Decreased sensory neuropeptide release in isolated bronchi of rats with cisplatin-induced neuropathy

We studied if attenuated neurogenic bronchoconstriction was associated with a change in sensory neuropeptide release in preparations from rats with cisplatin-induced neuropathy. Electrical field stimulation (100 stimuli, 20 V, 0.1 ms, 20 Hz) induced an increase in the release of somatostatin, calcitonin gene-related peptide (CGRP) and substance P determined by radioimmunoassay from baseline 0.18+/-0.01, 0.17+/-0.01 and 0.86+/-0.02, to 0.59+/-0.02, 1.77+/-0.04 and 5.96 fmol/mg wet tissue weight, respectively, in organ fluid of tracheal tubes from rats. This was significantly attenuated to post-stimulation values of 0.36+/-0.02, 0.45+/-0.02, 4.68+/-0.24 fmol/mg wet tissue weight for somatostatin, CGRP, and substance P, respectively, with a significant decrease in field stimulation-induced contraction of bronchial preparations from animals 11 days after a 5-day treatment period with cisplatin (1.5 mg/kg i.p. once a day). The cisplatin-treated animals developed sensory neuropathy characterized by a 40% decrease in femoral nerve conduction velocity. The results show that a decrease in tracheo-bronchial sensory neuropeptide release associates with feeble bronchomotor responses in rats with cisplatin-induced sensory neuropathy.     

Decreased sensory neuropeptide release from trachea of rats with streptozotocin-induced diabetes

We studied the release of somatostatin, calcitonin gene-related peptide (CGRP) and substance P in response to electrical field stimulation from isolated tracheas of rats following 4 weeks of streptozotocin (50 mg/kg i.v.)-induced diabetes. Field stimulation (40 V, 0.1 ms, 10 Hz for 120 s) increased the release of somatostatin, CGRP and substance P from the baseline 0.18+/-0.029, 0.17+/-0.027, and 1.77+/-0.086 to 0.51+/-0.022, 0.69+/-0.115, and 5.96+/-0.377 in control preparations and 0.31+/-0.081, 0.41+/-0.142, and 3.14+/-0.443 fmol/mg wet tissue weight in preparations from diabetic rats as measured by radioimmunoassay (control vs. diabetic P<0.01 for each). The results show a simultaneous decrease in release of the three sensory neuropeptides and an enhanced plasma somatostatin level in rats with streptozotocin-induced diabetes.     

Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.     

The myocardial infarct size-limiting and antiarrhythmic effects of acyl-CoA:cholesterol acyltransferase inhibitor VULM 1457 protect the hearts of diabetic-hypercholesterolaemic rats against ischaemia/reperfusion injury both in vitro and in vivo

The study was designed to characterise the influence of a novel acyl-CoA:cholesterol acyltransferase inhibitor, VULM 1457, on the severity of myocardial ischaemia-reperfusion injury in a model of diabetes mellitus and hypercholesterolaemia induced by co-administration of streptozotocin and a high fat-cholesterol diet. We used Langendorff-perfused rat hearts to measure the size of myocardial infarction after 30 min of regional ischaemia, followed by a 2-h reperfusion period, and open-chest rats were exposed to 6 min of ischaemia and 10 min of reperfusion to analyse ventricular arrhythmias. In addition to the high fat-cholesterol diet, VULM 1457 was administered to the diabetic-hypercholesterolaemic rats for 5 days. Decreased plasma and liver cholesterol levels and a significantly reduced occurrence of ventricular fibrillation (29% vs. 100%, P<0.01), determined via the mean number and duration of episodes (0.6+/-0.4 and 2.1+/-1.4 s vs. 2.8+/-0.8 and 53.5+/-14.4 s in diabetic-hypercholesterolaemic rats, both P<0.01), were observed in these animals. Lethal ventricular fibrillation was suppressed, and arrhythmia severity was also significantly decreased in these animals as compared to the non-treated animals (2.9+/-0.6 vs. 4.9+/-0.2; P<0.05). A smaller infarct size, normalised to the size of area at risk, was observed in the treated diabetic-hypercholesterolaemic group as compared to the non-treated group (16.3+/-1.9% vs. 37.3+/-3.1%; P<0.01). Aside from remarkable hypolipidaemic activity, VULM 1457 improved the overall myocardial ischaemia-reperfusion injury outcomes in the diabetic-hypercholesterolaemic rats by suppressing arrhythmogenesis as well as by reducing myocardial necrosis.     

Cardiovascular responses during stimulation of hindlimb skeletal muscle nerves in anaesthetized rats

1. Cardiovascular responses during static skeletal muscle contraction in anaesthetized rats appear to be contradictory. The present study attempted to explain such variations by stimulating different peripheral nerves supplying the hindlimb skeletal muscles using anaesthetized Sprague-Dawley rats. 2. Muscle contractions were evoked by a 30 s stimulation of the sciatic, tibial, peroneal nerves or the sciatic nerve with transected peroneal branch at threefold the motor threshold, 0.1 msec duration and 40 Hz frequency. 3. Contractions during stimulation of the tibial or the sciatic nerve with severed peroneal branch evoked similar increases in arterial pressure and heart rate. Following stimulation of the tibial nerve, blood pressure, heart rate and muscle tension increased by 23 +/- 3 mmHg, 31 +/- 5 b.p.m. and 789 +/- 34 g, respectively. For the sciatic nerve with transected peroneal branch, increases the respective increases were 27 +/- 5 mmHg, 32 +/- 6 b.p.m. and 802 +/- 43 g. In contrast, peroneal nerve stimulation produced depressor and bradycardic responses of -22 +/- 5 mmHg and -40 +/- 9 b.p.m., respectively. Interestingly, intact sciatic nerve stimulation elicited pressor, depressor or no responses (average being -10 +/- 8 mmHg), along with a consistent increase in heart rate of 24 +/- 7 b.p.m. 4. The results demonstrate that static muscle contraction following stimulation of the tibial or sciatic nerve with transected peroneal branch, elicits consistent increases in blood pressure and heart rate. Furthermore, stimulation of the peroneal nerve elicits a depressor response, while stimulation of the intact sciatic nerve evokes variable cardiovascular responses. Overall, anaesthetized rats can be excellent models to study the variable cardiovascular responses during activation of group III and/or group IV muscle afferents.     

Effects of mosapride citrate on human plasma levels of motilin, gastrin, somatostatin, and secretin

The effect of mosapride citrate (mosapride) on plasma levels of gastrointestinal peptides (motilin, gastrin, somatostatin, and secretin) was studied in five healthy volunteers. After a single oral administration of mosapride (15 mg), the plasma mosapride level (85.0+/-13.7 ng/ml) was highest in the 60-min sample after the administration and then the plasma level fell. Peak plasma motilin levels (18.6+/-1.7 pg/ml) were achieved 60 min after administration of mosapride (p<0.01 vs. placebo), and returned to baseline levels within a further 120 min. Plasma gastrin levels (42.4+/-3.6 pg/ml) increased 60 min after administration of mosapride (p<0.01 vs. placebo). Plasma somatostatin and secretin levels did not change significantly. These results suggest that the pharmacological effects of mosapride on gastrointestinal functions are closely related to changes in motilin-immunoreactive substance levels in human plasma.     

Inhibition of neurogenic vasodilation and plasma extravasation by substance P antagonists, somatostatin and [D-Met2, Pro5]enkephalinamide

The substance P (SP) analogues [D-Pro2, D-Phe7, D-Trp9]SP and [D-Pro2, D-Trp7,9]SP, which have been reported to be SP antagonists, inhibited the vasodilation and plasma extravasation induced by antidromic stimulation of the saphenous nerve or by i.a. infusion of SP. Somatostatin inhibited the vasodilatation and plasma extravasation induced by saphenous nerve stimulation, but had no effect on the vascular responses to i.a. infused SP. The opiate agonist [D-Met2, Pro5]enkephalinamide inhibited the vasodilation evoked by antidromic nerve stimulation in a naloxone reversible manner, but did not change the effect of i.a. infusion of SP. Calcitonin and caerulein had no effect on neurogenic vasodilatation. These results further support the concepts that neurogenic vasodilatation and plasma extravasation are mediated by SP, and that somatostatin and opiates inhibit the release of SP from peripheral sensory nerve endings.     

Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion.

Vasoactive neuropeptides, present in unmyelinated C-fibers, can be released from perivascular sensory axons by antidromic stimulation, to mediate vasodilation and extravasation of plasma protein (neurogenic inflammation). In this report, the effects of antidromic trigeminal stimulation on levels of calcitonin gene-related peptide (CGRP) in plasma were examined in the superior sagittal sinus and the effects of drugs that have been shown previously to block extravasation of neurogenic plasma determined. The levels of immunoreactive CGRP in plasma were measured both before and during electrical stimulation of the trigeminal ganglion (0.1-1.0 mA, 5 msec, 5 Hz, 3-5 min), using a highly specific and sensitive immunochemiluminometric assay. Levels of CGRP increased and became maximal within the first minute of stimulation. The increases were detectable at intensities of current as small as 0.1 mA. Peak levels related to the intensity of the stimulus. Samples from femoral arterial blood did not show concomitant increases at 1 min. Pretreatment with dihydroergotamine (DHE) (50 micrograms/kg i.v.) did not change the baseline levels but decreased levels of CGRP during stimulation (0.3 mA), by 55% at 1 min and 50% at 3 min. Sumatriptan (GR43175) (300 micrograms/kg) attenuated the increase by 57% at 3 min (0.1 mA, 5 msec, 5 Hz) but not after 1 min of stimulation, although decreases were observed at the latter time during an individual experiment. Drug-induced attenuation of levels of CGRP in plasma may reflect inhibition of release, to thereby provide evidence to explain blockade of neurogenic extravasation of plasma.     

Blockade of anaesthetic-induced preconditioning in the hyperglycaemic myocardium: the regulation of different mitogen-activated protein kinases

Preconditioning by volatile anaesthetics is blocked by hyperglycaemia. The regulation of mitogen-activated protein kinases during this effect has yet not been investigated. For infarct size measurements, anaesthetized rats were subjected to 25 min coronary artery occlusion followed by 120 min reperfusion. Control animals were not further treated. One group was preconditioned by two 5-min periods of desflurane inhalation (desflurane preconditioning, Des-preconditioning, 1MAC), each followed by 10-min washout. Four groups received glucose 50% in order to achieve blood glucose concentrations between 22.2 and 33.3 mM/l. Glucose infusion started 40 min before ischaemia (early hyperglycaemia, EH) and stopped with the onset of artery occlusion with (EH+Des-preconditioning) or without (EH) preconditioning. The other two groups received glucose during ischaemia (late hyperglycaemia, LH), again with (LH+Des-preconditioning) or without (LH) preconditioning. Additional hearts were excised for Western blot of mitogen-activated protein kinases. Infarct size was reduced from 51.7+/-9.0% in controls to 28.8+/-11.8% after Des-preconditioning (P<0.01 vs Con). Hyperglycaemia alone did not affect infarct size (EH, 51.5+/-9.0%, LH, 44.3+/-16.9%), but EH as well as LH blocked Des-preconditioning (49.1+/-12.3%, P<0.01, 48.1+/-17.6%, P<0.05 vs Des-preconditioning). All three mitogen-activated protein kinases showed a similar time course pattern of phosphorylation in the Des-preconditioning, EH and EH+Des-preconditioning group. Despite the lack of cardioprotection, mitogen-activated protein kinases are activated in hyperglycaemic myocardium. Therefore, it can be assumed that the hyperglycaemic induced blockade of Des-preconditioning is situated downstream or in parallel of these mitogen-activated protein kinases or involves different signal transduction pathways.     

SYMPATHETIC MODULATION OF SENSORY NERVE ACTIVITY WITH AGE: HUMAN AND RODENT SKIN MODELS

1. Sensory nerves serve an afferent role and mediate neurogenic components of inflammation and tissue repair via an axon reflex release of sensory peptides at sites of injury. Dysfunction of these nerves with age could contribute to delayed tissue healing. 2. Complementary animal and human skin models were used in the present studies to investigate changes in the modulation of sensory nerve function by sympathetic efferents during ageing. Laser Doppler flowmetry was used to monitor neurogenic skin vascular responses. 3. The animal model used skin of the hind footpad of anaesthetized rats combined with electrical stimulation of the sciatic nerve, while the human model comprised capsaicin electrophoresis to the volar surface of the forearm. Sympathetic modulation was effected by systemic phentolamine pretreatment in animals and local application in the human model. 4. The results obtained from the human model confirmed the reported decline in sensory nerve function and showed no change in sympathetic modulation with age. The results from the animal model confirm and expand results obtained from the human model. 5. The use of low (5 Hz) and high (15 Hz) frequency electrical stimulation (20 V, 2 ms for 1 min) revealed a preferential response of aged sensory nerves to low-frequency electrical stimulation parameters with differential sympathetic modulation that is dependent on the frequency o. stimulation.     

Anti-inflammatory effect of synthetic somatostatin analogues in the rat.

1. Somatostatin (6.11 nmol kg(-1) i.p.) inhibited neurogenic plasma extravasation evoked by 1% mustard oil and non-neurogenic oedema induced by 5% dextran in the rat skin. 2. Cyclic synthetic octapeptide (TT-248 and TT-250) and heptapeptide (TT-232) somatostatin analogues proved to be more effective in reducing neurogenic and non-neurogenic inflammatory reactions but octreotide had no influence on either neurogenic or non-neurogenic inflammation. 3. TT-232 administered i.p. or i.v. (1.06 - 42.40 nmol kg(-1)) inhibited in a dose-dependent manner the plasma extravasation evoked by mustard oil in the rat's paw. Neither diclofenac (15.78 - 315.60 micromol kg(-1)) nor the selective COX-2 inhibitor meloxicam (2.95 - 569.38 micromol kg(-1)) attenuated the mustard oil-induced neurogenic plasma extravasation. 4. TT-232, diclofenac and meloxicam dose-dependently diminished non-neurogenic dextran-oedema of the paw the ED(35) values were 1.73 nmol kg(-1) for TT-232 and 34.37 micromol kg(-1) for diclofenac. 5. TT-232 inhibited in the dose range of 1.06 - 21.21 nmol kg(-1) the bradykinin-induced plasma extravasation in the skin of the chronically denervated paw. 6. Mustard oil-induced cutaneous plasma extravasation was dose-dependently diminished by s.c. TT-232 1, 2, 4, 6 or 16 h after the treatment. TT-232 (2 x 106, 2 x 212 and 2 x 530 nmol kg(-1) per day s.c. for 18 days) caused dose-dependent inhibition of chronic Freund adjuvant-induced arthritis during the experimental period. 7. TT-232 (200 and 500 nM) inhibited the release of SP, CGRP and somatostatin from the rat isolated trachea induced by electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) or by capsaicin (10(-7) M), but did not influence the basal, non-stimulated peptide release. 8. It is concluded that somatostatin analogues without endocrine functions as TT-232 are promising compounds with a novel site of action for inhibition of non-neurogenic and neurogenic inflammatory processes.     

Sympathetic stimulation of renin is independent of direct regulation by renal nitric oxide

Nitric oxide (NO) regulates renin secretion through various pathways. The possibility that renal neuronal nitric synthase (nNOS) may mediate beta-adrenergic control of renin was tested. In six Inactin-anesthetized rats, renin secretion rate (RSR) was measured in response to the beta-agonist isoproterenol with and without selective inhibition of nNOS using 7-nitroindazole (7-NI, 50 mg/kg body weight [BW]). 7-NI had no effect on blood pressure (BP) or renal hemodynamics, while isoproterenol increased RSR by 9 ng AngI/h/min (P<.05) similarly with or without 7-NI. Isoproterenol decreased BP by 20 mm Hg (P<.001), but this depressor response was completely blocked by 7-NI. When acute endogenous stimulation of renal sympathetic nerve activity (RSNA) was induced by bilateral carotid occlusion, BP in 12 rats (105+/-5 mm Hg) rose transiently to peak at 121+/-6 mm Hg (P<.005) within 5 min, returning to baseline within 10 min. RSR rose threefold (2.1+/-0.5 to 7.6+/-3.3 ng AngI/ml/min/g kidney weight [KW]; P<.05). Next, 7-NI had no effect on BP (108+/-5 mm Hg), but subsequent carotid occlusion increased and sustained BP by 27+/-5 mm Hg (P<.001), but RSR did not change (2.46+/-0.94 ng AngI/ml/min/g KW). However, if after 7-NI treatment followed by carotid occlusion, the renal perfusion pressure was not allowed to rise, but held constant at 111+/-3 mm Hg, RSR increased from 3.03+/-0.79 to 12.97+/-3.41 ng AngI/ml/min/g KW (P<.025). Thus, neither beta-adrenergic stimulation of RSR with isoproterenol nor direct stimulation of RSR by activation of RSNA with carotid occlusion was modified by selective nNOS inhibition. These data suggest an important nNOS component in the regulation of BP in response to carotid occlusion, but do not support a direct role of renal nNOS mediating sympathetic regulation of RSR.     

The effects of dietary treatment with essential fatty acids on sciatic nerve conduction and activity of the Na+/K+ pump in streptozotocin-diabetic rats.

1. This study examined the effects of dietary essential fatty acid supplementation (5% (w/w) evening primrose oil) upon sciatic motor nerve conduction velocity and 86Rb+ pumping in sciatic nerve endoneurial preparations in rats with 4 to 5 weeks of streptozotocin-induced diabetes. 2. Control diabetic rats (dietary supplementation with 5% (w/w) hydrogenated coconut oil) exhibited a reduction in motor nerve conduction velocity (16%; P less than 0.05) compared to similarly-fed non-diabetic controls, but there was no significant alteration in ouabain-sensitive 86Rb+ pumping, a parameter reflecting activity of the Na+/K+ pump. 3. Treatment of diabetic rats with evening primrose oil prevented completely the development of the motor nerve conduction velocity deficit without affecting the severity of diabetes. Evening primrose oil treatment did not significantly affect motor nerve conduction velocity of non-diabetic animals. 4. Evening primrose oil treatment caused a significant reduction in activity of the Na+/K+ pump in sciatic nerves of diabetic animals (45%; P less than 0.05). 5. These results suggest that the acute conduction velocity defect arising in streptozotocin-diabetic rats, and the actions of evening primrose oil upon this, are independent of any effect on activity of the Na+/K+ pump. Other putative mechanisms are discussed.     

Pharmacological evidence that inducible nitric oxide synthase is a mediator of delayed preconditioning

Brief periods of myocardial ischaemia preceding a subsequent more prolonged ischaemic period 24-72 h later confer protection against myocardial infarction ('delayed preconditioning' or the 'second window' of preconditioning). In the present study, we examined the effects of pharmacological modifiers of inducible nitric oxide synthase (iNOS) induction and activity on delayed protection conferred by ischaemic preconditioning 48 h later in an anaesthetized rabbit model of myocardial infarction. Rabbits underwent a myocardial preconditioning protocol (four 5 min coronary artery occlusions) or were sham-operated. Forty-eight hours later they were subjected to a sustained 30 min coronary occlusion and 120 min reperfusion. Infarct size was determined with triphenyltetrazolium staining. In rabbits receiving no pharmacological intervention, the percentage of myocardium infarcted within the risk zone was 43.9+5.0% in sham-operated animals and this was significantly reduced 48 h after ischaemic preconditioning with four 5 min coronary occlusions to 18.5+5.6% (P<0.01). Administration of the iNOS expression inhibitor dexamethasone (4 mg kg(-1) i.v) 60 min before ischaemic preconditioning completely blocked the infarct-limiting effect of ischaemic preconditioning (infarct size 48.6+/-6.1%). Furthermore, administration of aminoguanidine (300 mg kg(-1), s.c.), a relatively selective inhibitor of iNOS activity, 60 min before sustained ischaemia also abolished the delayed protection afforded by ischaemic preconditioning (infarct size 40.0+/-6.0%). Neither aminoguanidine nor dexamethasone per se had significant effect on myocardial infarct size. Myocardial risk zone volume during coronary ligation, a primary determinant of infarct size in this non-collateralized species, was not significantly different between intervention groups. There were no differences in systolic blood pressure, heart rate, arterial blood pH or rectal temperature between groups throughout the experimental period. These data provide pharmacological evidence that the induction of iNOS, following brief periods of coronary occlusion, is associated with increased myocardial tolerance to infarction 48 h later.     

Intravenous atenolol and esmolol maintain the protective effect of ischemic preconditioning in vivo

Catecholamines bind to alpha- and beta-adrenoreceptors and are capable of preconditioning ischemic myocardium. Our purpose was to investigate the effect of acute either short or prolonged i.v. administration of beta-adrenoreceptor antagonists on ischemic preconditioning in vivo. Fifty-five anesthetized rabbits were divided into 10 groups (n=5-7 per group) and were subjected to 30-min regional ischemia of the heart after ligation of a prominent left coronary artery and 3-h reperfusion after releasing the snare. Ischemic preconditioning was obtained by three cycles of 5-min ischemia separated by 10-min reperfusion. beta-Adrenoreceptor blockade was obtained by the long acting beta-adrenoreceptor antagonist atenolol or by the short acting esmolol, which were given as a short 5-min infusion or as a prolonged 45-min infusion, starting respectively 20 min before and ending 15 min before the beginning of sustained ischemia, or starting 45 min before and ending immediately before the beginning of sustained ischemia. Atenolol was given at a rate of 0.2 mg min(-1) during 5 min or at a rate of 0.088 mg min(-1) as a 45-min infusion. Esmolol was given as an initial dose of 500 microg kg(-1) within 1 min, followed by a 4-min infusion at a rate of 50 microg kg(-1) min(-1) or as an initial dose of 3.4 mg within 1 min, followed by a 44-min infusion at a rate of 0.15 mg min(-1). Blood pressure and heart rate were continuously monitored. The infarcted and risk areas were delineated with the aid of tetrazolium chloride staining and fluorescent Zn-Cd particles. Infarct size was expressed in percent of the area at risk. All the animals without preconditioning developed an infarct size ranging between 36.3+/-2.4% and 49.6+/-7.6% (P=NS) and all the preconditioning groups developed an infarct size ranging between 14.9+/-1.2% and 21.0+/-2.2% (P=NS). All the preconditioning groups, independently of the use of beta-adrenoreceptor antagonists, had a smaller infarct size than the control group, which developed an infarct size of 47.3+/-2.5% (P<0.01). Intravenous atenolol and esmolol, independent of timing and mode of administration, does not seem to interfere with protection afforded by ischemic preconditioning in vivo.     

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

1. 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. 2. 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 micro U kg(-1)) euglycaemic (5.5 mmol kg(-1)) glucose clamp studies were performed to estimate insulin sensitivity. 3. 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. 4. 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. 5. 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 micro g 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. 6. 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. 7. 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.     

ANGIOTENSIN II BLUNTS, WHILE AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AUGMENTS, REFLEX SYMPATHETIC INHIBITION IN HUMANS*

1. The role of angiotensin (Ang)II in and the effects of angiotensin-converting enzyme (ACE) inhibitors on the regulation of sympathetic neural activity were examined in humans. 2. We measured baseline values of muscle sympathetic nerve activity (MSNA) and its reflex inhibition in 28 patients with essential hypertension with elevated plasma renin activity (PRA; > 1.0 ng/mL per h = 0.28 ng/L per s) before and after either acute or chronic oral administration of an ACE inhibitor or placebo and in 20 normotensive subjects before and after infusion of either AngII (5 ng/kg per min = 4.8 pmol/kg per min) or vehicle (5% dextrose). Muscle sympathetic nerve activity was recorded from the tibial nerve and its reflex inhibition was evaluated during pressor responses to bolus injection of phenylephrine (2 micrograms/kg, i.v.). 3. Blood pressure was significantly decreased (P < 0.01) after the acute oral administration of captopril (25 mg), accompanied by a slight increase in MSNA in patients with essential hypertension compared with control patients who received placebo administration. Reflex changes in MSNA were significantly augmented after oral administration of captopril (-4.1 +/- 0.5 vs -6.2 +/- 0.6%/mmHg, respectively; P < 0.01), with a significant reduction of plasma AngII, while they were not affected by placebo administration. 4. In contrast, acute AngII infusion was accompanied by decreases in both PRA and MSNA in normotensive subjects. Reflex changes in MSNA were significantly reduced after AngII infusion (-11.0 +/- 0.8 vs -7.4 +/- 1.0%/mmHg, respectively; P < 0.01) but not after vehicle alone. 5. Chronic ACE inhibition by 12 week oral imidapril administration (5-10 mg/day) significantly (P < 0.05) decreased baseline values of MSNA, which were accompanied by a significant (P < 0.05) increase in the reflex inhibition of MSNA, while plasma concentrations of noradrenaline were unaffected. 6. These results indicate that AngII blunts reflex inhibition of sympathetic neural activity and that inhibition of the renin-angiotensin system by an ACE inhibitor augments reflex regulation of sympathetic neural activity and reduces baseline values in patients with essential hypertension.     

Sensory nitrergic meningeal vasodilatation and non-nitrergic plasma extravasation in anaesthesized rats

The aim of the present study was to evaluate the role of nitric oxide (NO) of sensory neural origin in neurogenic inflammatory response in the trigeminovascular system. Antidromic vasodilatation and plasma extravasation in response to electrical stimulation (15 V, 5 Hz, 0.5 ms, 100 impulses) of the trigeminal ganglion were investigated in the dura mater and nasal mucosa/upper eyelid by laser Doppler flowmetry and [(125)I]-labelled bovine serum albumin, respectively. Electrical stimulation of the trigeminal ganglion of rats elicited a reproducible ipsilateral enhancement of both meningeal and nasal mucosal blood flow. N(omega)-nitro-L-arginine (L-NNA; 4, 8, and 16 mg/kg, i.v.), a nonselective inhibitor of nitric oxide synthase (NOS), inhibited antidromic vasodilatation both in the dura mater (15.86+/-2.05%, 22.82+/-2.51%, and 36.28+/-4.37%) and nasal mucosa (35.46+/-8.57%, 58.72+/-9.2%, and 89.99+/-8.94%) in a dose-dependent manner. Specific inhibitors of neuronal NOS, 7-nitroindazole (7-NI; 20 mg/kg, i.v.) and 3-bromo-7-nitroindazole (3Br-7NI; 10 mg/kg, i.v.) were administered to assess the possible role of NO released from the trigeminal sensory fibres. The meningeal vasodilatation was inhibited by both 3Br-7NI and 7-NI (63.36+/-7.7% and 49+/-6.5%, respectively). The nasal hyperaemic response was also reduced by 3Br-7NI (78.26+/-8.7%). Plasma extravasation in the dura mater and upper eyelid evoked by electrical stimulation of the trigeminal ganglion (25 V, 5 Hz, 0,5 ms, 5 min), expressed as extravasation ratios (ERs) of the stimulated vs. nonstimulated sides, was 1.80+/-0.8 and 4.63+/-1.24, respectively. This neurogenic oedema formation was not inhibited by neither L-NNA nor 3Br-7NI. It is concluded that neural nitrergic mechanisms are involved in the meningeal vasodilatation evoked by electrical stimulation of the trigeminal ganglion.     

Atenolol improves ventricular function without changing plasma noradrenaline but decreasing plasma atrial natriuretic factor in chronic heart failure

1 There is good evidence that beta-blockers improve ventricular function, disease progression and survival in patients with left ventricular systolic dysfunction. The aim of this study was to determine the effects of atenolol therapy on the sympathetic nervous system at rest and after ergometric exercise, on left ventricular function and on baseline plasma atrial natriuretic factor (ANF) in ambulatory patients with chronic heart failure (CHF). 2 Twenty-two patients [left ventricular ejection fraction (LVEF) <36%; New York Heart Association II-III] were studied before atenolol treatment. Because of cardiac events (new Hospital admission or death) only 13 patients completed 1 year of treatment. Baseline noradrenaline (NE) concentrations were similar in patients and controls while ANF was higher in patients than in controls (328 +/- 35 pg ml(-1) vs. 37 +/- 3 pg ml(-1); P<0.01). 3 Patients with events showed higher NE (540 +/- 87 pg ml(-1) vs. 303 +/- 44 pg ml(-1); P<0.01) and ANF (460 +/- 70 pg ml(-1) vs. 291 +/- 44 pg ml(-1); P<0.03) at rest; and greater NE response to exercise (2.003 +/- 525 pg ml(-1) vs. 694 +/- 121 pg ml(-1); P<0.005). Atenolol treatment improved LVEF (19.5 +/- 1.9% vs. 33 +/- 3.9%; P<0.001), increased exercise tolerance (9 +/- 3.2 min vs. 17 +/- 4.8 min; P<0.001) and decreased plasma ANF (292 +/- 42 pg ml(-1) vs. 133 +/- 35 pg ml(-1); P<0.01). 4 Reduced basal dihydroxyphenylglycol (DHPG)/NE ratio (3.4 +/- 0.46 vs. 4.3 +/- 0.35; P<0.01) was observed in patients compared with healthy volunteers. Atenolol increased DHPG plasma levels (1.398 +/- 129 pg ml(-1) vs. 913 +/- 86 pg ml(-1); P<0.005) but the DHPG/NE ratio during exercise was not modified after treatment, suggesting that re-uptake of released NE is not changed by beta-blocker treatment. 5 In conclusion, the fact that atenolol treatment improves ventricular dysfunction and clinical status without changing plasma NE levels in CHF patients, suggests that plasma NE is a poor surrogate measurement for cardiac sympathetic activity in this pathology. In addition, decrease in plasma ANF produced by atenolol treatment may reflect the improvement of ventricular function.     

Evidence against a role of inducible nitric oxide synthase in the endothelial protective effects of delayed preconditioning

Preconditioning the heart with brief periods of ischaemia induces delayed endothelial protection against reperfusion injury, but the precise mechanisms involved in this endogenous protein are still unclear. Induction of the type II-nitric oxide synthase (iNOS) acts as a mediator of the preconditioning against myocardial infarction and stunning. The present study was designed to assess whether iNOS also contributes to the delayed endothelial protective effects of preconditioning. Rats were subjected to 20 min ischaemia followed by 60 min reperfusion 24 h after sham surgery or preconditioning (one cycle or 2 min ischaemia/5 min reperfusion and two cycles of 5 min ischaemia/5 min reperfusion). At the end of the reperfusion, coronary segments were removed distal to the site of occlusion and mounted in wire myographs. Ischaemia-reperfusion (I/R) decreased the endothelium-dependent relaxations to acetylcholine (maximal relaxations: sham, 66+/-5%; I/R, 40+/-1%; P<0.05) and this impairment was prevented by preconditioning (maximal relaxation: 61+/-6%). Administration of N-(3-aminomethyl)benzyl)acetaminide (1400W), a highly selective inhibitor for iNOS, 10 min before prolonged ischaemia did not modify the beneficial effect of preconditioning (maximal relaxation: 66+/-5%). These data show that preconditioning induces delayed protection against reperfusion-injury. However, in contrast to the myocytes, these endothelial protective effects of delayed preconditioning do not involve iNOS.