In vivo pupillary constrictor effects of substance P in man.

The ocular effects of substance P (SP) were studied in 13 normal volunteers. Various concentrations of SP (0.135, 1.35 and 135 micrograms per 100 microliters) were instilled into the conjunctival sac and pupillary area changes were evaluated by means of an electronic pupillometer. The ability of SP to modify the mydriasis induced by pretreatment with 1% homatropine eyedrops was also studied. The instillation of SP produced miosis in a dose-dependent manner without provoking any ocular disturbances. Furthermore, the highest concentration tested was unable to reduce the homatropine-induced mydriasis. These findings indicate that SP exerts a pupillokinetic action in humans which probably occurs via a receptor mechanism. Since muscarinic blockade is not overcome by the peptide instillation, the results do not clarify whether SP causes miosis acting on iris muscles and/or cholinergic fibres.     

Pupillary effects of leucine and methionine enkephalin in rats after intraperitoneal administration

Changes in pupil size after peripheral administration of met-enkephalin, leu-enkephalin, or morphine were studied in the rat. With a simple pupillographic technique, the pupil diameter of male, S.D. rats (250–300 g) was measured by a series of photographs taken every 60 sec for at least 45 min after the last drug injection. Morphine (8 mg/kg, SC) caused mydriasis characterized by rapid and marked fluctuations of pupil size. Mydriasis also occurred after leu-enkephalin (5 and 10 mg/kg, IP) and met-enkephalin (20 mg/kg, IP). Both peptides induced morphine-like fluctuations. When given 15 min after morphine, leu-enkephalin (5 and 10 mg/kg) increased the mydriatic effect of morphine from 172 percent of control to 224 and 272 percent, respectively. Met-enkephalin (20 mg/kg, but not 10 mg/kg) also enhanced the mydriatic response of morphine, to 244 percent of control. These interactions appear to represent simple addition rather than potentiation. The effects of both peptides were reversed by naloxone (1 mg/kg, SC), suggesting an opiate receptor interaction for the pupillary effects of the enkephalins. The rat pupil thus provides one of the few in vivo models permitting quantification of enkephalin action after parenteral administration.     

Schistosoma mansoni: effects of bromolysergic acid diethylamide, verapamil, and Ca2+-free solution on the motor activity of the isolated male worm induced by electrical stimulation and oxamniquine

Electrical stimulation and oxamniquine effect the motor activity of isolated Schistosoma mansoni. Electrical stimulation produced contractions that increased with stimulus intensity. Oxamniquine (10(-4) M) produced an increase in basal tonus and in the frequency and amplitude of the worm's spontaneous contractions. Incubation in the absence of calcium produced a decrease in the basal tonus, abolished the spontaneous contractions of S. mansoni, and abolished the mechanical response induced by electrical stimulation and oxamniquine. The effects of electrical stimulation and oxamniquine were, respectively, significantly reduced and abolished by 10(-6) M verapamil (a calcium channel blocking agent). Bromolysergic acid diethylamide (3 X 10(-5) M), a serotonin blocking agent, reduced the motor response induced by high intensity electrical stimulation and blocked the response induced by oxamniquine. The effects of low intensity electrical stimulation were not modified in the presence of bromolysergic acid. We think that external Ca2+ is important for basal tonus, for spontaneous motor activity, and for motor responses of S. mansoni induced by electrical stimulation and oxamniquine. Serotonin may be important for mechanical responses induced by high intensity electrical stimulation and for responses induced by oxamniquine.     

Action of Thymoxamine on Mydriasis induced by Levodopa and Dopamine

Eye-drops of levodopa and dopamine induce pupillary dilatation which is inhibited by thymoxamine, an alpha-adrenergic blocking drug. This indicates that the mydriatic action of levodopa and dopamine involves excitation of alpha-adrenergic receptors of the dilator pupillae muscle. Such a conclusion is in accord with the previously expressed suggestion that levodopa is rapidly converted to dopamine, which displaces noradrenaline from adrenergic nerve endings.The findings that dopamine exerts alpha-adrenergic effects at the periphery may be construed as evidence in support of the view that the hypotensive action of levodopa is mediated via the central nervous system.     

视觉图形诱发的瞳孔反应

以图形变化刺激进行瞳孔反应研究,实验表明：（１）空间平均亮度守恒的光栅或棋盘格图形翻转能激发起瞳孔反应,为瞬态收缩波形,与ｐｕｐｉｌｌａｒｙ ｅｓｃａｐｅ相似;（２）光栅或棋盘格的空间频率的变化也能引起瞳孔反应,且反应幅度随空间频率差别增大而变大;（３）从均匀亮背景变化到棋盘格图形或者从棋盘格图形变化到黑暗背景,虽然不存在任何局部亮度增强,皆能引起瞳孔反应。实验结果明确证明了人的瞳孔反应系统除接收     

Stimulation of calcium pump activity in heart sarcolemma by timolol

The effects of beta-adrenergic blocking agents, timolol and atenolol (1-1000 microM), were studied on rat heart sarcolemmal ATPase and Ca2+ binding activities. Timolol, unlike atenolol, increased both Ca2+-stimulated ATPase and ATP-dependent Ca2+ binding; the maximal effects were seen at 1 microM concentration of timolol. Both timolol and atenolol did not alter the sarcolemmal Mg2+ ATPase and nonspecific Ca2+ binding activities. Sarcolemmal Ca2+-stimulated ATPase was also activated by concanavalin A (6-66 micrograms/mL) which is known to alter membrane fluidity; however, Mg2+ ATPase was unaffected by this agent. These results indicate that timolol may stimulate Ca2+ pump activity in heart sarcolemma by changing membrane fluidity in a manner similar to that of concanavalin A.     

A linear chromatic mechanism drives the pupillary response.

Previous studies have shown that a chromatic mechanism can drive pupil responses. The aim of this research was to clarify whether a linear or nonlinear chromatic mechanism drives pupillary responses by using test stimuli of various colours that are defined in cone contrast space. The pupil and accommodation responses evoked by these test stimuli were continuously and simultaneously objectively measured by photorefraction. The results with isochromatic and isoluminant stimuli showed that the accommodative level remained approximately constant (< 0.25 D change in mean level) even when the concurrent pupillary response was large (ca. 0.30 mm). The pupillary response to an isoluminant grating was sustained, delayed (by ca. 60 ms) and larger in amplitude than that for a isochromatic uniform stimulus, which supports previous work suggesting that the chromatic mechanism contributes to the pupillary response. In a second experiment, selected chromatic test gratings were used and isoresponse contours in cone contrast space were obtained. The results showed that the isoresponse contour in cone contrast space is well described (r(2) = 0.99) by a straight line with a positive slope. The results indicate that a /L - M/ linear chromatic mechanism, whereby a signal from the long wavelength cone is subtracted from that of the middle wavelength cone and vice versa, drives pupillary responses.     

Visual pigment processes and prolonged pupillary responses in insect photoreceptor cells

The visual pigment in the peripheral retinular cells of the hoverfly Syrphus balteatus was investigated by absorbance difference measurements. Different visual pigments were found in the dorsal versus the ventral part of the eye in the male, but not in the female. In the male in the dorsal part of the eye the visual pigment has an isosbestic point at 513 nm; in the ventral part this value is 490 nm. The latter value is found in the female in both parts of the eye.Prolonged pupillary responses were studied in the male Syrphus and appeared to be most marked in the ventral part of the eye. In both hoverfly and blowfly prolonged pupillary responses are induced by short wavelength light only; i.e., by light which excessively can convert rhodopsin into metarhodopsin. By contrast, in butterflies red light (and a long dark adaptation time) is necessary to evoke a prolonged pupillary response. It was demonstrated in both hoverfly and blowfly that long wavelength light, which reconverts metarhodopsin into rhodopsin, inhibits a prolonged pupillary response; or, accelerates pupil opening.Based on material presented at the European Neurosciences Meeting, Florence, September 1978     

Novel antiglaucoma prodrugs and codrugs of ethacrynic acid

The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.     

Peptidergic modulation of efferent sympathetic neurons in intrathoracic ganglia regulating the canine heart

When either substance P or vasoactive intestinal peptide was injected into an acutely decentralized intrathoracic sympathetic ganglion, short-lasting augmentation of cardiac chronotropism and inotropism was induced. These augmentations were induced before the fall in systemic arterial pressure occurred which was a consequence of these peptides leaking into the systemic circulation in enough quantity to alter peripheral vascular resistance directly. When similar volumes of normal saline were injected into an intrathoracic ganglion, no significant cardiac changes were induced. When substance P or vasoactive intestinal peptide was administered into an intrathoracic ganglion, similar cardiac augmentations were induced either before or after the intravenous administration of hexamethonium. In contrast, when these peptides were injected into an intrathoracic ganglion in which the beta-adrenergic blocking agent timolol (0.1 mg/0.1 ml of normal saline) had been administered no cardiac augmentation occurred. These data imply that in the presence of beta-adrenergic blockade intraganglionic administration of substance P or vasoactive intestinal peptide does not modify enough intrathoracic neurons to alter cardiac chronotropism and inotropism detectably. When neuropeptide Y was injected into an intrathoracic ganglion, no cardiac changes occurred. However, when cardiac augmentations were induced by sympathetic preganglionic axon stimulation these were enhanced following the intraganglionic administration of neuropeptide Y. As this effect occurred after timolol was administered into the ipsilateral ganglia, but not after intravenous administration of hexamethonium, it is proposed that the effects of neuropeptide Y are dependent upon functioning intrathoracic ganglionic nicotinic cholinergic synaptic mechanisms. Intravenous administration of either morphine or [D-ala2,D-leu5]enkephalin acetate did not alter the capacity of the preganglionic sympathetic axons to augment the heart when stimulated. Following the intravenous administration of naloxone, the positive inotropic cardiac responses induced by efferent preganglionic sympathetic axonal stimulation were enhanced minimally in control states and significantly following hexamethonium administration. Thus, it appears that enkephalins are involved in the modulation of intrathoracic ganglion neurons regulating the heart, perhaps via modification of beta-adrenergic receptors. Taken together these data indicate that substance P, vasoactive intestinal peptide, neuropeptide Y, or enkephalins modify intrathoracic ganglionic neurons which are involved in efferent sympathetic cardiac regulation.     

Responses of the autonomic nervous system in altitude adapted and high altitude pulmonary oedema subjects

Studies were carried out to ascertain the role of sympatho-parasympathetic responses in the process of adaptation to altitude. The assessment of status of autonomic balance was carried out in a group of 20 young male subjects by recording their resting heart rate, blood pressure, oral temperature, mean skin temperature, extremity temperatures, pupillary diameter, cold pressor response, oxygen consumption, cardioacceleration during orthostasis and urinary excretion of catecholamines; in a thermoneutral laboratory. The same parameters were repeated on day 3 and at weekly intervals for a period of 3 weeks, after exposing them to 3,500 m; and also after return to sea level. At altitude, similar studies were carried out in a group of 10 acclimatized lowlanders, 10 high altitude natives and 6 patients who had recently recovered from high altitude pulmonary oedema. In another phase, similar studies were done in two groups of subjects, one representing 15 subjects who had stayed at altitude (3,500–4,000 m) without any ill effects and the other comprising of 10 subjects who had either suffered from high altitude pulmonary oedema (HAPO) or acute mountain sickness (AMS). The results revealed sympathetic overactivity on acute induction to altitude which showed gradual recovery on prolonged stay, the high altitude natives had preponderance to parasympathetic system. Sympathetic preponderance may not be an essential etiological factor for the causation of maladaptation syndromes.     

Fade of the responses of the isolated, blood-perfused dog atrium to cholinergic interventions

In the isolated, blood-perfused, canine right atrium, intramural parasympathetic nerve stimulation and intra-arterial infusions of acetylcholine induced substantial negative chronotropic and inotropic responses. The responses to parasympathetic stimulation reached their maximum values quickly, and then usually faded back toward control levels over the next 1 or 2 min of stimulation. The fade of the responses at high stimulation frequencies (greater than or equal to 30 Hz) was significantly greater than that at lower frequencies. The inotropic responses to acetylcholine infusion (1 microgram/min) faded slightly but significantly, whereas the chronotropic responses did not fade at all. These results suggest that the fade of the cardiac responses to parasympathetic stimulation is mainly ascribable to a progressive reduction in the rate of acetylcholine release from the nerve endings, especially at higher stimulation frequencies. The fade of the inotropic responses was more pronounced and had a longer time course than that of the chronotropic responses. Furthermore, the fade of the inotropic responses diminished significantly as the response magnitude was augmented by an increase in stimulation voltage. Conversely, the fade of chronotropic responses was not significantly affected by this intervention. These differences in the inotropic and chronotropic responses to neural stimulation, and the occurrence of a slight fade of the inotropic response to acetylcholine infusion, suggest that in addition to the predominant prejunctional mechanism, a postjunctional phenomenon may also be partly responsible for the fade of the inotropic response to cholinergic interventions.     

Correlations Between Acetylcholinesterase Activity in Guinea-Pig Iris and Pupillary Function: A Biochemical and Pupillographic Study

: Acetylcholinesterase (AChE) in guinea pig iris was inhibited by methylisocyclopentylfluorophosphate (soman) administered topically or parenterally, and enzyme activity was correlated to pupillary diameter by infrared pupillography. After a single topical soman instillation into the conjunctival sac there was an almost linear relationship between the reduction in AChE activity and pupillary diameter. Topical administration of soman at 24-h intervals in doses capable of almost complete inhibition of AChE in iris was accompanied by a reduced miotic effect of this drug. This was indicated by a reduced rate of the soman-induced pupillary constriction, a less pronounced reduction in pupillary diameter, and a more rapid return of the pupillary diameter to normal size. The change in pupillary diameter occurred after three daily administrations and remained constant during 31 days of treatment. These observations were seen irrespective of inhibition of blood AChE. The decrease in response to repeated administration could not be explained by a reduced inhibitory effect of soman on AChE, by a more rapid de novo synthesis of AChE, or by a change in the number of the muscarinic receptors as determined by quinuclidinyl benzilate binding. When soman or DFP was administered subcutaneously in high doses a severe AChE inhibition was obtained in iris without any concomitant miosis.     

Increase of tonic parasympathetic outflow to the pupil produced by an analog of TRH (MK-771)

MK-771, a potent analog of thyrotropin-releasing, hormone, was found to cause a long-lasting, dose-dependent antagonism of the centrally induced pupillary dilation produced by clonidine in anesthetized cats. MK-771 had little direct effect on the dilated iris in cats treated with mecamylamine. Both MK-771 and TRH selectively antagonized the pupillary dilation, but not the contractions of the nicitating membrane induced by peripheral sympathetic nerve stimulation. MK-771 was found to increase nerve activity in the short ciliary nerve. TRH, although studied less extensively, produced similar effects. This action of MK-771 was not blocked by prior sectioning of the spinal cord, by elimination of the tonic light reflex pathway, or by treatment with scopolamine or atropine. These findings suggest that the pupillary effects of MK-771 (and TRH) are related to the ability to increase the parasympathetic tone to the iris.     

Light-dark variations in ocular timolol concentrations following topical solution instillation in the pigmented rabbit.

The objective of this study was to determine whether ocular absorption of topically applied timolol in the pigmented rabbit varied with the time of drop instillation. Twenty-five microliters of a 0.65% timolol maleate solution were instilled in the pigmented rabbit eye at 0600, 0900, 1200, 1500, 1800, 2100, 2400, or 0300 hr. Timolol concentrations in the conjunctiva, sclera, corneal epithelium, corneal stroma, aqueous humor, and iris-ciliary body at 15 and 30 min post-dosing were monitored using reversed phase HPLC. Ocular timolol concentrations were higher when the drug was administered during the light period (0900-1800 hr) than when it was administered during the dark period (1800-0600 hr). There exist, therefore, light-dark variations in the ocular absorption of topically applied timolol.     

Beta-Adrenergic Stimulation of Transmembrane Potential and Short Circuit Current of Isolated Rabbit Oviduct

THE secretions of the mammalian oviduct provide the immediate environment for fertilization and the first 3–4 days of embryonic development. While the importance of oestrogen and progesterone in modifying oviductal secretions is well established, there have been few investigations of the influence of autonomic drugs. Bishop¹ showed that pilocarpine, a parasympathomimetic agent, stimulated the rate of oviductal fluid secretion in anaesthetized rabbits, but others², using unanaesthetized rabbits, found that pilocarpine, scopolamine (a parasympathetic blocking agent) and phenoxybenzamine (an alpha-adrenergic . blocking agent) had no such effect.     

Neuromedin S regulates cardiovascular function through the sympathetic nervous system in mice

Intracerebroventricular (icv) injection of neuromedin S (NMS) in mice increased the heart rate in a dose-dependent manner. On the other hand, genetically NMS deficient mice (NMS-KO mice) exhibited a decreased heart rate and significant extension of the QRS and PR interval in the electrocardiogram complex. Although treatment with a parasympathetic nerve blocker, methylscopolamine, and a sympathetic nerve blocker, timolol, respectively increased and decreased the heart rate in both NMS-KO and wild-type mice, the extent of the decrease induced by timolol was smaller in NMS-KO than in wild-type mice. In addition, pretreatment with timolol completely inhibited the NMS-induced heart rate increase in wild-type mice. No expression of mRNA for NMS or the NMS receptor was evident in the heart by RT-PCR analysis. These results suggest that endogenous NMS may regulate cardiovascular function by activating the sympathetic nervous system.     

在双脉冲光刺激下瞳孔系统的采样控制特性

本文用实验揭示了瞳孔对光动态反应具有采样控制特性。实验中采用各种不同时间间隔的双脉冲光,以开环的方式(Maxwellian View)刺激瞳孔,当双脉冲之间间隔较长时,瞳孔反应相当于对双脉冲光的两次脉冲分别产生瞬态收缩;当双脉冲时间间隔短于0.6s 时,其反应就成了一次瞬态收缩,与单个光脉冲所引起的瞳孔反应一样。同—受试者的多次实验结果相同,不同受试者所得结果也基本一致。故瞳孔对脉冲刺激光引起反应后,必须至少约隔0.6s 才能对另一次脉冲光产生反应,这就说明了瞳孔动态反应具有离散的采样控制特性。实验还进一步证明,瞳孔系统的控制机制是双重模式的控制:不同的刺激条件下,瞳孔反应可呈现为瞬态反应(AC)或持续反应(DC),瞬态反应的 AC 通道为离散的采样控制,持续反应的 DC 通道为连续控制。     

Preliminary study of the topical use of thymoxamine

In this work the Authors have tried to show the efficacy of TMX, as a miotic drug, and to find out the lowest concentration which can give the best results with the minor complications. Seven patients, in whom TMX was instilled in both eyes at 0.50%, 1%, 2% concentrations, were studied. A mydriatic was instilled before in the right eye, in order to obtain mydriasis whereas the left eye served as control. The 0.5% concentration was as efficacious as 1% and 2% ones, but had less side-effects.     

Central and peripheral mechanisms underlying gastric distention inhibitory reflex responses in hypercapnic-acidotic rats

We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD-induced decreases in BP and HR responses. Efferent chronotropic responses involve both increased parasympathetic and reduced sympathetic activity, whereas the decrease in BP is mediated by reduced α-adrenergic tone.