Development of muscarinic analgesics derived from epibatidine: role of the M4 receptor subtype.
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Epibatidine, a neurotoxin isolated from the skin of Epipedobates tricolor, is an efficacious antinociceptive agent with a potency 200 times that of morphine. The toxicity of epibatidine, because of its nonspecificity for both peripheral and central nicotinic receptors, precludes its development as an analgesic. During the synthesis of epibatidine analogs we developed potent antinociceptive agents, typified by CMI-936 and CMI-1145, whose antinociception, unlike that of epibatidine, is mediated via muscarinic receptors. Subsequently, we used specific muscarinic toxins and antagonists to delineate the muscarinic receptor subtype involved in the antinociception evoked by these agents. Thus, the antinociception produced by CMI-936 and CMI-1145 is inhibited substantially by 1) intrathecal injection of the specific muscarinic M4 toxin, muscarinic toxin-3; 2) intrathecally administered pertussis toxin, which inhibits the G proteins coupled to M2 and M4 receptors; and 3) s.c. injection of the M2/M4 muscarinic antagonist himbacine. These results demonstrate that the antinociception elicited by these epibatidine analogs is mediated via muscarinic M4 receptors located in the spinal cord. Compounds that specifically target the M4 receptor therefore may be of substantial value as alternative analgesics to the opiates. (+info)
Salt-sensitivity classification in normotensive adults.
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The objectives of this study were to assess the reliability, sensitivity and specificity of salt-sensitivity classification in normotensive adults and to determine the predictive power of four clinical indices for salt-sensitivity. A total of 66 healthy, normotensive, free-living adults were administered 11-day salt-sensitivity diagnostic dietary salt challenges on two occasions to permit assessment of classification test-retest reliability. An oral glucose tolerance test, an acute saline loading test, gustatory testing and determination of salivary flow and sodium concentration were carried out to assess (by correlation analysis) their predictive power for salt-sensitivity. Following these procedures, 21 participants followed a reduced-sodium diet for 4 months, during which blood pressure was monitored monthly to allow evaluation of salt-sensitivity classification sensitivity and specificity. Regression was used to develop a predictive model for salt-sensitivity. Salt-sensitivity classification was not highly reliable (kappa-value=0.38), sensitive (0.73) or specific (0.60). No single index was highly predictive of classification status, but a model composed of five indices accounted for 92% of the variance in blood pressure response to acute salt challenge. The dietary salt challenge procedure used here for salt-sensitivity classification of normotensive adults had low test-retest reliability. While a battery of easily measured attributes may facilitate rapid salt-sensitivity classification, such a diagnosis provides only limited insight regarding blood pressure responsiveness to chronic dietary salt restriction in normotensive adults. (+info)
Pilocarpine hydrochloride relieves xerostomia in chronic graft-versus-host disease: a sialometrical study.
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Bone marrow transplantation is considered to be the treatment of choice for various hematological and solid malignancies, as well as for bone marrow failure syndromes and some genetic diseases. Unfortunately, a great number of patients who receive allogeneic BMT suffer from graft-versus-host disease (GVHD) following the procedure. Xerostomia is considered to be one of the most annoying complications of chronic GVHD (cGVHD), and the rapidly growing number of BMT patients with prolonged survival renders GVHD-related xerostomia a major clinical problem. As pilocarpine hydrochloride has been shown to relieve xerostomia in other disease categories, we administered pilocarpine hydrochloride 30 mg/day to six cGVHD patients and measured their whole saliva, parotid and submandibular-sublingual flow rates in both resting and stimulated conditions. Mean values of flow rates of whole saliva in resting conditions at 2 weeks, 2 months and 6 months following administration of pilocarpine hydrochloride 30 mg/day were 0.71 +/- 0.12 ml/min, 0.59 +/- 0.07 ml/min and 0.56 +/- 0.11 ml/min, respectively. In stimulated conditions, mean values were 1.7 +/- 0.3 ml/min, 1.0 +/- 0.17 ml/min and 0.94 +/- 0.21 ml/min, respectively. The mean values of whole saliva flow rates under both conditions represented an increase of 224-284% and 134-247%, respectively (P < 0.01). The pattern and magnitude of parotid and submandibular-sublingual flow rate increases following pilocarpine hydrochloride administration were similar. Patients were followed for 6 months and demonstrated increased levels of secretion, with some reduction after the initial peak values. The medication was discontinued at 2 months and reinstated after 2 weeks in three patients. This resulted in rapid flow rate reduction followed by another profound increase. Contrary to the sialometrical analysis, the subjective scoring showed no fluctuations during the study period. We discuss these results in the context of the clinical experience of xerostomic patients in whom even a minute increase in secretion may be significant. Our results demonstrate that objective and subjective relief from xerostomia in cGVHD patients can be achieved with the routine oral administration of pilocarpine hydrochloride. (+info)
Sicca symptoms, saliva and tear production, and disease variables in 636 patients with rheumatoid arthritis.
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OBJECTIVES: (1) To estimate the prevalence of ocular and oral sicca symptoms (SISY) or reduced saliva and tear production; (2) to relate SISY and sicca signs to measures of disease activity, damage, and health status; and (3) to examine the relation between symptoms and objective signs of tear and saliva production in a large sample of representative patients with rheumatoid arthritis (RA). METHODS: From an unselective county RA register 636 patients (age 20-70 years) were examined with Schirmer-I test (ST), unstimulated whole saliva (UWS), questions on SISY and measures of disease activity, damage and health status. RESULTS: Ocular sicca symptoms were reported in 38%, oral sicca symptoms in 50%, and a combination of both in 27%. Reduced tear production was present in 29%, and reduced saliva production in 17%. The minimum frequency of secondary Sjogren's syndrome was 7%. Measurements of exocrine disease manifestations were to variable extents bivariately correlated to disease activity measures, physical disability, pain, fatigue, and use of xerogenic drugs, but were not related to deformed joint count. Multivariate analyses revealed significant associations between disease activity and reduced saliva production. Only weak associations between SISY and tear or saliva production were observed. CONCLUSION: SISY, reduced tear and saliva production were frequent extra-articular manifestations in RA, but were only weakly intercorrelated. High disease activity and at least two SISY were independent predictors of reduced saliva production, but ocular and oral dryness did not seem to be closely related to disease duration, disease activity, damage or health status. (+info)
Heat acclimation and hypohydration: involvement of central angiotensin II receptors in thermoregulation.
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This investigation attempted to confirm the involvement of central ANG II-ergic signals in thermoregulation. Experiments were conducted on rats undergoing short (STHA)- and long (LTHA)-term heat acclimation, with and without superimposed hypohydration. Vasodilatation (VTsh) and salivation (STsh) temperature thresholds, tail blood flow, and heat endurance were measured in conscious rats during heat stress (40 degrees C) before and after losartan (Los), an ANG II AT(1)-selective receptor antagonist, administration either to the lateral ventricle or intravenously. Heat acclimation alone resulted in decreased VTsh. STsh decreased during STHA and resumed the preacclimation value, together with markedly increased heat endurance on LTHA. Hypohydration did not affect this biphasic response, although STsh was elevated in all groups. The enhanced heat endurance attained by LTHA was blunted. Neither Los treatment affected the nonacclimated rats. In the heat-acclimated, euhydrated rats, intracerebroventricular Los resulted in decreased VTsh, whereas intravenous Los resulted in elevated STsh. Both intracerebroventricular and intravenous Los led to markedly enhanced heat endurance of the LTHA hypohydrated rats. It is concluded that the LTHA group showed a loss of the benefits acquired by acclimation on hypohydration, whereas the STHA rats, which show an accelerated autonomic excitability in that phase, gained some benefit. It is suggested that ANG II modulates thermoregulation in conditions of chronic adjustments. Central ANG II signals may lead to VTsh upshift, whereas circumventricular structures, activated via circulating ANG II, decrease STsh. On hypohydration these responses seem to be desensitized. (+info)
The effect of potassium chloride infusion of parotid salivary flow and composition in conscious sheep.
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The composition and flow of parotid saliva in conscious sheep was measured before, during and after the intravenous infusion of 0-43 M-KCl or 0-43 M-NaCl at 2 ml./min for 2 hr. The salivary flow rate was depressed during the infusion of potassium chloride into both intact sheep and adrenalectomized sheep. As the salivary flow was unchanged by sodium chloride infusion it was concluded that the potassium ion was responsible for the decrease in flow and that this effect was not mediated through any of the adrenal hormones. The highly significant negative correlation between plasma potassium concentration and salivary flow throughout all potassium infusions indicated that the extent to which the salivary flow was depressed varied with the degree of hyperkalaemia. Except for situations where mineralocorticoid levels were likely to be elevated the concentrations of sodium and potassium in the saliva were positively correlated with the plasma concentrations of these ions. The salivary bicarbonate concentration of the saliva was negatively related to flow. The chloride concentration of the saliva was negatively correlated with salivary flow during all potassium chloride infusions. (+info)
Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice.
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Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions of the central and peripheral nervous system. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of the individual muscarinic receptor subtypes remain to be elucidated. Interestingly, the M(4) receptor subtype is expressed abundantly in the striatum and various other forebrain regions. To study its potential role in the regulation of locomotor activity and other central functions, we used gene-targeting technology to create mice that lack functional M(4) receptors. Pharmacologic analysis of M(4) receptor-deficient mice indicated that M(4) receptors are not required for muscarinic receptor-mediated analgesia, tremor, hypothermia, and salivation. Strikingly, M(4) receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses (as compared with their wild-type littermates) after activation of D1 dopamine receptors. These results indicate that M(4) receptors exert inhibitory control on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels. Our findings offer new perspectives for the treatment of Parkinson's disease and other movement disorders that are characterized by an imbalance between muscarinic cholinergic and dopaminergic neurotransmission. (+info)
Effects of reducing submandibular blood flow on secretory responses to parasympathetic stimulation in anaesthetized cats.
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Submandibular secretory responses to stimulation of the parasympathetic chorda-lingual nerve were investigated in five anaesthetized cats before, during and after withdrawal of blood (ca 20 ml kg-1) in order to investigate the consequences of a reduced blood flow through the gland. Stimulation at different frequencies (2, 4, 6 and 8 Hz) evoked a frequency-dependent increase in the flow of submandibular saliva, sodium concentration, electrolyte and protein output. When the blood pressure was reduced (by about 50%) there was a significant reduction in submandibular blood flow and the secretion of both saliva and protein during stimulation. Under each set of conditions the flow of saliva was linearly related to the blood flow through the gland. It is concluded that submandibular secretory responses to electrical stimulation of the parasympathetic innervation can be significantly attenuated when the blood flow through the gland is reduced under the conditions employed in this study. (+info)