suppresses neostigmine or histamine-induced central nervous system-mediated hyperglycemia.

We investigated the effect of GABA receptor agonists on the central nervous system (CNS)-mediated hyperglycemia induced by neostigmine or histamine in anesthetized fed rats. The injection of muscimol, GABAA receptor agonist (1, 2.5 nmol) into the third cerebral ventricle suppressed the hyperglycemia induced by intraventricular injection of neostigmine (1 x 10(-8) mol) or histamine (5 x 10(-7) mol). Baclofen, GABAB receptor agonist (1, 2.5 nmol), however, did not suppress these hyperglycemia. Neither muscimol nor baclofen (2.5 nmol) affected plasma glucose levels. These findings suggest that activation of GABAA receptor in the CNS suppresses the hyperglycemia induced by the stimulation of cholinoceptive neuron or histaminergic neuron, but activation of GABAB receptor does not affect them.