Analysis of the Zucker Diabetic Fatty (ZDF) type 2 diabetic rat model suggests a neurotrophic role for insulin/IGF-I in diabetic autonomic neuropathy.
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Dysfunction of the autonomic nervous system is a recognized complication of diabetes. Neuroaxonal dystrophy (NAD), a distinctive axonopathy involving distal axons and synapses, represents the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in human and several insulinopenic experimental rodent models. Recent studies have suggested that loss of the neurotrophic effects of insulin and/or IGF-I on sympathetic neurons and not hyperglycemia per se, may underlie the development of sympathetic NAD. The streptozotocin (STZ)-diabetic and BB/W rat, the most commonly used experimental rodent models, develop marked hyperglycemia and concomitant deficiency in both circulating insulin and IGF-I. These animals reproducibly develop NAD in nerve terminals in the prevertebral sympathetic ganglia and the distal portions of noradrenergic ileal mesenteric nerves. The Zucker Diabetic Fatty (ZDF) rat, an animal model of type 2 diabetes, also develops severe hyperglycemia comparable to that in the STZ- and BB/W-diabetic rat models, although in the presence of hyperinsulinemia. In our study, ZDF rats maintained for 6 to 7 months in a severely diabetic state, as assessed by plasma glucose and glycated hemoglobin levels, maintained significant hyperinsulinemia and normal levels of plasma IGF-I at sacrifice. NAD did not develop in diabetic ZDF rat sympathetic ganglia and ileal mesenteric nerves as assessed by quantitative ultrastructural techniques, which is in dramatic contrast to neuropathologic findings in comparably hyperglycemic 6-month STZ-diabetic insulinopenic rats. These data combined with our previous results argue very strongly that hyperglycemia is not the critical and sufficient element in the pathogenesis of diabetes-induced NAD, rather that it is the loss of trophic support, most likely of IGF-I or insulin, that causes NAD. (+info)
Central endogenous histamine modulates sympathetic outflow through H3 receptors in the conscious rabbit.
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1. This study examined the role of histamine H(3) receptors in vagal and sympathetic autonomic reflexes in the conscious rabbit, and in rabbit and guinea-pig isolated right atria. 2. The baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch-like and nasopharyngeal reflexes were assessed after these treatments (i.v.; with H(1) and H(2) receptor block): (i) vehicle (saline; n=11); (ii) H(3) receptor agonist, (R)-alpha-methylhistamine (R-alpha-MH) 100 micro g kg(-1)+100 micro g kg(-1) h(-1) (n=9); (iii) H(3) receptor antagonist, thioperamide 1 mg kg(-1)+1 mg kg(-1) h(-1) (n=11); (iv) R-alpha-MH and thioperamide (n=6); and (v) H(2) and H(3) antagonist, burimamide 6.3 mg kg(-1)+6.3 mg kg(-1) h(-1) (n=4). 3. R-alpha-MH caused a thioperamide-sensitive fall in mean arterial pressure (MAP) of 8+/-1 mmHg and tachycardia of 18+/-2 bpm (P<0.0005). Burimamide was without effect, however thioperamide elicited an increase in MAP of 4+/-1 mmHg (P<0.01), but no change in heart rate (HR). 4. R-alpha-MH caused a 44% decrease in the average gain of the baroreflex (P=0.0001); this effect was antagonised by thioperamide. Thioperamide caused a parallel rightward shift in the barocurve with an increase in MAP of 5 mmHg (P<0.05). Burimamide had no effect on the baroreflex. The vagally mediated bradycardia elicited by the Bezold-Jarisch and nasopharyngeal reflexes was unaffected by H(3) receptor ligand administration. 5. R-alpha-MH (+info)
Roles of alpha-adrenoceptors and sympathetic nerve in acute herpetic pain induced by herpes simplex virus inoculation in mice.
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Percutaneous inoculation with herpes simplex virus type-1 brings about herpes zoster-like skin lesions, tactile allodynia, and mechanical hyperalgesia in mice. This study was conducted to determine whether the sympathetic nervous system and alpha-adrenoceptors would be involved in these pain-related responses and whether the alpha(2)-adrenoceptor agonist clonidine would suppress these responses. The adrenergic neuron blocker guanethidine and the non-selective alpha-adrenoceptor antagonist phentolamine did not affect the pain-related responses, although these agents suppressed the pain-related responses induced by partial ligation of the sciatic nerve. The pain-related responses induced by herpetic inoculation was suppressed by intraperitoneal and intrathecal injections, but not by intraplantar and intracerebroventricular injections, of clonidine. The suppressive effect of an intraperitoneal injection of clonidine (0.1 mg/kg) was antagonized by intrathecal injections of phentolamine and the alpha(2)-adrenoceptor antagonist yohimbine, but not the alpha(1)-adrenoceptor antagonist prazosin. The results suggest that sympathetic nerves and alpha-adrenoceptors are not involved in the pain-related responses induced by herpetic infection. Clonidine suppresses the responses probably through the action on alpha(2)-adrenoceptors in the dorsal horn. (+info)
The preferential inhibitory effect of olmesartan, a new angiotensin II type 1 antagonist, on sympathetic nerve terminals in isolated canine splenic artery.
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Effects of olmesartan (RNH-6270: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1-methylethyl)-2-propyl[4- [2-(tetrazol-5-yl)-phenyl]phenyl]methylimidazol-5-carboxylase, an active form of olmesartan medoxomil (CS-866)) was investigated in isolated, perfused canine splenic arterial preparations. Neither exogenous noradrenaline- nor ATP-induced vasoconstrictor responses were modified by treatment with the used concentrations of olmesartan (1-100 nM). A high concentration of 10 nM angiotensin II caused a potentiation of either noradrenaline- and ATP-induced constrictions, although 1 nM angiotensin II did not induce any potentiating effects for these responses. These potentiations were inhibited by olmesartan in a concentration-related manner. Periarterial nerve electrical stimulation (PNS) readily induced a biphasic constriction consisting of an initial P2X purinoceptor-mediated vasoconstriction followed by a prolonged mainly alpha(1)-adrenoceptor-mediated response. PNS-induced 1st and 2nd peaked responses were significantly inhibited by olmesartan in a concentration-related manner. With a low concentration of 1 nM angiotensin II, which did not induce any vascular effects by itself, PNS-induced responses were markedly enhanced. The enhanced responses were inhibited by olmesartan. It is concluded that endogenous angiotensin II exerts its stimulating action on the releases of ATP and noradrenaline from the periarterial sympathetic nerve terminal, and olmesartan has an inhibitory property on angiotensin II-induced potentiation of endogenous ATP- and noradrenaline-induced responses. (+info)
Thoracic epidural anesthesia attenuates hemorrhage-induced impairment of intestinal perfusion in rats.
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BACKGROUND: During hemorrhagic hypotension, sympathetic vasoconstriction crucially contributes to gut mucosal damage. Sympathetic blockade by thoracic epidural anesthesia has been shown to increase mucosal microvascular perfusion and to improve survival after severe hemorrhage in laboratory animals. This study investigates the effects of thoracic epidural anesthesia on intestinal microvascular perfusion during hemorrhagic hypotension in rats. METHODS: In 32 anesthetized Sprague-Dawley rats either lidocaine 2% (thoracic epidural anesthesia) or normal saline (control) was infused via thoracic epidural catheters. Hemorrhagic hypotension (mean arterial pressure 30 mmHg for 60 min) was induced by withdrawal of blood, which was subsequently retransfused for resuscitation. Functional capillary density and erythrocyte velocity in the mucosa and muscularis were determined by intravital microscopy. Leukocyte-endothelium interaction was studied in postcapillary venules and sympathetic nerve fibers of the intestinal wall were identified by immunohistochemistry. RESULTS: During hypotension functional capillary density was significantly (P < 0.001) lower in the muscularis of the control group (median [25/75 percentile]: -46.5% [-59.6/-20.8%] change from baseline) as compared with animals that received thoracic epidural anesthesia (-6.1% [-13.4/1.1%]). There were no differences in erythrocyte velocity between groups throughout the experiment. Leukocyte rolling increased significantly (P < 0.001) after resuscitation in control (12 [6/15] vs. baseline 2.5 [1/8]) but not in thoracic epidural anesthesia (4 [2.3/7] vs. baseline: 5 [3/15.5]). Sympathetic nerve fibers were identified in the muscularis and submucosa but not in the mucosa. CONCLUSIONS: During hemorrhagic hypotension and after resuscitation, thoracic epidural anesthesia has beneficial effects on intestinal microvascular perfusion. Because of blockade of sympathetic nerves, thoracic epidural anesthesia prevents perfusion impairment of the muscularis during hypotension and attenuates leukocyte rolling after resuscitation. (+info)
Velocity recovery cycles of C fibres innervating human skin.
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Velocity changes following single and double conditioning impulses were studied by microneurography in single human C fibres to provide information about axonal membrane properties. C units were identified as mechano-responsive (n = 19) or mechano-insensitive (12) nociceptors, cold-sensitive (8) or sympathetic fibres (9), and excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25-2 Hz. The interval between single or paired (20 ms apart) conditioning stimuli and test stimulus was then varied between 500 and 2 ms, and recovery curves of velocity change against inter-spike interval constructed, allowing for changes in these variables with distance. All fibres exhibited an initial (4-24 ms) relative refractory phase, and a long-lasting (>500 ms) 'H2' phase of reduced velocity, attributed to activation of Na+/K+-ATPase. Mechano-responsive nociceptors exhibited an intermediate phase of either supernormality or subnormality, depending on stimulation rate. Mechano-insensitive nociceptors behaved similarly, but all were supernormal at 1 Hz. Sympathetic units exhibited only a long-lasting supernormality, while cold fibres exhibited a briefer supernormal and a late subnormal phase (H1), similar to A fibres. A pre-conditioning impulse doubled H2 and increased H1, but did not augment supernormality or the subnormality of similar time course. Like A fibre supernormality, these phenomena were explained by a passive cable model, so that they provide an estimate of membrane time constant. Nociceptor membrane time constants (median 110 ms, n = 17) were rather insensitive to membrane potential, indicating few active voltage-dependent potassium channels, whereas sympathetic time constants were longer and reduced by activity-dependent hyperpolarisation. (+info)
NANC inhibitory neurotransmission in mouse isolated stomach: involvement of nitric oxide, ATP and vasoactive intestinal polypeptide.
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1. The neurotransmitters involved in NANC relaxation and their possible interactions were investigated in mouse isolated stomach, recording the motor responses as changes of endoluminal pressure from whole organ. 2. Field stimulation produced tetrodotoxin-sensitive, frequency-dependent, biphasic responses: rapid transient relaxation followed by a delayed inhibitory component. 3. The inhibitor of the synthesis of nitric oxide (NO), l-NAME, abolished the rapid relaxation and significantly reduced the slow relaxation. Apamin, blocker of Ca2+-dependent K+ channels, or ADPbetaS, which desensitises P2y purinoceptors, reduced the slow relaxation to 2-8 Hz, without affecting that to 16-32 Hz or the fast relaxation. alpha-Chymotrypsin or vasoactive intestinal polypeptide 6-28 (VIP6-28), antagonist of VIP receptors, failed to affect the fast component or the delayed relaxation to 2-4 Hz, but antagonised the slow component to 8-32 Hz. 4. Relaxation to sodium nitroprusside was not affected by l-NAME, apamin or ADPbetaS, but was reduced by alpha-chymotrypsin or VIP6-28. Relaxation to VIP was abolished by alpha-chymotrypsin, antagonised by VIP6-28, but was not affected by l-NAME, apamin or ADPbetaS. Relaxation to ATP was abolished by apamin, antagonised by ADPbetaS, but was not affected by l-NAME or alpha-chymotrypsin. 5. The present results suggest that NO is responsible for the rapid relaxation and partly for the slow relaxation. ATP is involved in the slow relaxation evoked by low frequencies of stimulation. VIP is responsible for the slow relaxation evoked by high frequencies of stimulation. The different neurotransmitters appear to work in parallel, although NO could serve also as a neuromodulator that facilitates release of VIP. (+info)
Role of nitric oxide in non-adrenergic, non-cholinergic inhibitory junction potentials in canine ileocolonic sphincter.
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1. Electrical field stimulation causes neurally-mediated relaxation of the ileocolonic sphincter that is due to activation of non-adrenergic and non-cholinergic (NANC) nerves. Recent studies have suggested that nitric oxide (NO) is the neurotransmitter that mediates relaxation. 2. Using intracellular recording techniques, we have tested whether NANC inhibitory junction potentials (i.j.ps) in the canine ileocolonic sphincter are also mediated by NO. 3. Electrical field stimulation elicited excitatory and inhibitory junction potentials: e.j.ps were blocked by atropine (10(-6) M) and tetrodotoxin (TTX; 10(-6) M); i.j.ps were also blocked by TTX and partially blocked by apamin (10(-6) M). I.j.ps were unaffected by atropine, phentolamine and propranolol (all at 10(-6) M). 4. The arginine analogues, L-NG-nitroarginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), decreased the amplitude of i.j.ps and L-arginine, but not D-arginine, partially restored the i.j.ps. 5. I.j.ps were also inhibited by oxyhaemoglobin (1%), but not by methaemoglobin. 6. Exogenous NO (10(-7) M to 3 x 10(-5) M) caused concentration-dependent hyperpolarizations that were similar in amplitude to the NANC nerve-evoked i.j.ps. Hyperpolarizations to NO were unaffected by L-NAME, but were blocked by oxyhaemoglobin. 7. Tetrodotoxin, L-NAME and oxyhaemoglobin all caused depolarization of resting membrane potential. 8. The specific guanosine 3':5'-cyclic monophosphate phosphodiesterase inhibitor, M&B 22948, caused hyperpolarization, increased the maximum level of hyperpolarization reached during i.j.ps, and increased the duration of i.j.ps. 9. These data further support the hypothesis that NANC neurotransmission in the ileocolonic sphincter is mediated by NO or an NO-releasing compound. The data also suggest that tonic release of NO, possibly from spontaneous firing of NANC nerves, may regulate resting membrane potential and tone in this sphincter. (+info)