New hope for preventing major problems of the retina

February 12, 2003

Bethesda, MD -- The primary function of the retina is to capture light and initiate neural signals. The retina contains the photoreceptors, which are the site of sensory transduction in the visual pathway. Major landmarks in the retina are the fovea and macula, where light has a direct pathway to the receptors. An interruption of the blood supply to these landmarks can lead to age-related macular degeneration and diabetes, the cause of severe visual problems.

Dopamine is an intermediate in tyrosine metabolism and precursor of norepinephrine and epinephrine; it accounts for 90 percent of the catecholamines; its presence in the central nervous system and localization in the basal ganglia (caudate and lentiform nuclei) suggest that dopamine may have other functions. Now a new research study reveals that the body's dopaminergic system plays a role in the regulation of retinal blood flow in the body. In addition, their data presents evidence for the diminishing effect of dopamine on the pathways coupling sensory input to vascular response.

Dopaminergic functions in the eye are complex and affect several ocular tissues. These include transmitter effects and impacts on intraocular (within the eyeball) pressure (IOP) and ocular blood flow. It is known from several tissues that vascular effects of dopamine are not only mediated via specific dopamine receptors but also by influencing other effector pathways like catecholamine receptors, a major responder to stress.

Vascular dopaminergic effects in the eye in past studies have revealed that dopamine antagonists (domperidone and haloperidol) increase ocular blood flow in rabbits. Other dopamine antagonists had similar effects, whereas dopamine agonists did not affect beating ocular blood flow. Dopamine has been investigated extensively in glaucoma research. One previous effort found that D1 agonists (when combined with receptors initiate drug action) increase pressure within the eye, where D1 antagonists decrease IOP; D2 agents have opposite effects. Dopamine also has an important role in sensory processing. As a neurotransmitter, it is involved in regulating the rod pathway. However, dopamine actions are not restricted to the transmission of nerve impulses. It is also used as a neuromodulator distributed diffusely in the outer retina during light adaptation. The modulatory functions include horizontal cell and photoreceptor coupling to change the receptive field organization. A direct connection exists between sensory input and retinal blood flow. Diffuse luminance flicker stimuli increase retinal vessel diameter in humans. However, the how this pathway works is still elusive.

A New Study
A new study examines the effect of dopamine on retinal vessel diameters and its modulatory effect on flicker-induced vasodilatation, or widening of the vessel's tubes. Local retinal vascular effects were studied in healthy human subjects after intravenous administration of dopamine. The authors of the study, "Effects of Dopamine on Human Retinal Vessel Diameter and its Modulation During Flicker Stimulation," are Karl-Heinz Huemer, Gerhard Garhöfer, Claudia Zawinka, Elisabeth Golestani, Brigitte Litschauer, Leopold Schmetterer, and Guido T. Dorner, all from the University of Vienna Medical School, Vienna, Austria. Their findings appear in the January 2003 edition of the American Journal of Physiology--Heart and Circulatory Physiology.

Methodology
The research entailed a randomized, subject-blinded, placebo and time- controlled, two-way crossover study in 12 healthy male subjects. Placebo or dopamine was administered on two separate study days. After saline infusion, dopamine hydrochloride was infused in three consecutive doses. Plasma levels of dopamine were determined at each perfusion step. Arterial and venous retinal vessel diameters were measured with the use of a Zeiss retinal vessel analyzer. Diffuse luminance flicker stimuli of eight Hz were applied for 60 seconds. Blood pressure and pulse rate were monitored.

Results
Flicker stimulation (8 Hz) increased retinal vessel diameters under basal conditions. The response to 8-Hz flicker light was significantly reduced by dopamine administration. In addition, dopamine slightly but significantly increased retinal vessel diameters. Dopamine hydrochloride significantly increased systolic but not diastolic or mean arterial pressure.

For the first time, evidence exists displaying the for dopaminergic effects on retinal vessels in humans. This indicates that the dopaminergic system plays a role in the regulation of retinal blood flow in vivo. In addition, their data present evidence for an attenuating effect of dopamine on the pathways coupling sensory input to vascular response. The results also reveal that dopamine significantly increases vessel diameters of retinal arteries and veins in a dose-dependent manner. Their finding is that dopamine increases retinal vessel diameters in vivo is an indicator that dopamine probably has a local effect on retinal vessels (also supported by data showing a high density of D1 receptor antibodies in rabbit retinal vessels).

Conclusions
This study finds reveals that flicker response in both retinal arteries and veins is diminished by dopamine. Although this indicates a role of dopamine in the regulation of retinal vascular tone, it does not necessarily prove a crucial role of dopamine in the neuronal pathway regulating this neurovascular response. Their data are, however, compatible with results from many studies showing dopamine release during light-to-dark transitions and during photic stimulation.

On the basis of these previous data, the researchers hypothesize that dopamine increases during flicker-stimulation in the present experiments. Consequently, exogenous administration of dopamine blunts flicker-induced vasodilatation because vessels are already predilated via the dopamine pathway. In conclusion, their data indicate a dopaminergic contribution to retinal vascular tone in the human retina.

Dopamine appears to play a role in flicker-induced vasodilatation. This could implicate possible roles of dopaminergic agents in alleviating the reduction of blood to the retina, thereby saving thousands of Americans from future vision problems.
-end-
Source: January 2003 edition of the American Journal of Physiology--Heart and Circulatory Physiology.

American Physiological Society

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