Judith Szilvassy

Loss of preconditioning in rabbits with vascular tolerance to nitroglycerin.

A preceding right ventricular overdrive pacing (VOP) of 500 b.p.m. for 5 min, markedly reduced the severity of global myocardial ischaemia produced by a subsequent 5‐min VOP in conscious rabbits. This VOP‐induced preconditioning developed in parallel with an increase in cardiac cyclic guanosine 3′: 5′‐monophosphate (cyclic GMP) content. VOP‐induced preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of nitroglycerin (NG). In the heart of the NG‐tolerant rabbits, neither VOP nor preconditioning increased cyclic GMP content. This suggests that changes by NG tolerance of cyclic GMP metabolism may account for the loss of VOP‐induced preconditioning.

Hepatic insulin sensitizing substance: a novel ‘sensocrine’ mechanism to increase insulin sensitivity in anaesthetized rats

We recently described the sensory nitrergic nature of the hepatic insulin sensitizing substance (HISS) mechanism linked to postprandial activation of anterior hepatic plexus fibres in rabbits. This study is designed to assess the involvement of the sensory pathways in this mechanism. Selective sensory denervation of the anterior hepatic plexus (AHP) was achieved by a 3‐day perineurial treatment with 2% capsaicin solution in Wistar rats (230–250 g). After 1 week, hyperinsulinaemic (100 μU kg−1) euglycaemic (5.5 mmol kg−1) glucose clamp studies were performed to estimate insulin sensitivity. The rats with regional AHP sensory denervation exhibited a significantly decreased insulin sensitivity, that is, 9.1±1.0 mg kg−1 min−1 glucose reinstalled euglycaemia vs 13.3±1.9 mg kg−1 min−1 glucose (P<0.01) in control rats. Acute partial hepatic denervation by AHP cut was without effect on insulin sensitivity, whereas chronic hepatic denervation induced insulin resistance was similar to that achieved by regional AHP capsaicin treatment. Intraportal administration of L‐NAME (10 mg kg−1) decreased, whereas capsaicin (0.3 mg kg−1 min−1) increased insulin sensitivity. Neither atropine (1 mg kg−1) nor acetylcholine (1–10 μg mg min−1) produced any significant effect. In animals with preceding regional capsaicin desensitization, none of the pharmacological manoeuvres modified the resulting insulin‐resistant state. Cysteamine (200 mg kg−1 s.c.) is known to cause functional somatostatin depletion‐induced insulin resistance similar to that produced by either chronic partial hepatic denervation or perineurial AHP capsaicin desensitization. Intraportal capsaicin (0.3 mg kg−1 min−1) was unable to modify insulin resistance achieved by cysteamine. We conclude that capsaicin‐sensitive sensory fibres play a crucial role in neurogenic insulin sensitization known as the HISS mechanism without involvement of anatomical reflex‐mediated circuits. The results also suggest that HISS is identical to somatostatin of AHP sensory neural origin.

Regional differences in nitric oxide-mediated relaxation of the rabbit sphincter of Oddi

We studied the role of the L-arginine-nitric oxide (NO) pathway in non-adrenergic, non-cholinergic (NANC) relaxation of the rabbit sphincter of Oddi by recording changes in isometric tension in response to electrical field stimulation in two series of experiments. In a first set of experiments, biliary sphincters of Oddi removed from New Zealand white rabbits were placed horizontally in an organ bath containing oxygenized, buffered (pH 7.4) Krebs solution. Contractile responses of the whole sphincter to field stimulation were determined. In the second set of experiments, sphincter of Oddi was divided into two parts and the effects of field stimulation were studied separately on areas close to the duodenal papilla (area I) and areas close to the common bile duct (area II). In the whole sphincter of Oddi, field stimulation induced an initial twitch-like contraction followed by relaxation proportional to the number of stimuli (3 and 10 stimuli at 20 Hz, 50 V, 0.1 ms). The magnitude of the contractile responses was considerably reduced by 1 microM atropine, phentolamine and oxprenolol (NANC solution). Field stimulation produced dose-dependent contractions of both segments of sphincter of Oddi in response to the same protocol as used with whole sphincter of Oddi. However, preincubation with NANC solution produced monophasic relaxations in response to field stimulation in area I, whereas area II preparations such as the whole sphincter of Oddi responded with contractions followed by minimal relaxations. Field stimulation failed to induce either contractions or relaxations in the presence of 1 microM tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired nitrergic relaxation of the sphincter of Oddi of hyperlipidaemic rabbits

Field stimulation relaxed the sphincter of Oddi muscle rings of the rabbit after incubation with phentolamine, oxprenolol and atropine (all 1 microM). The relaxation was blocked by NG-nitro-L-arginine methyl ester (30 microM) and was reversed by 3 mM L-arginine but not D-arginine. Sphincter of Oddi preparations from hypercholesterolaemic rabbits exhibited contractions under the same conditions. We conclude that nitrergic relaxation is impaired in the sphincter of Oddi from hypercholesterolaemic rabbits.

Development of insulin resistance by nitrate tolerance in conscious rabbits.

Clinical evidence has been raised to suggest that transdermal nitroglycerin increases the sensitivity of peripheral tissues to the hypoglycemic effect of insulin. In this study we determined whether development of tolerance to the hypotensive effect of nitroglycerin also resulted in tolerance to the insulin-sensitizing effect in rabbits. Intravenous glucose disposal and hyperinsulinemic euglycemic glucose clamp studies were performed on naive and hemodynamic nitrate tolerant conscious New Zealand white rabbits. These rabbits were exposed to continuous “patch on” with nitroglycerin (0.07 mg/kg/h) or placebo patches over 7 days. Nitroglycerin treatment of 7 days produced a lack of hypotensive response to a single intravenous bolus of 30 &mgr;g/kg nitroglycerin, which caused a significant decrease in mean arterial blood pressure in control rabbits. A six-hour exposure to transdermal nitroglycerin significantly increased insulin sensitivity determined by hyperinsulinemic (100 &mgr;U/ml) euglycemic (5.5 mmol/l) glucose clamping as compared with that seen in rabbits treated with placebo patches. A significant decrease in insulin sensitivity was observed in the nitroglycerin patch-treated animals both in the presence and after the removal of the last patch when the patches were applied over 7 days. We conclude that acutely nitrate patches improve insulin sensitivity whereas a 7-day chronic treatment schedule that results in hemodynamic nitrate tolerance also produces insulin resistance.

Impaired bronchomotor responses to field stimulation in guinea-pigs with cisplatin-induced neuropathy

Pre-treatment with cisplatin (3 mg/kg) i.p. once a day over 6 days induced sensory neuropathy as confirmed by femoral nerve conduction velocity test and significantly decreased contractions induced by electrical field stimulation (100 stimuli, 20 V, 0.1 ms, 20 Hz) in isolated main bronchial rings from guinea-pigs. The field stimulation-induced non-adrenergic, non-cholinergic (NANC) relaxations, however, were amplified in rings from animals with cisplatin neuropathy. The NANC relaxation response was completely blocked by 30 microM N(G)-nitro-L-arginine methyl ester in preparations from both control and cisplatin-treated animals. Superoxide dismutase (40 units/ml) was without effect on NANC relaxation in control rings, however, it substantially decreased NANC relaxation in preparations from animals with cisplatin neuropathy. These results show that cisplatin-induced sensory neuropathy is accompanied by attenuation of neural bronchoconstriction and an enhanced NANC relaxation. The latter is in part attained by an increased peripheral superoxide production.

Cochlear implantation in a patient with grand mal epilepsy

A case is reported in which a Nucleus 22 channel intracochlear implant was used to treat a deaf Hungarian woman (aged 37 years) with a 34-year history of grand mal (GM) epilepsy maintained on carbamazepine-diazepam combination therapy who had not benefited from conventional hearing aids. Pre-operative electrical stimulation of the acoustic nerve, however, exhibited a good nerve function with no evidence of abnormal waveforms in the electroencephalogram (EEG). Successful intracochlear insertion of the 22 electrode resulted in a 40 dB hearing improvement at frequencies 250-2000 Hz in the implanted ear with no signs of pathologic wave activity at either the previously recognized epileptic focus (fronto-precentral region) or indeed, in other regions of the brain at use of the implant. We conclude that intracochlear implantation per se is not a hazardous intervention in patients with fronto-precentral epileptic foci.

Cochlear implantation of a Hungarian deaf and blind patient with discharging ears suffering from Behçet's disease

A case is reported in which a Nucleus 22 channel intracochlear device was implanted a deaf/blind Hungarian adult with discharging ears suffering from Behçets disease. Preconditioning surgery was employed three months prior to the implantation procedure to ensure a sterile, dry protected environment for the electrodes. One month after implantation, the patient exhibited excellent auditory discrimination capability at the time of the first switch on. We suggest that some deaf/blind individuals may serve as very good candidates for intracochlear implantation.

Involvement of glibenclamide-sensitive potassium channels in vasorelaxation by cochlear nerve stimulation.

Rabbit aortic rings relaxed with an increase in cyclic guanosine monophosphate and cyclic adenosine monophosphate content in response to exposure to organ fluid of isolated cochleas of the guinea pig following field stimulation (50 Hz, 80 V, 0.2 ms). Relaxations were blocked by 30 μMNG-nitro-l-arginine methyl ester added to the vessel rings. This inhibitory effect was reversed by 3 MMl-arginine. Removal of the vascular endothelium also blocked the relaxation response. Glibenclamide attenuated vasorelaxation in a concentration-dependent manner. We conclude that cochlear nerve stimulation induces an endothelium-dependent vasorelaxation involving activation of adenosine triphosphate-sensitive potassium channels.