January 1964 L E T T E R S T O T H E E D I T O R 131

Effects of Sympathetic Neurohumors on Differential Retinal Sensitivity to

Short- and Long-Wave Stimuli MARTIN H. KEELER, M. D.

University of North Carolina, School of Medicine, Chapel Hill, North Carolina

(Received 7 June 1963)

I N 1936, Kravkov1 reported that stimulation of the sympathetic nervous system sensitized the human visual system to blue

and green, as compared to red stimuli, and that parasympathetic stimulation had reverse effect. His studies pertained to the scotopic, or dark-adapted state; visual threshold and critical fre­quency of fusion were utilized as parameters of sensitivity.

The effect of circulating neurohumors on differential retinal sensitivity is of conceptual and practical interest. It would demon­strate a direct or indirect central control of retinal function; it would have bearing on the purpose of autonomic reaction and it might help explain inconsistencies in color matching among in­dividuals and in the same individual over time.

Further studies were undertaken to answer three related ques­tions. One: Does norepinephrine, as well as epinephrine, have such effect? Both neurohumors are secreted by the body in varying amounts, depending on the individual and his physiological and psychological state. Epinephrine is principally involved in alerting the organism to stimuli and in preparation for active behavior; norepinephrine is principally involved in maintaining a physiologi­cal state conducive to action. The more commonly noticed effects of epinephrine include cardiac and respiratory acceleration, in­creased systolic and decreased diastolic blood pressure, and my­driasis. The effects of norepinephrine, less noticeable, include cardiac deceleration and increased diastolic blood pressure. Two : Can epinephrine and norepinephrine effects on retinal sensitivity be demonstrated in a strictly controlled experiment in which neither subjects nor investigators know when a pharmacologically active agent is present? Three: Do these changes occur for stimuli in the photopic range?

Kaplan2 reported that autonomic stimulation differentially affected retinal sensitivity in the photopic state. His parameter of sensitivity was that of differences in the visual effect of stimuli of

various hues and of their induced negative afterimages, It should be noted, however, that both Kaplan2 and Lehmann,3 another in­vestigator of afterimage phenomena, demonstrated, but did not elaborate on the fact, that there was not a consistent relation be­tween the effect of some drugs on visual sensitivity as measured by CFF and sensitivity as measured by afterimage phenomena. CFF has been more extensively utilized than have afterimage phenomena as a parameter of retinal sensitivity.

To provide additional data pertinent to the effect of sympathetic stimulation on differential sensitivity to various wavelengths, CFF determinations were made during the double-blind intraven­ous administration of epinephrine, norepinephrine, and saline.

Method. Twelve young men who were apparently free from physiological or psychological abnormality participated as sub­jects. For each subject the procedure consisted of the continuous intravenous administration of isotonic saline for 1 h except for a 5-min period during which epinephrine at the rate of 4 μg per minute and a 5-min period during which norepinephrine in the same dosage was substituted. Neither subjects nor the operator of the CFF apparatus were aware of the nature of the experiment nor whether drugs were used nor when drugs were present. A 10-min rest period after the start of the intravenous saline permitted the subjects to become somewhat accustomed to this procedure. Six CFF determinations, each of which required between 2 and 4 min, were started at 10-min intervals. These were arranged to coincide with any period of drug administration. Intravenous epinephrine, in the dosage used, is almost immediately effective; the effect lasts during the entire period of administration and there is minimal aftereffect. Norepinephrine as given is similarly immediately and continuously effective but residual effects may occur; these would be comparatively mild 5 min after cessation of dosage. Four of the 12 subjects were aware of tachycardia, tachypnea, or an "anxiety­like" feeling during the administration of epinephrine but could not identify these as epinephrine reactions. One subject reported awareness of undefinable physiological change during the adminis­tration of norepinephrine.

Six subjects received epinephrine and six received norepine­phrine during the second CFF determination; the drug not given during the second was given to each subject during the sixth de­termination. This minimized the possibility of the presence of one drug while the other was being given. A mechanical CFF apparatus was utilized; stimuli were presented to a 1° foveal area, and the artificial pupil of lesser diameter than the meiotic human pupil precluded drug-induced changes in pupil size from affecting retinal illumination. Interference filters served to control wavelength: green (530 mμ) at 4.5-mL luminance, yellow (575 mμ) at 7.5-mL luminance, and red (620 mμ) at 5-mL luminance. The L/D ratio was one; three ascending runs were made with each of the three stimuli during each of the six test occasions.

Results. Table I indicates changes in CFF during the intravenous administration of epinephrine and norepinephrine as compared to the average CFF during four periods of administration of saline. There is an inevitable and considerable scatter of data in such a procedure, as participation in an experiment of unknown nature involving intravenous procedures may be expected to produce arousal which might affect CFF determinations. Epinephrine in­creased the CFF of a short-wave (green) stimulus as compared to the control condition to a degree that would occur by chance five times in a hundred trials (the two-tailed Wilcoxon Signed Rank test was used to test significance). Differences between CFF of the yellow and red stimuli in the epinephrine and control conditions were not individually significant.

The three colored stimuli were compared as to how many sub­jects each was the most, second most, and least increased as com­pared to the control condition. (When decrease occurred the greatest decrease was scored as the least increase.) A chi-square analysis of this array indicated that epinephrine-induced increases were progressively greater (or epinephrine-induced decreases were comparatively less) for red, yellow, and green stimuli in that order at the p <0.05 level.

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TABLE. I. Change in CFF (critical frequency of fusion) after administration of epinephrine and norepinephrine.

Norepinephrine did not significantly alter CFF for any in­dividual stimulus. Analysis of the changes for all three stimuli, as described above, indicates that norepinephrine-induced increases were greater (or norepinephrine-induced decreases less) for red, yellow, and green stimuli in that order at the p<0.05 level.

Discussion. The stimulus technique utilized was selected on two bases. Pilot studies had demonstrated that it was efficacious in demonstrating differential sensitization, and it is a technique not infrequently used in studies of aperture color. Although cone-based mechanisms are involved as a result of the central location and luminance of the stimuli, adaptation is not photopic and drug-induced changes in rod function might influence cone function. The results can, thus, be interpreted only in terms of over-all retinal reaction. The range of CFF values indicates that cone func­tion is involved; an increase in CFF in this circumstance most likely reflects increased sensitivity.

The effects of norepinephrine are difficult to evaluate. There is a possibility that a norepinephrine reaction may precipitate an epinephrine response. The fact that both neurohumors caused a differential shift in sensitivity and only epinephrine caused an increase in CFF for short-wave stimuli indicates that something more than a secondary epinephrine response was involved in the reactions to norepinephrine.

The mechanisms of a differential shift may depend on the action of circulating neurohumors on the retina or may be mediated by the effect of these agents on higher nervous centers; such centers could affect the retina through efferent sympathetic and parasym­pathetic pathways. Kravkov1 demonstrated that administration of drugs into the conjunctival sac altered differential sensitivity. This indicates that the retinal response to pharmacological agents need not be totally mediated by higher centers.

1 S. V. Kravkov, J. Opt. Soc. Am. 31, 335 (1941). 2 S. Kaplan, Psychiat. Res. Rept. 12. 104 (1960). 3 H. Davson, The Eye (Academic Press Inc., New York and London, 1962).