Response of the cat''s pad eccrine sweat glands to intravascular injections of catecholamines

1. Using a sensitive method for detecting and monitoring sweat secretion, a study has been made of the effects of adrenaline and noradrenaline on the cat's pad sweat gland activity in the anaesthetized cat.2. Intravenous or intra-arterial injections of adrenaline or noradrenaline only very occasionally caused these glands to secrete.3. The predominant effect of these drugs on glands which are already secreting in response to plantar nerve stimulation is inhibitory.4. The catecholamine inhibition could be reduced or blocked by phentolamine, but not by propranolol, dibenamine or phenoxybenzamine.5. It is concluded that these glands can be directly activated by intravascular injections of adrenaline or noradrenaline, but that the inhibitory effect of concomitant vasoconstriction usually prevents a response being detected at the skin surface.     

Pharmacologic responsiveness of isolated single eccrine sweat glands

Pharmacologic responsiveness of the eccrine sweat gland has never been studied under well-defined in vitro experimental conditions. Using isolated cannulated single monkey palm eccrine sweat glands, the dose response to both cholinergic and alpha- and beta-adrenergic agents and the effects of various antagonists on agonists were studied. The maximal sweat rate was highest after stimulation with cholinergic agonists, was lower with the beta-adrenergic agonist, and was least with the alpha-adrenergic agonist. Each secretory response was inhibited by its specific antagonist. Attempts to demonstrate the spare receptor, if any, by means of preincubation of the glands with N-(2-chlorethyl)dibenzylamine (Dibenamine) were unsuccessful. From the hyperbolic dose-response curves the values for KA and KB, dissociation constants for agonists and antagonists, respectively, were thus tentatively estimated according to Clark's classical receptor theory. Schild plots for each agonist-antagonist interaction produced straight lines with slopes of near unity, indicating the adequacy of the methodology. It was concluded that the isolated eccrine sweat glands retain their pharmacologic viability in vitro and show responsiveness to cholinergic as well as both alpha- and beta-adrenergic stimulations.     

Electron microscopic study on the innervation of the human axillary sweat glands

The innervation of human axillary sweat glands was studied at electron microscopic level. Nerve endings with many small agranular vesicles and few large dense-cored vesicles were found outside the basement membrane of the secretory coils. These nerve endings can be classified as cholinergic. This result confirms the previous knowledge that axillary sweat glands are innervated by sympathetic cholinergic nerves.     

Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo.

With the advent of numerous candidate drugs for therapy in cystic fibrosis (CF), there is an urgent need for easily interpretable assays for testing their therapeutic value. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) abolished beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-adrenergic response of the sweat gland may serve both as an in vivo diagnostic tool for CF and as a quantitative assay for testing the efficacy of new drugs designed to restore CFTR function in CF. Hence, with the objective of defining optimal conditions for stimulating beta-adrenergic sweating, we have investigated the components and pharmacology of sweat secretion using cell cultures and intact sweat glands. We studied the electrical responses and ionic mechanisms involved in beta-adrenergic and cholinergic sweating. We also tested the efficacy of different beta-adrenergic agonists. Our results indicated that in normal subjects the cholinergic secretory response is mediated by activation of Ca(2+)-dependent Cl(-) conductance as well as K(+) conductances. In contrast, the beta-adrenergic secretory response is mediated exclusively by activation of a cAMP-dependent CFTR Cl(-) conductance without a concurrent activation of a K(+) conductance. Thus, the electrochemical driving forces generated by beta-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller beta-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the beta-adrenergic agonists, isoproprenaline and salbutamol, induced sweat secretion only when applied in combination with an adenylyl cyclase activator (forskolin) or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, aminophylline or theophylline). We surmise that to obtain consistent beta-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a beta-adrenergic agonist alone are essential. beta-Adrenergic secretion can be stimulated in vivo by concurrent iontophoresis of these drugs in normal, but not in CF, subjects.     

Renin-like (Angiotensinogenase) activity in human eccrine sweat

The presence of renin or renin-like activity (RLA) was demonstrated in human eccrine sweat incubated with purified sheep angiotensinogen, using rat bioassay and angiotensin I radioimmunoassay. Following cholinergic stimulation, sweat RLA was found to range between 0 (unmeasurable) and 266 ng/ml·h, i.e. RLA-values of sweat can be about 10 times higher than those of plasma. Therefore, renin synthesis in sweat glands could be assumed. RLA following activation of -adrenergic receptors by the administration of isoprenaline (Aludrin^®) did not exceed the mean values obtained by cholinergic activation. After \-adrenergic receptor blockade by propranolol (Dociton^®), RLA became unmeasurably low. Higher RLA-values were found after local injection of dibutyryl-c-AMP (90–210 ng/ml·h). The results indicate a \-adrenergic regulation of RLA-release in human sweat glands. Human sweat glands appear to be useful for studying extrarenal renin release.This work was supported by the Deutsche Forschungsgemeinschaft (Da 93/7)     

Sweat gland innervation is pioneered by sympathetic neurons expressing a cholinergic/noradrenergic co-phenotype in the mouse

Classic neurotransmitter phenotypes are generally predetermined and develop as a consequence of target-independent lineage decisions. A unique mode of target-dependent phenotype instruction is the acquisition of the cholinergic phenotype in the peripheral sympathetic nervous system. A body of work suggests that the sweat gland plays an important role to determine the cholinergic phenotype at this target site. A key issue is whether neurons destined to innervate the sweat glands express cholinergic markers before or only after their terminals make target contact. We employed cholinergic-specific over-expression of the vesicular acetylcholine transporter (VAChT) in transgenic mice to overcome sensitivity limits in the detection of initial cholinergic sweat gland innervation. We found that VAChT immunoreactive nerve terminals were present around the sweat gland anlage already from the earliest postnatal stages on, coincident selectively at this sympathetic target with tyrosine hydroxylase-positive fibers. Our results provide a new mechanistic model for sympathetic neuron-target interaction during development, with initial selection by the target of pioneering nerve terminals expressing a cholinergic phenotype, and subsequent stabilization of this phenotype during development.     

Influence of prostaglandins and a prostaglandin H synthase inhibitor on cervical secretion of the guinea-pig.

The modulatory effects of several prostaglandins and a prostaglandin H synthase inhibitor (indomethacin) on basal as well as nerve stimulation induced secretion from the cervical glands of the guinea-pig were studied. Hypogastric nerve stimulation resulted in a secretory response of +113%. Indomethacin dose dependently inhibited this secretory response. Prostaglandins E2, F2 alpha and I2 inhibited and 19-OH prostaglandin E1 reduced nerve stimulation induced secretion. Prostaglandin I2 and 19-OH PGE1 markedly enhanced basal secretion, while indomethacin as well as PGE2 and PGF2 alpha did not induce any secretion of cervical glands. However, PGF2 alpha in combination with the alpha-adrenergic blocker phentolamine resulted in an increase in secretion. The inhibitory effect of prostaglandins on cholinergic secretory innervation might be due to stimulation of adrenergic nerves exerting an inhibitory influence on cholinergic secretomotor innervation. It is suggested that PGI2 and 19-OH PGE1 exert postjunctional stimulatory effects on the secretory lining and that a lack of secretory effect of PGF2 alpha at least in part may be due to stimulatory effects on adrenergic neurons, inhibiting cholinergic secretomotor transmission. Thus, in this in vitro study it is shown that metabolites of the arachidonic acid cascade and a prostaglandin H synthase inhibitor can modulate cervical secretion and thus maybe influence fertilization.     

Is Mediation of Sweating Cholinergic,Adrenergic, or Both? A Comment on the Literature

Research on SNS mediation of human eccrine and apocrine sweating was examined. Both types of sweat glands in humans are innervated primarily by cholinergic fibers and, at least sparsely, by adrenergic fibers. Both types of sweat glands are also stimulated by circulating catecholamines, but the mechanism for this action has not been unequivocally established. Recent research developments in the physiology of the sweat glands are discussed as they bear on persistent problems in psycho physiological research.     

The response of the sweat glands of the new-born baby to thermal stimuli and to intradermal acetylcholine

1. Measurements of evaporative sweat loss were made on fifty-six premature and full-term babies 1-67 days after birth with an infra-red analyser and a ventilated capsule placed on the thigh. Measurements were also made of total evaporative water loss while in a closed metabolic chamber and of the regional distribution of sweating with starch-iodine paper.2. No sweating to thermal stimuli could be detected in infants of less than 210 days post-conceptual age, even when rectal temperature rose as high as 37.8 degrees C. In older infants sweat was detected first on the forehead and temple, later on the chest, and usually by 240-260 days post-conceptual age on the legs (term approximately 268 days). Generalized sweating on the limbs appeared at an earlier post-conceptual age in the more prematurely born infants.3. The response of sweat glands on the thigh to an intradermal injection of 2 mug acetylcholine (ACh) was tested. No sweat response was detected in infants under 225 days post-conceptual age, while all infants born within 2 weeks of term responded. The response was often augmented after 2-5 tests at 5-10 min intervals; all the eight infants born within 2 weeks of term who were examined twice in the first 2 weeks of life showed a greater response on the second occasion.4. An average of 414 active sweat glands/cm(2) were detected on the thigh in eight babies 7-10 days old born within 2 weeks of term. This was 6(1/2) times the number found in adults. The mean peak sweat rate to chemical stimulation was however only 2.4 nl./gland.min, which was 3 times lower than the maximum rate recorded in adults.5. In five infants with congenital defects of the brain and complete absence of temperature control there was no sweat response to thermal or direct chemical stimulation of the glands.6. Functional maturation appears to depend on intact central innervation and is marginally hastened by post-natal factors. Immaturity of the sweat glands can account for the lack of any response to thermal stimuli in premature babies, but not for the modest thermal response obtained in babies at term.     

Effect of carbachol on 45Ca uptake and protein secretion in rat lacrimal gland.

Carbachol stimulates 45Ca uptake and protein secretion in rat lacrimal glands. At low concentration (10-8 M) atropine inhibits these effects but phentolamine and propranolol (10-5 M) are ineffective. The optimum response in both processes is obtained at the same concentration (10-6 M) of the cholinergic agonist. Vinblastine (10-4 M) reduces protein discharge induced by carbachol without modifying the uptake of 45Ca stimulated by the parasympathetic mediator. Calcium influx is proposed as the primary effect of cholinergic inducers in secretory processes.     

Intimacy of the neuroeffector junction and resistance to α-adrenoceptor-blockade of the neurogenic contractile response in vasa deferentia from guinea pig and rat

The effect of phentolamine on the neurogenic contractile response in vasa deferentia from rat and guniea pig was studied during Wallerian degeneration. This response was also investigated after partial denervation (surgery or chemical sympathectomy by guanethidine treatment) in vasa deferentia from guinea pig. During Wallerian degeneration the response showed a gradual increase in sensitivity to phentolamine and was abolished in the late stages. The neurogenic contractile response of the partially denervated vas deferens was blocked by low concentrations of phentolamine. It is concluded that decreased intimacy of the neuroeffector junctions leads to increased susceptibility to α-adrenoceptor blockade of the contractile response to nerve stimulation. It is further concluded that the motortransmission in the vas deferens is essentially adrenergic. The resistance to α-adrenoceptor blockade of the initial phase of the contractile response to nerve stimulation of intact vasa deferentia from guinea pig and rat might well be explained by the “proximity theory” of Dale & Gaddum although participation of supplementary mediators cannot be excluded.     

Anthracycline-associated cardiac and renal damage in rabbits. Evidence for mediation by vasoactive substances

We tested the hypothesis that anthracycline-induced cardiac and renal damage is mediated by vasoactive substances. A 1-minute exposure to 5 micrograms per ml. of doxorubicin (DXR, Adriamycin) produced cardiac histamine release in isolated rabbit hearts. Under conditions in which histamine uptake and metabolism were impaired, the administration of DXR, 2 mg. per kg., over 1 minute was associated with elevations in arterial histamine and catecholamines. The chronic weekly administration of DXR produced severe cardiac and renal damage. The administration of combined histaminic and adrenergic blockade with diphenhydramine, cimetidine, phentolamine, and propranolol (DCPP) pre- and immediately post-DXR resulted in near total protection against DXR-mediated cardiac damage and prevented the majority of the renal lesions. The combined administration of diphenhydramine, cimetidine, phentolamine, and propranolol did not appear to be acting by mechanisms other than blockade of vasoactive amine receptors as cardiac uptake of DXR and the DXR antitumor response were not altered by diphenhydramine, cimetidine, phentolamine, and propranolol. This study demonstrates that anthracycline-associated cardiac and renal toxicity may be mediated by vasoactive substances and that anthracycline cardiomyopathy is potentially preventable.     

THE PERIPHERAL MECHANISM OF THE GALVANIC SKIN RESPONSE

Darrow held that the galvanic skin response (GSR) appears to be a complicated phenomenon because a number of events are sequentially involved. The mechanism resulting in the peripheral components of electrodermal phenomena is not complicated. Following excitation, sympathetic impulses to cutaneous tissues and subsequent release of acetylcholine account for initial negative polarity and resistance changes. When these incoming impulses are sufficiently persistent and strong, and when the cholinergic response of the sweat glands is sufficient, then if temperature and circulatory conditions are favorable, secretion by the sweat glands is initiated. Sweating is the major factor contributing to the positive potential and large drops in skin resistance during excitation, but at low levels of excitation, when skin resistance is high and before sweating has reached a critical level, epidermal activities other than those of the sweat glands may contribute appreciably to negative potential and resistance changes.     

Role of calcium in cholinergic and adrenergic mechanisms of eccrine sweat secretion

The role of Ca2+ in eccrine sweat secretion was studied using isolated cannulated monkey palm eccrine sweat glands in vitro. Removal of Ca2+ from the incubation medium promptly abolished sweat secretion induced by methacholine or phenylephrine. In contrast, isoproterenol-induced sweat secretion lasted from 40 to 220 min in a Ca2+-free medium. The methacholine-induced maximal sweat rate was a hyperbolic function of the Ca2+ concentration in the bath and reached a plateau at 1 mM Ca2+. Higher Ca2+ concentrations rather suppressed the secretory rate. The Ca2+ ionophore A23187, but not X537A, at 3 X 10(-6) M induced copious prolonged sweat secretion after a latent period of 10 min. A23187-induced sweat secretion was not inhibited by either atropine or propranolol. D 600 (methoxyverapamil) at 10(-3) M inhibited sweat secretion induced by methacholine or by isoproterenol, although the latter lasted longer than methacholine sweating (20 vs. 5 min) in the presence of D 600. The data support the notion that Ca2+ influx into the cell plays a crucial role in cholinergic and alpha-adrenergic sweating, whereas a partial supply of Ca2+ for isoproterenol-induced sweating is derived from an intracellular store.     

Influence of prostaglandins and a prostaglandin H synthase inhibitor on cervical secretion of the guinea-pig

The modulatory effects of several prostaglandins and a prostaglandin H synthase inhibitor (indomethacin) on basal as well as nerve stimulation induced secretion from the cervical glands of the guinea-pig were studied. Hypogastric nerve stimulation resulted in a secretory response of + 113%. Indomethacin dose dependently inhibited this secretory response. Prostaglandins E₂, F_2α and I₂ inhibited and 19-OH prostaglandin E₁ reduced nerve stimulation induced secretion. Prostaglandin I₂ and 19-OH PGE₁ markedly enhanced basal secretion, while indomethacin as well as PGE₂ and PGF_2α did not induce any secretion of cervical glands. However, PGF_2α in combination with the α-adrenergic blocker phentolamine resulted in an increase in secretion. The inhibitory effect of prostaglandins on cholinergic secretory innervation might be due to stimulation of adrenergic nerves exerting an inhibitory influence on cholinergic secretomotor innervation. It is suggested that PGI₂ and 19-OH PGE₁ exert postjunctional stimulatory effects on the secretory lining and that a lack of secretory effect of PGF_2α at least in part may be due to stimulatory effects on adrenergic neurons, inhibiting cholinergic secretomotor transmission. Thus, in this in vitro study it is shown that metabolites of the arachidonic acid cascade and a prostaglandin H synthase inhibitor can modulate cervical secretion and thus maybe influence fertilization.     

Rodent eccrine sweat glands: A case of multiple efferent innervation

The sweat territories of peripheral nerves to the hind-paw of the mouse were defined by a silastic impression mold method that allowed identification of every secreting sweat gland. It was found that the tibial, sural, saphenous and peroneal nerves all contribute to the innervation of foot pad sweat glands, and there is extensive overlapping of the sweat territories of the different peripheral nerves. Most sweat glands could be activated by electrical stimulation of axons in two or three peripheral nerves or in separate fascicles of one nerve. This was interpreted to indicate that these sweat glands receive multiple innervation and that sweat glands in the overlap regions between autonomous zones of adjacent cutaneous nerves can receive axons from each nerve. Partial denervation of sweat glands by section of one source of innervation did not prevent the gland from sweating during stimulation of intact axons to the gland, or after pilocarpine treatment. Totally denervated glands did not exhibit denervation hypersensitivity; they became unresponsive to pilocarpine, acetylcholine and adrenaline. These characteristics allowed detection of the appearance and progression of reinnervation (and reactivation) of denervated sweat glands by collateral branching from sudomotor fibers.Not only do these results increase our basic understanding of the anatomical relations between peripheral nerves and the sweat glands they innervate, but they also demonstrate that the mouse sweat gland provides a useful model system for studying neuropathology of the sympathetic nervous system.     

Effect of skin temperature on the cholinergic sensitivity of the human eccrine sweat gland

Although sweat gland activity is directly controlled by the central nervous system, which detects changes in core body temperature, sweat glands can also be influenced by local cutaneous thermal conditions. OBJECTIVE: The present study sought to determine the effect of local skin temperature on pilocarpine-induced sweating within a range of typical skin temperatures. METHODS: Thirteen subjects (30 +/- 6 years; 172 +/- 11 cm; 72.8 +/- 11.0 kg) had forearm sweat rates measured at rest following pilocarpine iontophoresis at each of three skin temperatures in randomized order: warm (T(warm) = 37.1 +/- 0.9 degrees C), control (T(con) = 32.3 +/- 1.4 degrees C), and cool (T(cool) = 26.6 +/- 1.3 degrees C). T(skin) was raised and lowered with an electric heating pad and gel ice pack, respectively. Forearm T(skin) was measured with a skin temperature probe. Pilocarpine iontophoresis was used on an approximately 7 cm(2) area of the anterior forearm to stimulate localized sweating. Following stimulation, sweat was collected from the area for 15 min with a Macroduct Sweat Collection System. RESULTS: There was a higher sweat rate at T(warm) (p = 0.001) and T(con) (p = 0.006) compared to that at T(cool). However, there was no difference between the sweat rate at T(warm) and that at T(con) (p = 0.127). CONCLUSION: These results indicated that skin temperatures below approximately 32 degrees C affect local sweat production primarily by altering glandular sensitivity to the neurotransmitter, whereas skin temperatures above approximately 32 degrees C predominantly affect neurotransmitter release. Furthermore, sweat glands display maximal or near maximal cholinergic sensitivity at resting skin temperature in a thermoneutral environment.     

Effects of α-adrenoceptor blockade by phentolamine on basal and stimulated insulin secretion in the mouse

The sympathetic nervous system is known to innervate the pancreatic islets and to have the capability to influence islet hormone release. The effects are, however, complex since the islet nerves contain catecholaminergic as well as peptidergic fibres, and the catecholamines stimulate α- as well as β-adrenoceptors. The present study was undertaken to establish the possible influence of the a-adrenoceptors on basal and stimulated insulin secretion under in vivo conditions. The α-adrenoceptor blocker phentolamine was injected at various dose levels i.p. to mice and a dose-dependent increase in plasma concentrations of insulin was seen. The maximal plasma insulin levels were observed 10 min after injection and were accompanied by decreased plasma glucose concentrations. Additionally, plasma glucose levels fell in response to phentolamine by an apparent insulin-independent manner, since at the low dose of 2.6 μmol kg^-1, plasma glucose levels did decrease without any apparent increase in plasma insulin levels. After injection of a low dose of phentolamine 10 min prior to a rapid i.v. injection of one of four different insulin secretagogues, the following effects on insulin release were observed. Glucose (+ 55%) and the cholinergic agonist carbachol (+ 140%) displayed a potentiated insulin secretory response after phentolamine pretreatment, whereas the β₂-adrenoceptor agonist terbutaline (-45%) had a blunted, though not abolished, insulin response. The absolute insulin secretory response to CCK-8 was unaffected by phentolamine despite the fact that plasma glucose levels were lowered by phentolamine. In conclusion, phentolamine enhanced insulin secretion and depressed plasma glucose levels in mice. Further, it influenced stimulated insulin secretion by a manner dependent on the nature of the secretagogue. The results thus suggest that α-adrenoceptors are involved in the precise regulation of basal and stimulated insulin secretion, and that a-adrenoceptor blockade does not always result in a potentiated insulin secretion.