Eye (1990) 4, 319-325
Control of Retinal and Choroidal Blood Flow
A. BILL and G. O. SPERBER Uppsala, Sweden
Summary Earlier studies on the control of retinal and choroidal blood flow are reviewed and some recent observations on the effectsof light on retinal metabolism and retinal and choroidal blood flow in monkeys (Macaca fascicularis) are reported in preliminary form. The retina is nourished by the retinal blood vessels, where blood flow is auto regulated and the choroidal blood vessels where autoregulation is absent. Studies with the deoxygiucose method of Sokoloff indicate that flickering light tends to increase the metabolism of the inner retina, while constant light reduces the metab olism in the outer retina. Retinal blood flow in flickering light, 8 Hz, is higher than in constant light. The sympathetic nerves of the choroid are probably involved in a pro tective mechanism, preventing overperfusion in fight and flight situations with acute increments in blood pressure. The facial nerve contains parasympathetic vasodilator fibres to the choroid; the physiological significance of these fibres is unknown. The neuropeptides 'NPY, VIP and PHI are likely to be involved in autonomic reflexes in the eye.
Choroidal and retinal blood flow choroidal and retinal circulation mainly via In most tissues, the control of the circulation autonomic nerves and report on some recent is complex because of the many factors influ observations on effects of light on retinal encing the vascular resistance: local myogenic metabolism and blood flow. responses, endothelium derived substances The blood flow, Q, in the intraocular tissues and local metabolic factors as well as circu as in other tissues depends on the local arterial lating substances and the autonomic nerves. blood pressure, Pa, the local venous pressure and the resistance to flow, R. In the eye the The general strategy is that local factors strive pertinent venous pressure for practical pur to optimise the conditions with regard to such poses can be assumed to equal the intraocular factors as carbon dioxide and oxygen tensions pressure, lOP, except at very low intraocular and pH, (autoregulation of blood flow), while pressures.! The perfusion pressure for blood circulating factors and autonomic nerves are flow through the eye thus equals the local involved in moment to moment adjustment of arterial blood pressure in the arteries entering the distribution of the cardiac output accord the intraocular tissues minus the lOP. The two ing to certain priorities. There are great varia pressures have to be measured with the same tions between tissues with respect to the zero level, for obvious reasons. relative importance of local and other factors. Q = (Pa-IOP)/R In this communication we will give an over view of earlier work concerning the control of A reduction in perfusion pressure may be
From Department of Physiology and Medical Biophysics, University of Uppsala, Sweden.
Correspondence to: Professor A. Bill, Department of Physiology and Medical Biophysics,BMC, Box 572, S-751 23 Uppsala, Sweden. 320 A. BILL AND G. O. SPERBER caused by a rise in lOP as well as a fall in metabolites from the retina on the choroidal systemic blood pressure, but it may also be vascular resistance. caused by changing the position of the body. It seems likely that myogenic factors and Thus in the sitting or standing positions the local oxygen and carbon dioxide tensions and perfusion pressure is lower than in the recum pH as well as metabolites resulting from any bent position, due to the decrease in local tendency to abnormal metabolism are arterial blood pressure that takes place for involved in autoregulation of retinal blood hydrostatic reasons. This is not compensated flow. There is also the possibility that locally by the slight decrease in lOP that may take released transmitters involved in vision may place. affect the retinal blood vessels in a way that Studies in different species have demon cannot be foreseen from experiments with strated that reductions in perfusion pressure intravascular administration; the blood-ret cause corresponding reductions in choroidal inal barrier may prevent diffusion of the trans blood flow. In the retina on the other hand mitter from blood into the retina. moderate changes in perfusion pressure have In most tissues there is a need for variations only minor or no effects on the blood flow in in nutrition based on variations in activity. In experimental animals! as well as man.2 Alter vitro studies have indicated that there may be ations in perfusion pressure are thus compen variations in activity also in the retina. It does sated by factors that strive to maintain normal then become an intriguing question whether blood flowin the retina but not in the choroid. variations in retinal activity are accompanied The difference in control between the ret by variations in retinal and choroidal blood inal and choroidal vessels may be explained flow. Retinal blood flow might change due to by the location of the vessels and differences autoregulatory mechanisms, but for varia in blood flow rates; in the retina the blood tions in choroidal blood flow to occur there vessels are distributed within the inner layers would probably be a need for the involvement of the tissue and the metabolic situation in the of autonomic nerves. tissue may thus affect the resistance vessels directly. The oxygen extraction is about Role of autonomic nerves 40-50% ,3 which is similar to that in the brain. The eye has a rich supply of autonon'llc The extraretinal supply to the retina from the nerves, but these nerves are distributed only choroid is an obvious optical advantage but within the uvea and the extraocular parts of leads to diffusion over relatively large dis the retinal blood vessels. Sympathetic nerves tances which requires high extravascular con originate in the superior cervical sympathetic centrations of substrates in the choroid. The ganglion, parasympathetic nerves in the oxygen tension as well as the glucose concen pterygopalatine and ciliary ganglia. Experi tration in the tissue fluid of the choroid are ments with electrical stimulation of the sym indeed exceptionally high, little lower than in pathetic and facial and oculomotor nerves arterial blood.4 have revealed effects of such stimulations but There is a steep fall in oxygen tension in the the precise role of the nerves is not very well outer retina.5 The minimum is located in the understood. region of the outer nuclear layer. 6 Thus in this Choroidal vasodilatation achieved by intra region the oxygen consumed comes both from cranial stimulation of the oculomotor nerveis the retinal and choroidal vascular beds. A moderate, long-lasting and may in fact be due prerequisite for the high extravascular con to simultaneous antidromic co-stimulation of centrations of substrates in the choroid is that the ophthalmic division of the trigeminal blood flow per gram tissue is high; it is in fact nerve.7 It will not be discussed any further higher than in any other tissue of the body.! here. The arrangement of the blood vessels of the Stimulation of the cervical sympathetic choroid is another interesting feature. The chain causes frequency dependent vasocon arteries and arterioles are separated from the striction and reduced blood flow in the chor retina by the choriocapillaris layer. With this oid with near maximal effect at 10 Hz.! There arrangement there can be little influence by is practically no effect on retinal blood flow CONTROL OF RETINAL AND CHOROIDAL BLOOD FLOW 321
20
(n=10) (n=l7) 0 J J -20 .s -40 (n=10) (n=13) t -60 (n=14) (n=7) *** ., -80
-100 2 4 10 Frequency (Hz)
Fig. 1. The effect of sympathetic nerve stimulation at different frequencies on choriodal blood flowunder normal conditions 0 and after blockade of the alpha-adrenergic receptors •. The blood flow was determined with the labelledmicrosphere technique. From Granstam and Nilsson9• and also the preretinal oxygen tension is In rabbits sympathetic nerve stimulation essentially unaffected even at high frequen results in vasoconstriction even after massive cies indicating that the oxygen tension in the blockade of the adrenergic
Darkness Daylight
C/) C 0) - '"0
cu u +-' Q. o
v c v c
Retina Retina
2 mm. temporal of optic nerve, M and SEM,
12 sections_ V = vitreous, C = choroid_
Fig_ 3_ Effect of constant daylight on the accumulation or H-2-deoxyglucose in the retina. The average dptical density profile in autoradiographs of the retina at a position 2 mm temporal of the optic nerve head shows that constant light caused a moderate reduction in accumulation of tracer in the outer part of the retina. CONTROL OF RETINAL AND CHOROIDAL BLOOD FLOW 323
nerve mediated vasodilatation might be of ing light from a stroboscope reflectedfrom the bnportance during sleep; there is then a com same screen. After dark exposure of the con bination of darkness, which stimulates photo trol eye for at least 30 minutes and light expo receptor metabolism and episodes with sure of the experimental eye for at least 10 marked reductions in blood pressure. minutes deoxyglucose was injected intra According to a recent report there is a rise in venously and 40 minutes later the animal was intraocular pressure in the first 30 minutes killed and paracentesis was performed bilat aftersubjects sleep. 12 This rise might be due to erally. The whole head was frozen at - 40 DC, parasympathetic activation. Interestingly, the sectioned according to Ullbergl6 and auto nerves are not activated by a blood pressure radiographs were made. fall caused by haemorrhage.13 Figure 3 shows densitometric scans from the retinal side to the choroidal in an experi Effects of light on retinal metabolism ment with daylight on one side. Such light at Wel4 have recently studied the effectsof light about 220 Lux moderately reduced (about in cynomolgus monkeys (Macaca fascicularis) 30%) the accumulation of tracer in the outer on retinal metabolism with the 2-deoxy part of the retina but had no clear effect on the glucose method developed by Sokoloffl5 for inner layers. This reduction indicates a reduc studies on cerebral metabolism. In the experi tion in glucose metabolism. With flickering ments, one eye had the lids sutured and the light at 8 Hz there was a moderate increase whole orbit covered with black fabric and (about 30%) in accumulation of tracer in the plastic. The other was exposed in some inner parts of the central retina indicating experiments to laboratory light or daylight enhanced glucose consumption but no clear reflected from a white screen placed in front effectin the outer parts, (Fig. 4). These obser of the animal, in other experiments to f1icker- vations are in agreement with observation of
Darkness Flicker, 8Hz
Q. o
v c
Retina Retina
1 mm. temporal of optic nerve, M and SEM, 16 sections.
v = vitreous, C = choroid. Fig. 4. Effect of flickering light on the accumulation of 3 H-2-deoxyglucose in the retina. The average optical density profile in autoradiographs of the retina at a position 1 mm temporal of the optic nerve head shows that constant light caused moderate enhancement of tracer accumulation in the inner part of the retina. V: vitreious side, Ch: choroidal side of the retina. 324 A. BILL AND G. O. SPERBER
Table I Effects of flickering light, 8 Hz (n=8), and experiments with constant light to those with daylight (n=10 ) as compared to darkness on retinal and flickering light in spite of the fact that the choroidal blood flow. Mean values±SE. metabolism in the outer retina changed only in constant light and was then reduced. Thus, Blood flow, g/min Retina Choroid if vasodilatation occurred it was not an adjust ment to increased metabolic needs of the 8Hz O.062±O.0066 1.23±O.11 outer retina. The small effect of light on ret dark O.052±O.0076 l.34±O.16 inal blood flow observed in the present study light O.046±O.0040 l.30±O.19 is at variance with the results of previous stud dark O.057±O.0052 1.25±O.17 ies,19.20 in humans using the laser Doppler velocitometry method; according to these Sickel17 that in the isolated frog retina con studies retinal blood flow increased by 67% stant light reduced the metabolism while the and 40-70%, respectively, during dark expo onset of light caused a spurt of metabolism. sure. It seems possible that the laser light stimulated the metabolism of the inner retina Effects of light on retinal and choroidal resulting in a spurt of oxygen consumption blood flow and local vasodilatation. The labelled microsphere method was used as described elsewhere18 to determine the effects Metabolism and blood flow of light on retinal and choroidal blood flow The results of our recent studies in monkeys rates. The animals were anaesthetised with are in good agreement with the hypothesis urethan, arterial blood pressure, oxygen and that retinal blood flow is autoregulated, local carbon dioxide tensions and pH were checked metabolic factors playing an important role in to have normal values and blood flow deter preventing deficient nutrition. Choroidal minations were made at times which made the blood flow on the other hand is not autoregu results comparable to those performed with lated and independent of the metabolism in the deoxyglucose method. It was found in the outer retina; it seems to be set at a non these experiments, Table I, that retinal blood critical level in the sense that it is high enough flow tended to be higher in the eye subjected to permit adequate nutrition under physio to flickering light than in the control, the logical variations in metabolism in the outer difference being 0.01O±0.004 g/min (n = 8, retina. One can speculate that the role of the
P = 0.03 with one-tailed t-test). In the eye choroid in retinal temperature control has subjected to constant light the retinal blood determined the set point.21 This of course flow tended to be lower than in the control, does not mean that the flowis high enough to this difference being 0.011±0.05 g/min provide the nutrients necessary under all con
(n = 10, P = 0.03). ditions such as at high altitudes or at abnormal It is of interest also to compare retinal arterial or intraocular pressures. In cats even blood flowvalues for the retina under flicker moderate increments in lOP caused alter ing light and constant light. Under flickering ations in the dark-adapted standing poten light, the blood flow was 0.016 g/min higher tial,22 which may be a sign of hypoxia-induced than in constant light (p = 0.02). These reduction in metabolism.23 Such metabolic results suggest that the changes in retinal adaptation may explain why even marked blood flow that were caused by light were reductions in perfusion pressure have only small, flickering light tending to increase the moderate effects on the glucose consumption blood flow by some 20% and constant light in the retina in monkeys; evidence for tending to reduce the flow by a similar enhanced anaerobic glycolysis was found only percentage. at perfusion pressures that reduced also the There was no evidence for a unilateral retinal blood flow.24 effect of light on choroidal blood flow. How A fall in local oxygen tension in the outer ever, the possibility of a bilateral effect of light retina in darkness has been reported by Lin on choroidal blood flow (cf Parver11) cannot senmeier6 and was suggested to be due to be ruled out. If that occurred it was similar in enhanced metabolism under such conditions, CONTROL OF RETINAL AND CHOROIDAL BLOOD FLOW 325
The experiments with deoxyglucose and 9 Granstam E and Nilsson SFE: Non-adrenergic sym blood flowdeterminations reported here sup pathetic vasoconstriction in the eye and some other facial tissues in the rabbit. (Submitted for port this opinion. A high metabolic rate in the pUblication) 1989. photoreceptor layer of the retina can be 10 Nilsson SFE: Studies on ocular blood flow and aque expected in darkness due to the dark current ous humor dynamics. Acta Universitatis Upsalien which is due to enhanced sodium leakage into sis 1986, 43: 1-38. 11 the cells; rising intracellular sodium concen Parver LM, Auker CR, Carpenter DO, Doyle T: II Reflexive control in the monkey. Arch Ophthal trations are likely to stimulate the Na/K mol 1982, 100: 1327-30. ATPase involved in sodium transport out of 12 Brown B, Wildsoet CF, Swann PG: Sleep, light, dark the cells.25 and intraocular pressure. Invest Ophthalmol Vis Sci Suppl 1989, 30: 28. Effects of circulating substances 13 Linder J: Effects of facial nerve section and stimu A number of transmitters and hormones act lation on cerebral and ocular blood flow in hemo rrhagic hypotension. Acta Physiol Scand 1981, ing from the blood side may be expected to 112: 185-3. affectthe choroidal vessels and there may be 14 Bill A and Sperber GO: Aspects of oxygen and glu effects also on the retinal vessels. 1 Epineph cose consumption in the retina; effects of high rine, norepinephrine and angiotensin II may intraocular pressure and light. Graefe's Arch Ophthalmol (in press). be mentioned here. However, none of these . 15 Sokoloff L: Basic principles in imaging of regional can be expected to be involved in the regu cerebral metabolic rates. In Sokoloff L ed. Brain lation of retinal and choroidal blood flow imaging and brain function. Raven Press, New according to the varying needs of the retina. York, 1985, 1-47. 16 Ullberg S: The technique of whole body autoradiog We wish to thank Ms Lena Stjernschantz and Mr Alf raphy. Cryosectioning of large specimens. SCience Johansson for expert technical assistance. Tools, the LKB Instrument Journal (Bromma, Supported by Grant 5Rol EY 00475 from the Sweden): special issue on Whole-body Auto National Eye Institute, US Public Health Service and radiography, 1977: 1-29. by Grant 88-04X-00147 from the Swedish Medical 17 Sickel W: Retinal metabolism in dark and light. In Research Council. Handbook of sensory physiology. Fuortes MGF ed. Physiology of Photoreceptor Organs. 1972: References 667-26. 1 Bill A: Circulation in the eye. in Renkin EM, Michel 8 1 Aim A and Bill A: The oxygen supply to the retina. CC eds. Handbook in physiology. Microcircula II. Effects of high intraocular pressure on uveal tion, Part 2, The American Physiological Society and retinal blood flow in cats. A study with 1984, 1001-34. labelled microspheres including flow determina 'Robinson F, Riva EC, Grunwald JE, Petrig BL, Sin tions in brain and some other tissues. Acta Physiol clair SH: Retinal blood flow autoregulation in Scand 1972, 84: 306-19. response to an acute increase in blood pressure. 19 Feke GT, Zuckermann R, Green GJ, Weiter JJ: Invest Ophthalmol Vis Sci 1986, 27: 722-6. Response of human retinal blood flow to light and 3 Tornquist P and Aim A: Retinal and choroidal con dark. Invest Ophthalmol Vis Sci 1983, 24: 136-41. tribution to retinal metabolism in vivo. A study in 2 () Riva CE, Grunwald JE, Petrig BL: Reactivity of the Acta Physiol Scand pigs. 1979, 106: 315-3. human retinal circulation to darkness: A laser 4 Bill A, Tornquist P, Aim A: Permeability of the doppler velocimetry study. Invest Ophthalmol Vis Trans Ophthalmol Soc, intraocular blood vessels. Sci 1983,24:737-40. UK 1980, 332-6. 2 100: 1 Bill A, Sperber GO, Ujiie K: Physiology of the chor 5 Alder WA and Cringle S: The effect of raised intra oidal vascular bed. Internat Ophthalmol1983, 6: ocular pressure on the intraretinal oxygen pro 101-7. files. Invest Ophthalmol Vis Sci 1988, 29: 247 22 Yancey CM and Linsenmeier RA: The electroreti (Abstr). nogram and choroidal PO, in the cat during ele 6 Linsenmeier RA: Effects of light and darkness on vated intraocular pressure. Invest Ophthalmol Vis oxygen distribution and consumption in the cat Sci 1988, 29: 700-7. retina. J Gen Physiol1986, 88: 521-42. 23 Steinberg RH: Monitoring communications 7 Stjernschantz J, Aim A, Bill A: Effects of intra between photoreceptors and pigment epithelial cranial oculomotor nerve stimulation on ocular cells: effects of "Mild" systemic hypoxia. Invest blood flow in rabbits. Modification by indo Ophthalmol Vis Sci 1987, 28: 188-204. methacin. Exp Eye Res 1976, 23: 461-70. 2 4 Sperber GO and Bill A: Blood flow and glucose con 8 Bill A, Linder M, Linder J: The protective role of sumption in the optic nerve, retina and brain; ocular sympathetic vasomotor nerve in acute effccts of high intraocular pressure. Exp Eye Res arterial hypertension. Bibl Anat 1977,16:47-50. 1985,41: 639-53. (Proceedings of the 9th Europ Conf Microcir 25 Zuckerman R and Weiter JJ: Oxygen transport in culation, Antwerp 1976). the bullfrog retina. Exp Eye Res 1980, 30: 117-7.