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The effects and mechanisms of tastes on labial minor salivary gland (LMSG) secretion were investigated in 59 healthy individuals. Stimulation with each of the five basic tastes (i.e., sweet, salty, sour, bitter, and umami) onto the tongue induced LMSG secretion in a dose-dependent manner. Umami and sour tastes evoked greater secretion than did the other tastes. A synergistic effect of umami on LMSG secretion was recognized: a much greater increase in secretion was observed by a mixed solution of monosodium glutamate and inosine 5′-monophosphate than by each separate stimulation. Blood flow (BF) in the nearby labial mucosa also increased following stimulation by each taste except bitter. The BF change and LMSG secretion in each participant showed a significant positive correlation with all tastes, including bitter. Administration of cevimeline hydrochloride hydrate to the labial mucosa evoked a significant increase in both LMSG secretion and BF, while adrenaline, atropine, and pirenzepine decreased LMSG secretion and BF. The change in LMSG secretion and BF induced by each autonomic agent was significantly correlated in each participant. These results indicate that basic tastes can induce the gustatory-salivary reflex in human LMSGs and that parasympathetic regulation is involved in this mechanism.

We studied the effect of losartan on baroreflex sensitivity (BRS) and heart rate variability (HRV) of adult Wistar rats during acute and chronic inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME). Chronic L-NAME administration (50 mg/kg per day for 7 days, orally through gavage) increased mean arterial pressure (MAP), heart rate but significantly decreased BRS. In addition, a significant fall of standard deviation of normal RR intervals, total spectral power, high frequency spectral power and a rise of low frequency to high frequency (LF: HF) ratio was seen. Acute L-NAME administration (30 mg/kg, i.v. bolus dose) also raised MAP and impaired HRV but it was associated with augmented BRS for bradycardia reflex. Losartan treatment (10 mg/kg, i.v.) in both acute and chronic L-NAME treated rats, decreased MAP but the difference was not significant. On the other hand, losartan administration normalized depressed BRS for bradycardia reflex and significantly reduced LF to HF ratio in chronic L-NAME treated rats. But this improvement was not observed in acute L-NAME group. These results indicate importance of mechanisms other than renin-angiotensin system in the pressor response of both acute as well as chronic L-NAME. However, autonomic dysregulation especially following chronic L-NAME appears to be partly angiotensin dependent.

We studied hemodynamic responses to alpha- and beta-receptor agonists in eight healthy men before and after 14 days of 6 degrees head-down tilt (HDT) to test the hypothesis that increased adrenoreceptor responsiveness is induced by prolonged exposure to simulated microgravity. Steady-state infusions of isoproterenol (Iso) at rates of 0.005, 0.01, and 0.02 microgram.kg-1.min-1 were used to assess beta 1- and beta 2-adrenoreceptor responsiveness. Infusions of phenylephrine (PE) at rates of 0.25, 0.50, and 1.00 microgram.kg-1.min-1 were used to assess responsiveness of alpha 1-vascular adrenoreceptors. Slopes calculated from linear regressions between Iso and PE doses and changes in beat-to-beat heart rate, blood pressure, and leg vascular resistance (occlusion plethysmography) for each subject were used as an index of alpha- and beta-adrenoreceptor responsiveness. HDT increased the slopes of heart rate (1,056 +/- 107 to 1,553 +/- 83 beats micrograms-1.kg-1.min-1; P = 0.014) and vasodilation (-469 +/- 111 to -1,446 +/- 309 peripheral resistance units.microgram-1.kg-1.min-1; P = 0.0224) to Iso infusion. There was no alteration in blood pressure or vascular resistance responses to PE infusion after HDT. Our results provide evidence that simulated microgravity causes selective increases in beta 1- and beta 2-adrenoreceptor responsiveness without affecting alpha 1-vascular adrenoreceptor responses.

1. Positive inotropic responses to calcitonin gene-related peptide (CGRP) were evaluated in atria isolated from in vivo rat models of hyper-sensory-motor innervation (following neonatal guanethidine treatment) and hypo-sensory-motor innervation (following neonatal capsaicin treatment), to explore the hypothesis that functional responsiveness of atrial myocardium to CGRP may correlate with tissue levels of the sensory-motor neurotransmitters. Comparative of inotropic responses to CGRP following in vitro treatment of atria with guanethidine was also performed. 2. Following long-term guanethidine treatment, positive inotropic responses to CGRP were significantly attenuated, while supersensitivity to the sympathetic transmitter noradrenaline was shown. Maximal inotropic responses to CGRP (30 nM) were 214.0 +/- 28.1 (n = 8) and 146.8 +/- 21.7 mg (n = 8; P < 0.01) increase of the basal contractile tension in control and treated preparations, respectively. The pD2 values for noradrenaline were 6.71 +/- 0.12 (n = 8) and 7.26 +/- 0.13 (n = 6; P < 0.01) in control and treated atria, respectively. Acute application of guanethidine in vitro did not modify the positive inotropism by CGRP or the beta-adrenoceptor agonist isoprenaline. 3. Sensory-motor hypoinnervation following chronic treatment with capsaicin did not affect the inotropic responses to CGRP. Neither guanethidine nor capsaicin treatment affected the contractile apparatus of myocytes, as demonstrated by similar basal contractile tension as well as calcium-evoked inotropic responses in control and treated preparations. 4. In summary, increased sensory-motor innervation, following long-term sympathectomy with guanethidine, resulted in attenuation of the inotropic responses of the rat atrium to CGRP, while no changes in the inotropic responses were seen following sensory-motor denervation with capsaicin. Down-regulation of CGRP receptors or altered post-receptor signalling may be involved in the reduced responsiveness to CGRP.

Two types of Ca2+ currents with characteristics of T- and L-type Ca2+ currents were recorded in ventricular myocytes of dogfish (Squalus acanthias). The T-type Ca2+ current activated near -70 mV and had a peak current density of 9.8 pA/pF at -34 mV. The L-type Ca2+ current activated near -50 mV and had a peak current density of 10.6 pA/pF near 0 mV. The threshold for activation of the T-type Ca2+ current was 20 mV negative to that of the tetrodotoxin-sensitive Na+ current. Inactivation of the T-type Ca2+ current was rapid with a limiting time constant of 5 ms at positive potentials. The T-type Ca2+ current was not modulated by isoproterenol or acetylcholine. In dogfish the T-type Ca2+ channel has current densities equivalent to the L-type channel and is likely to activate before the Na+ channel, contributing significantly to generation of the foot of the action potential.

Previous studies including ours showed that cyclosporine (CSA) causes baroreflex dysfunction and hypertension. Here we tested the hypothesis that oxidative damage in central and peripheral tissues underlies the hypertensive, baroreflex and autonomic actions elicited by CSA in rats. We investigated the effects of individual and combined 7-day treatments with CSA (25 mg/kg/day, n=7) and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol, superoxide dismutase mimetic, 100 mg/kg/day, n=7) on blood pressure, reflex heart rate responses to peripherally mediated pressor and depressor responses, and biomarkers of oxidative stress. CSA elevated blood pressure and reduced reflex bradycardic (phenylephrine) and tachycardic (sodium nitroptrusside) responses. The ability of muscarinic (atropine, 1 mg/kg i.v.) or β-adrenoceptor blockade (propranolol, 1 mg/kg i.v.) to reduce reflex heart rate responses was reduced in CSA-treated rats, suggesting the impairment by CSA of reflex cardiac autonomic control. Concurrent administration of tempol abolished CSA-induced hypertension and normalized the associated impairment in baroreflex gain and cardiac autonomic control. Tempol also reversed the CSA-induced increases in aortic and brainstem nitrite/nitrate and malondialdehyde (MDA) and decreases in aortic superoxide dismutase (SOD). These findings implicate oxidative stress in peripheral and central cardiovascular sites in the deleterious actions of CSA on blood pressure and baroreceptor control of heart rate.

The NADH/NAD ratio is a measure of potential metabolic energy in smooth muscle tissue. Previous studies on bladder smooth muscle demonstrated that during active contraction when energy utilization is high, NADH is rapidly oxidized to NAD resulting in a decrease in the ratio of NADH/NAD. Intracellular systems utilizing ATP as an energy source are characterized by changes in the NADH/NAD ratio. This ratio can be monitored simultaneously with changes in smooth muscle tissue tone using an optical fiber probe which continually monitors NADH fluorescence and contractile activity of the same smooth muscle preparation. The present study correlates alterations in the ratio of NADH/NAD with both spontaneous and induced contractions and relaxations in the rabbit corpora cavernosa. The results show a high degree of correlation between a decrease in spontaneous fluorescence (decrease in the NADH/NAD ratio) and spontaneous contraction. An increase in tension was followed in time by a decrease in the NADH/NAD ratio. This was consistent for all strips showing significant spontaneous activity. ATP caused a rapid decrease in tension which was correlated with a decrease in fluorescence. The relative decrease in NADH fluorescence was proportional to the relative decrease in tension. Under basal conditions (0.8 g passive tension) ATP and nitroprusside stimulated a marked reduction in tension, but only ATP stimulated a substantial decrease in NADH fluorescence. Bethanechol and isoproterenol relaxed the corporal tissue to a relatively small degree which correlated with relatively small decreases in fluorescence. Methoxamine stimulated a substantial contraction of corporal smooth muscle which correlated with a rapid and significant decrease in NADH fluorescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Field stimulation of rabbit corporus cavernosum tissue strips can result in relaxation, contraction, or a biphasic response depending on the frequency and the power utilized. In this study we characterized the autonomic components of this response by exposing corporal tissue strips to a variety of autonomic agonists and antagonists including phentolamine, isoproterenol, methoxamine, propranolol, bethanechol, atropine, and ATP. Low frequency electrical field stimulation produced a bi-phasic response characterized by an initial relaxation followed by a contraction. High frequencies (≥ 32 Hz) produced contraction only. All responses were abolished by tetrodotoxin, indicating that both the contractile and relaxant responses to field stimulation are mediated by complex neural mechanisms. The initial relaxation response involves a combination of mediators which include musca-rinic cholinergic stimulation, purinergic, beta-adrenergic, and non-adrenergic, non-cholinergic (NANC) stimulation. The non-cholinergic contribution to corporal smooth muscle relaxation appeared to be approximately equal in significance to the cholinergically mediated relaxation. Beta adrenergic stimulation mediated a direct relaxation of the corporal smooth muscle. The contractile portion of the bi-phasic response was mediated by alpha-adrenergic stimulation. Additionally we have noted a rebound contraction following termination of field stimulation at all frequencies that is not affected by adrenergic or cholinergic blockade and may reflect the field-stimulated release of an endogenous smooth muscle contractile factor.

1. When ferret right ventricular papillary muscles were stimulated with threshold punctate pulses (0.33 Hz; 30 degrees C), cocaine, 10(-5) M, increased peak tension development from 815 +/- 120 to 1125 +/- 180 mg (P less than 0.05) and increased the rate of relaxation from peak tension (time to 80% decline from peak tension decreased from 155 +/- 11 to 144 +/- 11 ms; P less than 0.05). These changes in the twitch were associated with comparable changes in the amplitude and time course of the calcium transient measured with aequorin (amplitude increased from 62 +/- 4 to 90 +/- 7% (P less than 0.05) of maximal values; time to 80% decline from peak amplitude decreased from 84 +/- 8 to 64 +/- 3 ms; P less than 0.05). These effects were markedly attenuated in the presence of the beta-adrenoceptor-blocking agent, propranolol, 6 x 10(-7) M, or by maximization of catecholamine release from the adrenergic nerve endings with field pulses of suprathreshold strength, indicating that catecholamine release from the adrenergic nerve endings is responsible for the positive inotropic and lusitropic responses to low and moderate doses of cocaine (i.e., less than or equal to 10(-5) M). 2. High doses of cocaine (i.e., greater than 10(-5) M) produced negative inotropic and lusitropic effects that were associated with a decreased amplitude and prolonged duration of the calcium transient. 3. In aequorin-loaded intact fibres, cocaine 10(-5) M did not affect the force-calcium relationship unless catecholamines were present. Cocaine, 10(-5) M, significantly shifted the force-calcium relationship of saponin-skinned muscles (pCa50 = 6.14 +/- 0.05 versus 5.92 +/- 0.07; P less than 0.05), indicating reduced responsiveness of the myofilaments to calcium. F. (maximal Ca2+-activated force) was reduced to 58% of control in the presence of 10- M cocaine, while the slope of the calcium-force curve remained unchanged. These data indicate that cocaine may also decrease myofilament calcium sensitivity and maximal calciumactivated force, via mechanisms independent of catecholamines, when cellular diffusion barriers are eliminated.

Previous work in this laboratory has demonstrated that the bladders of 1-day-old and 1-week-old rabbits generate higher pressures in whole-bladder preparations than bladders from mature 8-week-old rabbits. In addition, the density of cholinergic receptors does not change during this maturation period. The present study was designed to determine if the increased responsiveness of the neonatal bladder was specific for cholinergic stimulation. Using bladder strips, we have demonstrated that the newborn bladders generated much greater tension in response to ATP, serotonin, histamine, and substance P. The response of the 1-day-old bladder smooth muscle to these contractile agents was at least double the response of the 8-week-old bladders. However, the response of all age groups to bethanechol was approximately the same, and the response to KCl was only 40% greater in the 1-day-old bladders as compared to the adult. These current studies indicate that the newborn bladder responds to a variety of nonadrenergic, noncholinergic agonists to a significantly higher degree than the adult bladder, and that maturation is accompanied by substantial changes in the pharmacology of the bladder.

Stimulation of parasympathetic innervation of the submandibular gland (2 or 20 Hz continuously or 20 Hz for 1 s at 10 s intervals), in the ferret, produced secretion of fluid and protein and a fall in vascular resistance. The responses following the administration of N omega-nitro-L-arginine methyl ester (L-NAME; 2 mmol kg-1 i.a.) to block the synthesis of nitric oxide (NO) were reduced, and the persisting responses were abolished (at 2 Hz continuously and 20 Hz intermittently) or further reduced (at 20 Hz continuously) by the additional administration of atropine. The output of vasoactive intestinal peptide (VIP) from the gland was not affected. Neither the secretory nor the vascular response to intra-arterial infusions of acetylcholine (1.25 nmol kg-1) was affected by L-NAME, whereas the vascular responses to both VIP (10 pmol kg-1) and pituitary adenylate cyclase-activating peptide (1-38) (PACAP) (0.5 pmol kg-1) were reduced thereby. Neither peptide evoked a fluid secretion per se. However, when infused during parasympathetic stimulation of saliva secretion, VIP increased both flow rate and the output of protein. These effects of VIP were abolished by L-NAME. The experiments were performed in the presence of sodium nitroprusside at doses (4-8 nmol min-1 kg-1 i.v.) aimed to counterbalance the systemic effects of L-NAME. The results show that, in the ferret, parasympathetic nerve activity increases submandibular blood flow, and elicits the flow of saliva and output of protein by mechanisms that involve in situ generation of NO, upon which the effects of VIP and PACAP but not acetylcholine are largely dependent.

Warm- and cold-acclimated rats could withstand prolonged exposure to cold after restriction of food. Their catecholamine excretion rapidly attained maximal values and the animals died in hypothermia. The same happened with warm-acclimated rats whose insulation had been reduced by removal of the fur. Cold-acclimated clipped rats survived in the cold, but their catecholamine response was much more intense than that of intact cold-acclimated animals. These two series of experiments strongly support the view that acclimation to cold is limited by the finite capacity of the organism to produce and/or secrete sufficient amounts of catecholamines to maintain thermal balance. They also emphasize the necessity for coldacclimated animals to reach a new level of acclimation when conditions are changed. The previous degree of acclimation increases the chances to attain that new state of equilibrium by virture of an increased sensitivity of cold-acclimated rats to catecholamines, thus extending the time at which the catecholamine production and/or secretion becomes saturated. The importance of adrenaline as a supplementary hormone of defense against cold is shown by the lower ability of adrenalectomized corticoids maintained rats to support cold exposure under severe conditions. (Author)

Background A coronary α 1 -adrenergic constrictor tone exists under conditions associated with increased sympathetic stimulation but not during resting conditions in the normal heart. During renovascular hypertension, elevated circulating angiotensin II may enhance sympathetic stimulation of the heart, even at rest. This study tested the hypothesis that an α 1 -adrenergic constrictor tone imposes limitations on coronary blood flow in resting dogs after development of renovascular hypertension, exacerbates coronary α-constrictor tone during exercise, and increases coronary vascular adrenergic responsiveness. Methods and Results Left circumflex blood flow velocity (CFV), aortic pressure (AoP), and heart rate (HR) were examined in five quietly resting dogs during control conditions and after selective α 1 -adrenergic blockade using an intracoronary injection of 0.5 mg prazosin. In the normotensive state, AoP was 87±7 mm Hg (mean±SD), HR was 105±25 beats per minute, and CFV was 28±6 cm/s. These parameters were not affected by α 1 -adrenergic blockade. During submaximal exercise, removal of an α 1 -adrenergic constrictor resulted in a 14±4% increase in CFV ( P P 1 -adrenergic blockade caused a 28±6% increase in CFV at rest ( P P Conclusions It appears that renovascular hypertension results in a significant coronary α 1 -adrenergic constrictor tone in the resting dog and an enhanced constrictor tone during exercise.

Although it has been reported that myocardial contractility is reduced in diabetic animals (1–6), very little is known about cardiac responses to administered adrenergic and cholinergic agents. The present study, therefore, was designed to investigate the myocardial contractile response of perfused hearts isolated from experimental diabetic rats and insulin-treated diabetic rats to adrenergic and cholinergic agents.

Single intraperitoneal (IP) injection of bradykinin (BK) in anesthetized guinea pigs caused concentration-related pressor effects and slight, not significant tachycardia. Intravenous injections of BK in the same animal model evoked hypotension and a marked tachycardia. IP injection of des-Arg9-BK, a selective B1 receptor agonist, caused no changes of blood pressure or heart rate. The pressor response to IP BK was reduced by concomitant IP injection of lidocaine or of D-Arg[Hyp3,D-Phe7,Leu8]BK, a B2 receptor antagonist. It was also inhibited by acute animal pretreatment with sympatholytic drugs, by chronic animal exposure to capsaicin, or acute spinalization, but it was not affected by atropine, propranolol, indomethacin, [Leu8]des-Arg9-BK, a B1 receptor antagonist, or by acute cervical vagotomy. These results suggest that pressor responses to IP BK in anesthetized guinea pigs are reflex in nature, involving abdominal, capsaicin-sensitive, nonvagal visceral afferents, efferent components of the sympathetic nervous system and possibly supraspinal centers, and likely to be mediated by B2 receptors of kinins presumably located on abdominal visceral afferents.

We hypothesized the existence of vagal arginine sensors in the liver which modulate arginine-induced pancreatic hormone secretion. The present study was carried out to examine the efferent pathways and receptor mechanisms from arginine sensors using selective vagotomies and autonomic drugs on the secretion of insulin and glucagon after ip injection of L-arginine (1 g/kg BW) in rats in an unanesthetized and unrestrained state. Hepatic vagotomy (sectioning of the hepatic branch of the vagus nerve) enhanced both plasma insulin and glucagon concentrations after ip arginine more than those in sham-vagotomized (control) rats. The effect of hepatic vagotomy was blocked by adding celiac vagotomy (sectioning of the celiac branches of the vagus nerve) or by previous administration of atropine methyl nitrate (10 mg/kg BW), but not by phentolamine (1 mg/kg BW) or propranolol (2 mg/kg BW). Celiac vagotomy alone did not affect the plasma insulin concentration; however, it reduced the plasma glucagon concentration after ip arginine compared to that in sham-vagotomized rats. Administration of atropine alone did not affect plasma insulin or glucagon concentrations after ip arginine. These results suggest that celiac branches of the vagus nerve act as efferent pathways to the pancreas through a muscarinic receptor mechanism in the hepatic arginine sensor-mediated pancreatic neuroendocrine system. The physiological role of these hepatic sensors may be to prevent arginine-induced exaggerated pancreatic hormone secretion and maintain blood glucose homeostasis.

1. The mechanical responses to some autonomic drugs and neuropeptides of longitudinal muscle (LM) and circular muscle (CM) strips isolated from the carp intestinal bulb were investigated in vitro. 2. Acetylcholine and carbamylcholine caused concentration-dependent transient contraction of both LM and CM strips. Tetrodotoxin had no effect, but atropine selectively decreased the contractile responses to acetylcholine and carbamylcholine. 3. Excitatory alpha-2 and inhibitory beta adrenoceptors were present in both LM and CM strips. 4. 5-Hydroxytryptamine (5-HT) caused concentration-dependent contraction of both LM and CM strips. Tetrodotoxin, atropine and methysergide decreased the contractile responses to 5-HT. 5. Some neuropeptides (angiotensin I, angiotensin II, bombesin, bradykinin, neurotensin, somatostatin and vasoactive intestinal polypeptide) did not cause any mechanical response (contraction or relaxation) in either smooth muscle strip. 6. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) caused contraction of both LM and CM strips. However, the time course of the contraction in LM was different from that in CM. The order of potency was NKA greater than SP greater than NKB in LM strips and NKA greater than SP much greater than NKB in CM strips. In LM strips, the contractile responses to tachykinins were unaffected by spantide and methysergide, but partly decreased by tetrodotoxin and atropine. On the other hand, the contractile responses of CM strips were unaffected by tetrodotoxin, atropine, methysergide and spantide. 7. Dynorphin (1-13) (DYN), leucine-enkephalin (L-Enk) and methionine-enkephalin (M-Enk) caused concentration-dependent contraction of both LM and CM strips. The order of potency was DYN greater than M-Enk greater than L-Enk. Naloxone selectively decreased the responses to opiate peptides. 8. The present results indicate that acetylcholine, carbamylcholine, catecholamines, 5-HT, tachykinins (SP, NKA and NKB) and opiate peptides (DYN, L-Enk and M-Enk) affect the mechanical activity of LM and CM strips isolated from the carp intestinal bulb through their specific receptors.

The effects of several autonomic agents on total protein, amylase, RNase, calcium, potassium, and sodium levels and also on flow rate of mouse parotid saliva were investigated during the process of evaluating the in vivo mouse parotid gland preparation as a pharmacological tool. Acetylcholine and pilocarpine were used as secretagogues and produced different sequential patterns of sodium and enzyme levels secreted in mouse parotid saliva. Additionally, propranolol treatment was able to alter amylase and sodium levels produced by pilocarpine stimulation significantly, as well as alter calcium levels produced by both acetylcholine and pilocarpine stimulation. Phentolamine treatment resulted in higher amylase levels with both acetylcholine and pilocarpine stimulation. The use of acetylcholine as a secretagogue allows one to perform in vivo anticholinergic experiments which alter flow rates without significantly altering protein or ion levels secreted in mouse parotid saliva.

The formation of inositol phosphates in response to agonists was studied in brain slices, parotid gland fragments and in the insect salivary gland. The tissues were first incubated with [3H]inositol, which was incorporated into the phosphoinositides. All the tissues were found to contain glycerophosphoinositol, inositol 1-phosphate, inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate, which were identified by using anion-exchange and high-resolution anion-exchange chromatography, high-voltage paper ionophoresis and paper chromatography. There was no evidence for the existence of inositol 1:2-cyclic phosphate. A simple anion-exchange chromatographic method was developed for separating these inositol phosphates for quantitative analysis. Stimulation caused no change in the levels of glycerophosphoinositol in any of the tissues. The most prominent change concerned inositol 1,4-bisphosphate, which increased enormously in the insect salivary gland and parotid gland after stimulation with 5-hydroxytryptamine and carbachol respectively. Carbachol also induced a large increase in the level of inositol 1,4,5-trisphosphate in the parotid. Stimulation of brain slices with carbachol induced modest increase in the bis- and tris-phosphate. In all the tissues studied, there was a significant agonist-dependent increase in the level of inositol 1-phosphate. The latter may be derived from inositol 1,4-bisphosphate, because homogenates of the insect salivary gland contain a bisphosphatase in addition to a trisphosphatase. These results suggest that the earliest event in the stimulus-response pathway is the hydrolysis of polyphosphoinositides by a phosphodiesterase to yield inositol 1,4,5-trisphosphate and inositol 1,4-bisphosphate, which are subsequently hydrolysed to inositol 1-phosphate and inositol. The absence of inositol 1:2-cyclic phosphate could indicate that, at very short times after stimulation, phosphatidylinositol is not catabolized by its specific phosphodiesterase, or that any cyclic derivative liberated is rapidly hydrolysed by inositol 1:2-cyclic phosphate 2-phosphohydrolase.

To help characterize the L-dopa-mediated release of glucagon, rats were given either L-dopa or dopamine (10 mg/kg) intravenously; portal plasma levels of insulin, glucagon and glucose were measured in the presence and absence of adrenergic and ganglionic blockers. The alpha-adrenergic blocker (phentolamine) suppressed the glucagon and glucose response to L-dopa and increased plasma insulin levels. Beta-adrenergic blockade with propranolol ameliorated the L-dopa-mediated glucagon and glucose responses but had no effect on plasma insulin levels. Ganglionic blockade with pentolinium tartrate was ineffective and did not alter any of the L-dopa-mediated responses of glucagon, insulin or glucose. These data indicate that L-dopa and dopamine probably act via the sympathetic nervous system through known pathways enchancing the release of glucagon. Furthermore they substantiate the fact that the adrenergic nervous system is involved in the regulation of the endocrine pancreas. (Author)

There is evidence to indicate that the transport of an egg through the rabbit oviduct is controlled through an interaction of the sympathetic nervous system and ovarian hormones. The effect of norepinephrine (NE) on the contractility of the oviduct during the first 8 days of gestation was studied using the rabbit perfused oviduct. The sensitivity of the α -adrenergic receptors of the oviduct to NE decreased progressively during early gestation. This was reflected in a potency change and a decrease in the maximal response obtained. These data support the concept that an isthmic sphinctering effect mediated by the autonomic nervous system may play a role in the regulation of egg transport through the oviduct. Blood pressure responses to NE did not change during early pregnancy except that the responses to NE were significantly enhanced immediately after mating. This suggests that the sensitivity changes to autonomic agents during early gestation may be selective for reproductive tissues.

We studied the development of selective adrenergic and cholinergic neuroeffector transmission in primary cultures of isolated ventricular muscle cells. Explants of either thoracolumbar sympathetic ganglia or sacrococcygeal spinal cord were added to newborn rat ventricular cultures harvested prior to the onset of in vivo autonomic innervation. Neuronal growth, migration, and the formation of neuromuscular junctions were observed with light and scanning electron microscopy. Glyoxylic acid histofluorescence, reflecting catecholamine synthesis, was found in only the sympathetic neuromuscular cultures. Choline acetyltransferase activity was detected in both spinal cord and sympathetic neuromuscular cultures, but was significantly higher in the spinal cord neuromuscular cultures. The isolated ventricular muscle cells remained at a constant spontaneous contraction frequency, regardless of the type of culture preparation. Guanethidine sulfate application produced a positive chronotropic response, blocked by propranolol, in the sympathetic neuromuscular cultures, but not in the spinal cord neuromuscular cultures. Bethanechol sulfate produced a negative chronotropic response, blocked by atropine, in the spinal cord neuromuscular cultures, but not in the sympathetic neuromuscular cultures. Isolated ventricular muscle cells in the absence of neurons failed to respond to either agent. Direct microelectrode stimulation of adrenergic or cholinergic neurons likewise respectively produced either a positive or negative ventricular muscle cell chronotropic response. These studies are the first to establish the selective production of functional cholinergic and adrenergic innervation of isolated cardiac muscle cells in vitro.

Five female rhesus monkeys were treated with natural estrogens, 5 mg/day for three weeks, after which ovarian contractility was studied in vitro in one of the ovaries. Estrogen treatment was followed by progesterone, 25 mg/day for three weeks, after which the contractility of the remaining ovary was similarly measured. Responses to autonomic agents and prostaglandins were studied in both groups. Spontaneous ovarian contractility and ovarian contractile responsiveness to prostaglandins and norepinephrine were found to be enhanced after progesterone treatment. Cholinergic agonists had a stimulatory effect after progesterone and an inhibitory effect after estrogens. Our results suggest that ovarian contractile responsiveness is modified by the local steroid environment, perhaps through intracellular changes in cyclic AMP.

Actions of some autonomic drugs on upper, middle and lower portion of isolated dog ureters under quiescent state were investigated quantitatively. Noradrenaline and adrenaline at lower concentrations evoked contractions in each portion of the ureters and increased the concentration-dependent frequency and tension of these contractions, but attenuated them at higher concentrations. Phentolamine significantly depressed these contractions, while propranolol enhanced them. Phenylephrine increased the concentration-dependent frequency and tension of contractions, which were suppressed by phentolamine. Acetylcholine at higher concentrations produced contractions of the ureters, and phentolamine or hexamethonium suppressed them. The results indicate that ureteral contractions may be stimulated through an activation of alpha-adrenoceptors and be attenuated through an activation of beta-adrenoceptors, and that acetylcholine may release noradrenaline from sympathetic nerve endings through an activation of presynaptic nicotinic receptors, resulting in ureteral contractions.

The characteristics of the glycoproteins contained in the secretory segments of the three major salivary glands of adult male rats and the secretion of these various glycoproteins in response to autonomic agents were examined by micro-disc electrophoresis. Characterization of the glycoproteins showed that the acinar segments from the three major salivary glands and the segments of the convoluted granular tubules from the submandibular gland each contain characteristic species of glycoproteins. The glycoproteins characteristic of the acinus of the submandibular gland were secreted into saliva in response to carbachol or dobutamine, those characteristic of the parotid gland by carbachol, methoxamine, or dobutamine, and those of the sublingual gland by carbachol, whereas glycoproteins characteristic of the convoluted granular tubules of the submandibular gland were only elicited by methoxamine. The secretory response of carbachol, methoxamine and dobutamine, respectively, were almost completely reduced by pretreatment with atropine, prazosin and metoprolol. The relative proportions of glycoproteins secreted into the oral cavity from secretory cells of the three major glands varied significantly with the nature of the stimulant.

The purpose of this investigation was to examine the effects of autonomic neurohormones, cyclic nucleotides, and related agents on the immunologic discharge of lysosomal enzymes from, and phagocytosis by, purified human neutrophils. In order to discern the possible intracellular mechanisms by which certain neurohormones influence neutrophil function, the concentrations of cyclic AMP and cyclic GMP in neutrophils were assessed during cell contact with phagocytizable particles and autonomic agents. The model system employed for study was the interaction of purified human neutrophils with rheumatoid arthritic (RA) serum-treated zymosan particles at 37°C in a neutral, balanced salt solution containing glucose. Neutrophils ingested the particles and discharged ß-glucuronidase but not lactate dehydrogenase activity during 30 min of incubation. Treatment of zymosan particles with RA serum was more effective than treatment with normal serum with regard to the extent of both particle uptake and lysosomal enzyme release. During contact of neutrophils with RA serum-treated zymosan particles epinephrine, isoproterenol, and cyclic AMP inhibited both particle ingestion and ß-glucuronidase discharge. These actions of epinephrine were associated with a concomitant elevation of cyclic AMP levels. In contrast to the actions of catecholamines and cyclic AMP, acetylcholine and cyclic GMP accelerated lysosomal enzyme release without affecting particle uptake. The actions of acetylcholine were associated with a concomitant elevation of cyclic GMP levels. Increases in neutrophil levels of cyclic GMP but not of cyclic AMP were associated also with the discharge of ß-glucuronidase provoked by particles in the absence of added cholinergic agents. The data suggest that the immunologic release of lysosomal enzymes from human neutrophils can be regulated by autonomic neurohormones, perhaps via the selective formation of appropriate nucleotides.

The tonus and rate of spontaneous contractions measured in vivo from the tunicaalbugineaof rabbit testes were augmented by epinephrine, acetylcholine and prostaglandin (PG)F2 �. Neither reserpine, dibenamine nor atropine decreased autorhythmic contractility. Indomethacin injections ip significantly decreased the mean amplitude of testicular contractions. This treatment effaced motility in two of eleven preparations. Injections of 5,8,11,14-eicosatetraynoic acid (TYA) did not significantly decreasetheamplitudeof contraction. Electrical stimulation of the spermatic artery (site of thespermaticnerve) in rabbits and in rats failed to alter testicular tonus or motility. The above evidence suggests that local factors such as PG5 may contribute more to smooth muscle activity in the tunica albuginea of rabbittestesthan do autonomic nerves. The rhythmical contractions observed in vivo, however,continuedinthe presenceof indomethacin in the bathing medium, and may not requirestimulationby PG5 fortheirorigination. Rat testes, unlikerabbit testes, did not contract rhythmically in vivo. Isolated rat testescontractedin responseto administered PGF20, while PGE1 abolished the induced contraction. Such modulators of muscular tonus feasibly could alter intratesticular pressure for the intact animal.

Active ion transport by the airway epithelium plays an important role in maintaining the effective defense mechanisms of the airway by regulating the volume and composition of the airway fluid. We investigated the abilities of adrenergic agents, cholinergic agents, and chemical mediators to modulate ion transport in canine tracheal epithelium, using Ussing-type chambers. Transepithelial electric potential difference (PD), resistance (R), and short circuit current (SCC) of the tracheal epithelium were measured before and during exposure to a drug or after a change in the perfusate composition. The mean values and S.E. (N = 41) of PD, R, and SCC during the control period were -18 +/- 4 mV (luminal negative to submucosa), 240 +/- 42 omega.cm2, and 50 +/- 5 microA/cm2, respectively. Ouabain (10(-4) M), an inhibitor of Na+-K+-ATPase, in the mucosal bath abolished PD and SCC. Replacement of luminal Na by choline reversibly reduced PD and SCC. These findings suggest that PD and SCC of the tracheal epithelium are maintained by the transcellular transport of luminal Na toward the mucosa. Isoproterenol (10(-5) M), epinephrine (10(-4) M), and norepinephrine (10(-4) M) markedly increased both PD and SCC. Acetylcholine (10(-4) M) and histamine (10(-4) M) did not alter SCC significantly. Prostaglandin E1 (10(-6) M) and F2 alpha (10(-5) M) slightly increased PD and SCC. These results indicate that adrenergic and cholinergic agents induce different patterns of effect on ion transport (adrenergic-dominant) in the tracheal epithelium. Thus, the effects of autonomic agents and chemical mediators on ion transport may explain, in part, the pathogenesis of airway disorders observed in many respiratory diseases.

To determine whether endogenous alpha-adrenergic activity contributes to abnormal insulin secretion in nonketotic, hyperglycemic, diabetic patients, alpha-adrenergic blockade was produced in normal and diabetic subjects. The diabetics had a significantly (P less than 0.01) greater increase in circulating insulin 1 h after an intravenous phentolamine infusion than did the normal subjects. During the phentolamine infusion, there was also a significant augmentation of acute insulin responses to intravenous glucose (20 g) pulses in normal subjects (P less than 0.05) and diabetics (P less than 0.02); this augmentation was fivefold greater in the diabetics. Simultaneous treatment with the beta-adrenergic blocking agent, propranolol, did not alter these findings. Thus a role for exaggerated endogenous alpha-adrenergic activity in abnormal insulin secretion of the diabetic subjects is suggested. To determine whether this alpha-adrenergic activity might be related to elevated circulating catecholamines, total plasma-catecholamine levels were compared in normal and nonketotic diabetic subjects given intravenous glucose pulses. These levels were significantly greater (P less than 0.02) in the diabetic compared to the normal group before the glucose pulse, and increased significantly in both groups (P less than 0.02 and less than 0.001, respectively) after the pulse. These data suggest that excessive catecholamine secretion may lead to an abnormal degree of endogenous alpha-adrenergic activity, which contributes to defective insulin secretion in diabetic subjects.

Myometria of pregnant and nonpregnant Myotis lucifugus were studied in vitro by using electrical field stimulation as well as autonomic agonists and antagonists to determine whether functional responses corresponded with structural evidence showing abundant adrenergic and sparse cholinergic innervation, which uniquely does not disappear during pregnancy. Field stimulation (70 V, 0.6 ms, 5.0-s pulse train, 2.5 - 60 Hz) of myometria from nonpregnant (hibernating) bats produced graded responses consisting of an initial alpha-adrenergic contraction and a subsequent beta-adrenergic relaxation phase. Responses were sensitive to both the nerve poison tetrodotoxin and the adrenergic antagonist guanethidine, demonstrating that they resulted from stimulation of intrinsic adrenergic nerves. Field stimulation responses were unaffected by atropine indicating that there was no functional cholinergic innervation, even though carbachol-induced contraction showed that muscarinic receptors were present. In contrast, functional innervation of cervical tissue was cholinergic and nonadrenergic-non-cholinergic, but not adrenergic. At the beginning of active gestation, some myometrial preparations exhibited little of no response to field stimulation. However, as uterine size increased, the biphasic response to field stimulation was enhanced, particularly the inhibitory (beta-adrenergic) phase. Moreover, the contractile phases, though reduced, was not abolished by alpha-adrenergic antagonists. The residual contractile response was also tetrodotoxin-resistant, suggesting that the myometrium was sensitive to direct electrical stimulation. Near the end of pregnancy, myometrial tissue became nonresponsive to both field stimulation and autonomic agonists, suggesting an absence of available receptor sites on muscle cells.

The effects of cholinergic and adrenergic agonists and antagonists on ion transport and bioelectric properties of excised canine trachea, main-stem bronchi, and subsegmental bronchi were studied. Acetylcholine (ACh) induced in bronchi a dose-dependent reduction in net Na+ absorption, maximal (30%) at 10(-5) M, that reflected a raised Na+ flux from submucosa to mucosa. Because conductance (G) did not change we speculate that the increased flow in the “passive” direction represents the induction of bidirectional Na+ transport. ACh (10(-4) M) increased net Cl- secretion in the trachea and main-stem bronchi and reduced Na+ absorption. ACh effects in all regions were blocked by atropine. In bronchi, alpha- or beta-adrenergic agonists, 10(-5) and 10(-3) M, raised G and unidirectional Cl- fluxes without affecting short-circuit current (Isc) or inducing Cl- secretion. Small reductions in Na+ absorption were noted at 10(-5) M. In contrast, adrenergic agents increased Isc and Cl- secretion in the trachea. We concluded that neurohumoral agonists induce different patterns of effects on ion transport in central compared with more distal airways. Agonists of both classes induced Cl- secretion in the trachea and reduced but did not abolish net NaCl absorption in the bronchi.

Intraluminal pressure was measured in the isolated, fluid-filled trachea of the guinea pig, with autonomic innervation on the right side intact. Increases or decreases in intraluminal pressure reflected excitatory or inhibitory responses respectively, in the tracheal smooth muscle. Stimulation of the cervical vagus nerve evoked a cholinergic excitatory response. After cholinergic blockade with atropine, a non-adrenergic, non-cholinergic inhibitory response was obtained. Stimulation of the cervical sympathetic trunk, or stellate ganglion, evoked beta-adrenergic inhibitory responses. In the presence of propranolol, sympathetic stimulation evoked alpha-adrenergic excitatory responses which were of low amplitude (less than or equal to 5% of cholinergic excitatory responses). In the presence of phentolamine but not prazosin, beta-adrenergic inhibitory responses were potentiated. Neostigmine potentiated responses to vagal stimulation, increasing the amplitude and duration of response. At higher concentrations neostigmine (i) raised intraluminal pressure, a response blocked by atropine, and (ii) attenuated sympathetic inhibitory responses, an effect largely blocked by atropine. Histamine increased intraluminal pressure and this response was attenuated by atropine. In the presence of histamine, vagal excitatory responses were attenuated. Sympathetic inhibitory responses at low frequencies of stimulation (up to 10 Hz) were inhibited by histamine. 5-Hydroxytryptamine (5-HT) increased intraluminal pressure also, an effect partially blocked by atropine. 5-HT had no effect on vagal excitatory responses. Like histamine, 5-HT attenuated sympathetic inhibitory responses at lower frequencies of stimulation.

In order to determine whether the human pattern of circulating melatonin resembles that previously described in lower animals, men 19-32 years old were exposed to a light-dark cycle with 14 hours of light per day (L:D 14:10). In whites and blacks, nocturnal (dark phase, sleeping) melatonin levels were almost always elevated to 0.05-0.1 ng/ml plasma compared with lower or undetectable levels during the day, measured by the tadpole bioassay. Thin-layer migration of bioactive material was identical to that for melatonin standard. A rhythm with nocturnal elevation of urinary 5-hydroxyindoleacetic acid (5-HIAA) was observed. Nocturnal (sleep phase) rise in blood melatonin (but not urinary 5-HIAA) continued during 21/2 day-night cycle lengths after the onset of constant light. Though the dark phase plasma melatonin rise was less marked after reversal of the sleep-wake cycle (no change in the light cycle), dark phase rise in urinary 5-HIAA continued. Though marked cardiovascular and other effects were produced by intravenous isoproterenol or scopolamine, no definite effect on melatonin levels was observed after either drug during the light phase in waking subjects.

We studied the effects of a variety of noncholinergic, nonadrenergic agents on the smooth muscles of the cat urethra. Prostaglandin F2α contracted both urethral muscle layers to a similar extent. Prostaglandin E2 contracted the longitudinal and relaxed the circular muscle layers. The effects of the prostaglandins seem to be directly myogenic since cholinergic and adrenergic blockers and tetrodotoxin did not affect them. Bradykinin and substance P contracted both urethral muscle layers. Other tested agonists (neurotensin, vasoactive intestinal peptide, cyclic 3,5 adenosine monophosphate, adenosine diphosphate sodium, cyclic 3,5 guanosine monophosphate sodium, bombesin) had no effect on the cat urethral smooth muscles.

ラット顎下腺の唾液分泌機構で交感神経性α1-受容体(Re)を介する分泌応答の特性を明らかにすることを試みた。実験はα1-Re刺激に特異性のたかいメソキサミンを腹腔内投与し,採取した顎下腺唾液性状を検討したもので,分泌は明確な用量依存性を示し,6mg/kg体重以上で分泌量,蛋白質量とも急激な増加を示し,蛋白成分像も血清に類似したγ-型からα-型に変換した。これはピロカルピンによる副交感刺激唾液の無機成分量,蛋白成分像(β-型),蛋白分子量及びアミノ酸組成を含む分泌動態比較で明確に区別できた。α1-Re機能はフェノキシベンザミンとジヒドロエルゴタミンで完全に遮断されるが, α2機能をフェントラミン, ヨヒンビンなどで遮断しても, また逆に刺激条件を与えても抑制がかかり, 蛋白成分像が変換する経路が存在した。このことは同様にコリン性Reや,交感性β-Reを刺激,あるいは遮断条件下にα1-Re機能を刺激した揚合も認められた。分泌蛋白質成分の特性はin vitroでは各種刺激条件あるいは遮断条件を与えても出現せず,成分像はすべてαβγ-型となった。またβ-Re遮断条件下で,腺内のcAMPとcGMP量は変動せず,α2-Re遮断ではcAMPが,ムスカリン性Re遮断では両ヌクレオチッド量がそれぞれ上昇した。以上のことからラット顎下腺のα1-Reは個有の刺激応答性を示すとともに,他種受容体との間では機能上でそれぞれ特定の相関を有し合うことが考へられた。

To determine whether the elevated plasma renin activity in some cases of mild essential hypertension expresses sympathetic-nervous-system over-activity, we compared indexes of sympathetic activity in 16 patients with mild high-renin essential hypertension, 15 hypertensive patients with normal plasma renin activity and 20 normal subjects. Patients with elevated activity exhibited a raised plasma norepinephrine concentration (P less than 0.05), a greater fall in cardiac output with cardiac beta-adrenergic blockade by intravenous propranolol (P less than 0.01), reduction in total peripheral vascular resistance with alpha-adrenergic blockade produced by intravenous phentolamine (P less than 0.01), and reduction to normal of blood pressure by "total" autonomic blockade (atropine, propranolol and phentolamine). On psychometric testing, patients with high-renin hypertension, but not those with normal plasma renin activity, exhibited suppressed hostility (P less than 0.01), a behavioral pattern linked to increased sympathetic activity. The hypertension in these patients with high renin activity is neurogenic and possibly psychosomatic in origin.

The autonomic nervous system is divided into the parasympathetic and sympathetic systems, with three types of adrenergic receptors: alpha (smooth muscle contraction), beta1 (cardiac acceleration and fatty acid mobilization) and beta2 (smooth muscle relaxation). Substances affecting the function of the adrenergic system are the agonists or stimulators, which mimic the effects of endogenous norepinephrine or epinephrine, and antagonists or blockers, which block the receptors and prevent stimulation by the agonists. Autonomic stimulation in the eye mediates various changes which apparently affect outflow facility and rate of formation of aqueous humor. Alteration of either or both of these factors by autonomic agonists or antagonists may have a direct or an indirect effect on intraocular pressure. Beta-adrenergic blocking substances have been used to treat a variety of diseases. Some of the effects of these drugs are attributable to properties other than beta blockade, such as intrinsic sympathomimetic activity and local anaesthetic activity. Side effects of this class of drugs require caution in cases of congestive heart failure and in asthmatics. Autonomic agents used in the treatment of ocular hypertension and glaucoma include pilocarpine, a chilinergic agonist, epinephrine, an adrenergic agonist, and various beta adrenergic blockers or antagonists including propranolol, atenolol and timolol. The physico-chemical properties and pharmacokinetics of timolol are reviewed. Data showing a significant reduction in intraocular pressure as a result of ocular instillation of timolol are presented. Reduction of the rate of aqueous formation appears to be the mechanism of action. A low incidence of non-serious side effects is reported.

Spirally cut strips of ovine pulmonary vein and artery were studied in isolated organ baths and their responses to selected autacoid and autonomic agents were compared. In addition blood vessels taken from horse plasma-sensitized sheep were compared with their respective controls. Pulmonary vein and artery exhibited qualitative and quantitative differences in their autacoid and autonomic reactivity. Veins were more sensitive in responding with contractions to histamine (HIST) and carbachol (CARB) when compared with arteries. Responses of these vessels differed qualitatively to 5-Hydroxytryptamine (5HT); phenylephrine (PE) and adrenaline (ADR): arteries responded with strong contraction and veins with relaxations. Isoproterenol (ISOP) effectively relaxed veins but was either without effect or produced 10%-15% relaxations of precontracted arterial strips. Phentolamine competitively antagonized ADR and PE-induced contractile responses of arteries while on veins, ISOP and PE dose-response curves (DRCs) were shifted to the right in the presence of propranolol. Mepyramine inhibited venous and arterial responses to HIST. Comparisons between sensitized and non-sensitized sheep vasculature revealed a significant (P less than 0.05) decrease in the activity of spasmolytic agonists on veins, i.e. relaxant actions of 5HT, PE and ISOP were significantly impaired. In addition the activity of 5HT to contract pulmonary artery was significantly (P less than 0.05) increased when compared with controls. Present investigation suggests: (i) the predominance of H1-histaminergic receptors in ovine pulmonary vasculature; (ii) the preponderance of alpha and beta-adrenergic receptors in pulmonary artery and vein, respectively; (iii) that antigenic sensitization exaggerates the pathological state by causing a decrease in spasmolytic activity with a parallel increase in spasmogenic activity.

1. The acetylcholine distribution in hearts of normal cats and in hearts of animals treated with hemicholinium no. 3 was tested.

1. It was demonstrated with 21 rabbits that causation of alkalosis, ligation of the carotid artery, administration of excess water, and acetylcholine application to the cerebral cortex were capable of increasing the predisposition to convulsions. Examination was made of the action potentials of the autonomic nerves and the brain under these five conditions (including intravenous injection of metrazol alone). 2. From the changes in action potential of the autonomic nerves, the conditions for increasing the predisposition to convulsions may be classified into three types: sympathetic, sympathetic-parasympathetic, and parasympathetic. Under a condition of increasing the predisposition to convulsions, there is brought about a state of unbalance in action potential between the sympathetic and the parasympathetic, In this respect, the importance of the excessively tonic state of the sympathetic has been emphasized. 3. Causation of alkalosis and application of acetylcholine to the cerebral cortex belong to the sympathetic type, and are characterized by a decrease of fast waves (39.2 to 24 cycles per second) in the sympathetic. 4. Intravenous injection of metrazol and ligation of the carotid artery belong to the sympathetic-parasympathetic type, and are characterized by a decrease of fast waves (39.2 to 24 cycles per second) in the sympathetic and an increase of intermediate waves (15.5 to 9.8 cycles per second) in the vagus. 5. Administration of excess water belongs to the parasympathetic type, and is characterized by an increase of intermediate waves (15.5 to 9.8 cycles per second) in the vagus. 6. The changes in the EEG under conditions for increasing the predisposition to convulsions are characterized by a prolongation of the period and increase of intermediate waves (15.5 to 6.2 cycles per second) and slow waves (6.2 to 2.4 cycles per second).

The influence of changes in the condition of the nervous system due to the effect of autonomic agents (pilocarpine, carbocholine, atropine and adrenalin) and thyroldin on the secretion and content of milk in goats and cows was investigated. The above research was carried out together with the study of the secretion of salivary glands, as well as of the tone of the autonomic part of the central nervous system. This gave the opportunity for better understanding of the relationship between the organism as a whole and the mammary gland. It was established by this work that the introduction of pilocarpine and carbocholine into the organism, as well as of the sympathicotropic substances-adrenalin and thyroidin-causes increased secretion and the change of content of milk. Increased quantity of dry residue in milk is the result of increased synthetic activity of the cells of the mammary gland under the influence of excitation of the nervous system by the above substances. Block of the parasymphathetic nerve endings by atropine causes pronounced decrease of milk secretion. However, it is not completely arrested. The process of milking and massage of the udder causes excitation of the central nervous system resulting in reflex increase of salivary secretion. The mammary gland receives impulses which appear due to stimulating effect of milking, sucking and massage. Nervous and nervous humoral mechanisms take part in it under the control of the central nervous system.

1. The specificity of several ganglion stimulants has been tested on the isolated guinea-pig ileum by measuring the dose ratios produced by concentrations of hexamethonium.2. Most ganglion stimulants are also active at postganglionic receptors, some as blocking agents (for example, lobeline and dimethylphenylpiperazinium), others as agonists (for example, o-aminophenethyltrimethylammonium and, to a lesser extent, nicotine). The most specific ganglion stimulant, with the least activity at postganglionic receptors, was p-aminophenethyltrimethylammonium.3. The affinity constants of lobeline and dimethylphenylpiperazinium for the muscarine sensitive receptors in the guinea-pig ileum are 1.05 x 10(6) and 3.71 x 10(4), respectively.4. The antagonism of p-aminophenethyltrimethylammonium by hexamethonium gave results consistent with competition up to dose ratios of about 20. Such results could also be obtained if the antagonism were non-competitive, however, provided large responses could be obtained with less than about 5% of the receptors in the ganglia activated. The affinity constant of hexamethonium is about 2.6 x 10(5).5. It is suggested that the affinity of hexamethonium can largely be ascribed to hydrophobic bonding.

In the rat seminal vesicle, sensitivity to norepinephrine, epinephrine, acetylcholine and tyramine was increased by castration and the contractile responses showed a spontaneous phasic contraction. The sensitivity was markedly increased by estradiol treatment after castration and decreased by testosterone treatment. In the vas deferens, the contractile response to acetylcholine was weaker than that of norepinephrine, while in the 30 day castrated group it increased only the sensitivity to acetylcholine and testosterone treatment depressed only the sensitivity. Rhythmic contraction was observed on the vas deferens in the 30 day castrated rats. Testosterone treatment inhibited rhythmic response. In the 35_??_40 day castrated rats, spontaneous rhythmic contraction was also observed in the vas deferens. The frequency of the contraction was increased by application of high-K+ 10_??_40mM, and was decreased by high-Ca++ 1_??_10mM, however, the contractile response was increased. The spontaneous rhythmic contraction was not affected with TTX, atropine, cocaine, procaine, propranolol and reserpinization, however, a high dose of guanethidine, phentolamine depressed the contraction. From these observations, it is considered that the motility of the vas deferens and the seminal vesicle is controlled by gonadal hormones, and that androgen especially, exerts an inhibitory action on the motility of the genital musculature of the male rats while castration increases the sensitivity of the postsynaptic membrane.

The changes produced by reserpine and the ganglionic blocking agent, chlorisondamine chloride on the blood pressure, peripheral flow and blood vessel caliber of the hamster have been studied in an attempt to determine the first cause of the hypotensive effect of these compounds.

Summary 1 One vas deferens of a rat was denervated by stripping away the serous coat; the other vas was left intact as a control. One week later the sensitivity in vitro of both vasa deferentia to noradrenaline, adrenaline, dopamine, oxymetazoline or acetylcholine was measured. 2 Log concentration response curves for the mean responses of both vasa from a group of four rats for each drug were plotted. Denervated vasa were more sensitive than control vasa to noradrenaline (16-fold), to adrenaline (8-fold), to dopamine (2-fold) and to oxymetazoline (2-fold). Denervated vasa were more sensitive to acetylcholine over the lower half of the concentration range only. 3 It is concluded that these results support the theory that at least part of the increased sensitivity of denervated smooth muscle to catecholamines is due to an abolition or reduction of the neuronal uptake process. There is also a small non-specific increase in sensitivity.

INVESTIGATIONS on the electrocardiogram (ECG) of the normal chicken with modern electrocardiographic procedures have been performed by Sturkie (1949), Kisch (1951), Bond et al. (1961) and Douglas (1962). Furthermore, Sturkie (1951 Furthermore, Sturkie (1954) and Sturkie et al. (1954, 1957) reported on the effects of some minerals, vitamins and sex hormones on the ECG of the chickens. No investigations, however, which dealt with the exact relationship between the effects of the autonomic agents and the changes of the ECG of the chicken have been found other than the brief description with respect to the ergot alkaloids by Vander Brook et al. (1940) and the atropine sulfate by Sturkie (1950). It has been considered that epinephrine or norepinephrine and acetylcholine are the basic and representative drugs among all autonomic agents. The purpose of the experiment reported herein was mainly to clarify the effects of epinephrine and acetylcholine on the ECG of the chicken…

Effects of autonomic agents on the responses produced by hypogastric nerve and transmural stimulation of the hypogastric nerve-seminal vesicle preparation of the guinea-pig were examined. Hexamethonium and nicotine blocked the responses to hypogastric stimulation leaving the contractions due to transmural stimulation . TTX and xylocaine blocked both responses. Spontaneous contraction which was observed in 30% of the preparation was not abolished by TTX, hexamethonium, guanethidine and atropine. Acetylcholine, metacholine and noradrenaline elicited or potentiated the spontaneous activity.Adrenaline, noradrenaline, phenylephrine and nialamide enhanced the responses produced by the stimulation of hypogastric and transmural stimulation while guanethidine and phenoxybenzamine reduced the responses. Acetylcholine, metacholine, carbachol and cholinesterase inhibitors increased the responses. Atropine and bevonium inhibited the responses. Required pulse number in the transmural stimulation for producing the contraction was decreased in nialamide, metacholine, carbachol, physostigmine and neostigmine and increased in phenoxybenzamine, guanethidine and atropine.The possibility that adrenergic and cholinergic mechanisms operate independently of each other in the seminal vesicle preparation was discussed.

Summary 1 . Increasing the concentration of KC1 in Krebs-Henseleit bicarbonate solution enhanced the formation of 14C-noradrenaline (14C-NA) from 14C-tyrosine in the guinea-pig vas deferens. In 52 mm KC1 Krebs-Henseleit solution the specific activity of the newly formed 14C-NA was double that of controls. 2 . The rate of synthesis of 14C-NA from 14C-tyrosine was constant for up to 2 h in 52 mm KC1 Krebs-Henseleit solution and for 4 h in unmodified Krebs-Henseleit solution. 3 . There was no increase in NA formation in the presence of KC1 rich Krebs-Henseleit solution if 14C-DOPA was used as the starting substrate instead of 14C-tyrosine. 4 . The specific activity of 14C-tyrosine in the high KC1 treated vas deferens was 80% of that of control tissues. Thus the enhanced synthesis of 14C-NA in high KC1 Krebs-Henseleit solution did not arise from an increase in the specific activity of precursor. 5 . The effect of K+ on NA synthesis was not mimicked by ganglionic stimulants nor blocked by tetrodotoxin. 6 . Removal of Ca2+ ions or increasing the concentration of Mg2+ ions abolished the increase in synthesis of NA seen in high KC1 Krebs-Henseleit solution but left the basal rate of NA synthesis in unmodified Krebs-Henseleit solution unaltered. 7 . The spontaneous release of newly synthesized catecholamines (14C-labelled) or tritiated noradrenaline (3H-NA) from vasa deferentia was increased in 52 mm KC1 Krebs-Henseleit solution. Removal of Ca2+ ions reduced the increased efflux of newly synthesized amine in high KC1 media to that seen in unmodified Krebs-Henseleit solution. The efflux of 3H-NA was reduced to one-third of its former rate in the absence of Ca2+. 8 . High KC1 Krebs-Henseleit solution caused a substantial contraction of the vas deferens which was not abolished by tetrodotoxin. Release of 3H-NA paralleled the contractile response, and was likewise unaffected by tetrodotoxin. 9 . No evidence was obtained for any alterations in the activity of tyrosine hydroxylase, the rate limiting enzyme in the formation of NA from tyrosine, in homogenates of vas deferens which had been treated with 52 mm KC1 Krebs-Henseleit solution. 10 . These results support the hypothesis that acceleration of NA synthesis occurs when tyrosine hydroxylase is freed from end-product inhibition by the release of noradrenaline, brought about in this case, by high concentrations of KC1.