Volume 23 Number 5. Reports 683

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1 Volume 2 Number 5 Reports 68 in the vitreous body of the cat. Acta Physiol Scand 84:261, Niemeyer G: The function of the retina in the perfused eye. Doc Ophthalmol 9(1):5, Enroth-Cugell C, Goldstick TK, and Linsenmeier RA: The contrast sensitivity of cat retinal ganglion cells at reduced oxygen tensions. J Physiol 04:59, Linsenmeier RA, Mines AH, and Steinberg RH: Effects of hypoxia and hypercapnia on the light peak and electroretinogram of the cat. (Submitted for publication.) 9. Landers MB III: Retinal oxygenation via the choroidal circulation. Trans Am Ophthalmol Soc 76:528, Niemeyer G and Steinberg RH: Effects of low ph and high CO Z on the b-wave and light peak of the DC ERG in the perfused cat eye. INVEST OPHTHAL- MOL VIS SCI 20(ARVO Suppl.):4, Tsacopoulos M: Le role des facteurs metaboliques dans la regulation du debit sanguin retinien. Adv Ophthalmol 9:2, Winkler B: ERG in isolated rat retina. Vision Res 12:118, Steinberg RH, Schmidt R, and Brown KT: Intracellular responses to light from cat pigment epithelium: origin of the electroretinogram c-wave. Nature 227:728, Rodieck RW: The Vertebrate Retina. San Francisco, 197, W. H. Freeman and Co., ch. 18. Effects of changes in systemic blood pressure on the electroretinogram of the cat: evidence for retinal autoregulation. EVA DEMANT, KUNIHIKO NAGAHARA, AND GUNTER NIEMEYER. Systemic blood pressure was increased and decreased in anesthetized cats by intravenous infusion of angiotensin and by gradual exsanguination, respectively. The b- and c-wave amplitudes of the electroretinogram were used as indicators of activity of the inner retina and outer retina with pigment epithelium, which are supplied by the retinal and choroidal circulations, respectively. The amplitude of the b-wave remained stable during increases in mean arterial blood pressure () up to 225 mm Hg but decreased rapidly if the was lowered below 55 mm Hg. This wide range of stability of the b-wave is likely to be brought about by autoregulation of the blood supply to the inner retina. No such stability was seen in the c-wave, the amplitude of which changed inversely to increases or decreases in the. The c-wave thus appears to respond to changes in choroidal blood flow. The data provide new electrophysiologic evidence for autoregulation of the retinal vasculature and suggest that choroidal blood flow may influence the amplitude of the c-wave. (INVEST OPHTHALMOL Vis Sci 2:68-687, 1982.) Autoregulation is defined as the ability of the vasculature to maintain constant blood flow to an organ in accordance with its needs. Autoregulation of the vasculature in the eye in response to changes in systemic blood pressure has not been studied by electrophysiologic means as yet. The electroretinogram (ERG) is suitable for this purpose because stability or change in the amplitude of its components, the b-wave and the c-wave, can be expected to reflect properties of the retinal or choroidal circulation, respectively. The b-wave represents activity of the inner nuclear layer of the retina, which is supplied by the retinal circulation. The c-wave represents hyperpolarization of the retinal pigment epithelium combined with a retinal component; both sources are supplied by the choroidal circulation. We recorded ERGs during rises and falls in the systemic blood pressure induced by intravenous infusion of angiotensin and by gradual exsanguination. We correlated changes in amplitudes of b- and c-waves with changes in the mean arterial blood pressure (). Materials and methods. Four cats weighing 2.8 to.8 kg were premedicated with atropine sulfate 0.1 mg/kg subcutaneously and pentobarbital sodium 50 mg/kg intramuscularly (Nembutal; Abbott Laboratories, North Chicago, 111.). The animals were intubated, paralyzed by alcuronium chloride 0.5 mm/kg intramuscularly (Alloferin; Roche Laboratories, Nutley, NJ.) and ventilated with room air. Non-rebreathing, intermittent positive-pressure ventilation at a rate of 20/min and tidal volume of 0 ml was provided by a Harvard Model 660 respirator. Anesthesia and paralysis were maintained by repeated intramuscular injections of pentobarbital sodium and alcuronium chloride, respectively. The temperature was monitored by a rectal thermistor probe and kept stable at an average of 7.4 C by an adjustable heating pad. Intravenous infusion of Ringer's lactate solution was adjusted to maintain a normal hematocrit value. 1 After injection of bupivacaine 0.5% (Carbostesin; Astra-Bofors) into the pressure areas, the head of the animal was mounted in a stereotactic frame. Flashes presented by a Grass photostimulator were distributed in a Ganzfeld stimulator, cm in diameter. A corneal contact lens carrying an Ag-AgCl wire was used as the active electrode, and Ag-AgCl electrodes were placed under the skin of the forehead (reference) and a hind leg (ground). The pupil was dilated with 1% atropine sulfate and the animal was dark adapted until the ERG responses to stimuli of low intensity were /82/ $ Assoc. for Res. in Vis. and Ophthal., Inc.

2 684 Reports Invest. Ophthalmol. Vis. Sci. November 1982 mln min sec Fig. 1. Changes in b- and c-vvaves of the ERG during a blood pressure decrease (A) and a blood pressure increase (B). The decrease lasted 10 min, and the increase lasted 1 min. Time (min) is indicated on the left of each trace, and the corresponding values of the are indicated on the right of each trace. The initial a-wave (negative) is followed by the b-vvave (positive) and a later c-wave (positive). The stimulus (~20 //.sec) coincides with the beginning of each trace. Vertical calibration, 100 /xv. stable. This usually took about 1 hr. A constant light stimulus of an intensity of log units above the b-wave threshold (25 /x.v criterion) was then applied every 0 sec. The ERG was amplified at a bandpass of 0.0 to 00 Hz, displayed on an oscilloscope, and stored on FM tape for later analysis; it revealed a small negative a-wave and prominent positive b- and c-waves (Fig. 1). The c-wave was measured from the baseline of the ERG trace. Systemic blood pressure was monitored via a femoral artery catheter. was calculated as follows: = diastolic BP + systolic BP - diastolic BP Angiotensin was infused by intermittent intravenous administration to raise for periods of 2 to 10 min. After the angiotensin infusion was stopped, the returned spontaneously to control levels or slightly higher. The control and the steepness and height of the blood pressure rises varied between individual infusions of angiotensin, and the reached a maximum of 225 mm Hg. Decreases in blood pressure were produced by repeated reversed exsanguination. Results. Typical changes in the ERG during a blood pressure increase are shown in Fig. 1, B, and the data are plotted in Fig. 2. Blood pressure increases were induced in four animals for a total of seven times, reaching an of 1 to 225 mm Hg. All responses were similar, as is summarized in Table I. The b-wave amplitude remained stable even during the most rapid changes in blood pressure. The c-wave amplitude showed a biphasic change, i.e., a decrease as soon as rose, followed by an increase as soon as started falling. This pattern also was seen when the c-wave was measured from the troughs of the a-wave or the b-wave. During one of the seven blood pressure increases the c-wave decreased and subsequently returned to control without an overshoot. The a-wave showed no consistent changes, ex-

3 Volume 2 Reports 6 Number ERG response to blood pressure increase 150 WO, -A * * * 1 I ^ 100 b - wave o c - wa ve =9* 60 w time C minutes) Fig. 2. Typical response of the b- and c-wave amplitudes to an increase in blood pressure. Table I. Blood pressure increases and ERG I c-wave amplitude Experiment No. Increase in * Maximum b-wave amplitude decrease Subsequent increase t *E.xpressed in percent of control values for comparison, tlllustrated in Fig. 2. cept for a decrease in amplitude during experiments with induced decrease in. However, stimulus and adaptation were not selected to study the a-wave in particular. Typical changes in ERG during a blood pressure decrease are shown in Fig. 1, A, and the data are plotted in Fig.. We decreased the blood pressure five times to an of 45 to mm Hg. All responses are summarized in Table II. The b-wave amplitude remained stable as long as the was higher than 55 mm Hg; below this level the b-wave amplitude decreased in parallel with the decrease in and subsequently disappeared at an of 45 mm Hg. The c-wave amplitude increased initially, then decreased, and eventually was abolished. This pattern occurred in four of five blood pressure decreases. One c-wave series lacked the initial increase in amplitude; it fell steadily throughout. Discussion The b-wave and autoregulation. In the cat the retinal circulation forms two to three layers of capillary nets that supply the inner retina up to the outer border of the inner nuclear layer. The retinal vessels of the cat have been shown to autoregulate in response to changes in systemic blood pres-

4 686 Reports Invest. Ophthalmol. Vis. Sci. November ERG response to blood pressure decrease * O I 120 \ 10 \ 80 h 60 X 4o \ 20 \ 0 5 b - wave o c - wave time ('minutes) Fig.. Typical response of the b- and c-wave amplitudes to a decrease in blood pressure. Table II. Blood pressure decreases and ERG Changes in amplitude Experiment No. in * Minimum b-wave c-wave Subsequent It * Expressed in percent of control values for comparison, tlllustrated in Fig.. sure. 2 ' :! The present data add electrophysiologic evidence for autoregulation of the retinal circulation by showing stability of the b-wave, and thus of "retinal function," during changes in between 55 and 225 mm Hg. Retinal function largely depends on tissue Po 2. Under constant oxygenation in these experiments, the flow rate in the retinal vessels determines tissue PO 2. That the b-wave amplitude changes with change in retinal blood flow has been shown in man 4 as well as in the perfused mammalian eye in vitro. 5 From the remarkable stability of the b-wave during wide-ranging rises and falls in systemicblood pressure in our experiments, we conclude that the blood flow in the retinal circulation is kept stable by an autoregulatory mechanism. An upper limit of autoregulation has not been reached in our experiments; the lower limit is found at of 55 mm Hg. At levels lower than this the b-wave amplitude changes in parallel with the systemic blood pressure. The lower limit of autoregulation in the retina corresponds to the lower limit of cerebral autoregulation in man 6 and in dog, where it is given as an of 50 mm Hg in response to lowering the cardiac output. 7 In monkeys the lower limit of autoregulation in the peripapillary retinal vessels was found at perfusion pressure of cm H 2 O (corresponding to 0 mm Hg) in response to increases in intraocular pressure. 8 In man, retinal autoregulation has been shown to maintain a constant blood flow in the macular capillaries during decreases in perfusion pressure to 27 ± 6 mm Hg, i.e., by as much as 6%. 9

5 Volume 2 Number 5 Reports 687 The c-wave. We found that in all experiments the amplitude of the c-wave changed in the direction opposite to the change in, whether the blood pressure change was primarily induced or accompanied exposure to various gas mixtures. 10 It is likely that a rise in and its subsequent fall to control levels are paralleled by an increase and decrease in choroidal blood flow. 11 ' 12 In our experiments this postulated increase in choroidal flow was consistently accompanied by a decrease in c-wave amplitude, and conversely, a decrease in choroidal flow may have induced the increase in c-wave amplitude. We suggest that the c-wave amplitude is inversely affected by the choroidal blood flow via an unknown mechanism. The changes in c-wave amplitude may occur either in the pigment epithelial component of the c-wave or in the retinal component. Due to autoregulation 10 of the retinal circulation, it seems unlikely that the retinal component contributes to changes in the c-wave. It is possible that the changes in choroidal blood flow are influenced by choroidal vasoconstriction via the sympathetic innervation, which was kept intact in our experiments. We thank Mrs. V. Szabo for reliable secretarial assistance and Mr. I. Glitsch and Mr. P. Bar for their help in preparing the illustrations. From the Neurophysiology Laboratory, Departments of Ophthalmology and Otorhinolaryngology (K. N.), Universitatsspital, Zurich, Switzerland. Supported in part by Swiss National Science Foundation grant Submitted for publication Feb. 16, Reprint requests: G. Niemeyer, M.D., Department of Ophthalmology, Universitatsspital, CH-8091 Zurich, Switzerland. Present address (K. N.): Department of Otolaryngology, Kyoto National Hospital, Fushimiku Kyoto 612, Japan. Key words: autoregulation, electroretinogram, b-wave, c-wave, retinal circulation, choroidal blood flow, blood pressure REFERENCES 1. Nagahara K, Fisch U, and Dillier N: Experimental study on the perilymphatic pressure. Am J Otol :1, Porsaa K: Experimental studies on the vasomotor innervation of the retinal arteries. Acta Ophthalmol Suppl. 18, Aim A and Bill A: The oxygen supply to the retina. I. Effects of changes in intraocular and arterial blood pressures and in arterial po 2 and pco 2 on the oxygen tension in the vitreous body of the cat. Acta Physiol Scand 84:261, Jacobsen J and Lincoln M: Effect of vasodilator drugs and stellate ganglion block upon the electroretinogram. Arch Ophthalmol 52:917, Niemeyer G: ERG dependence on flow rate in the isolated and perfused mammalian eye. Brain Res 57:20, Lassen NA: Cerebral blood flow and oxygen consumption in man. Physiol Rev 9:18, Rappaport H, Bruce D, and Langfitt T: The effect of lowered cardiac output on cerebral blood flow. In Cerebral Circulation and Metabolism, Langfitt TW et al., editors. New York, 1975, Springer Verlag, pp Geijer C and Bill A: Effects of raised intraocular pressure on retinal, prelaminar, laminar and retrolaminar optic nerve blood flow in monkeys. INVEST OPHTHALMOL VIS SCI 18:100, Riva CE, Sinclair SH, and Grunwald JE: Autoregulation of retinal circulation in response to decrease of perfusion pressure. INVEST OPHTHALMOL VIS SCI 21:4, Niemeyer G, Nagahara K, and Demant E: Effects of changes in arterial po 2 and pco 2 on the electroretinogram in the cat. INVEST OPHTHALMOL VIS SCI 2: 678, Bill A: Intraocular pressure and blood flow through the uvea. Arch Ophthalmol 67:6, Macri FJ: The action of angiotensin on intraocular pressure. Arch Ophthalmol 7:528, 19.