Effect of sympathetic stimulation on ocular ...

Effect of sympathetic stimulation on ocular hemodynamics Milton Best, Samuel Masket, and Asher Zeev Rabinovitz

Although previous studies have indicated that cervical sympathetic stimulation reduces ipsilateral ocular blood flow, the mechanism of this effect is not apparent because simultaneous measurements of alterations in vascular perfusion pressure to the eye were not obtained. In the present study, the effects of cervical sympathetic stimulation on ocular hemodynamics and systemic blood pressure were investigated in the rabbit and the cat to determine whether ocular blood flow was altered by an active process and uveal vasoconstriction or passively in response to alterations in vascular perfusion pressure. In the rabbit, cervical sympathetic stimulation induced a decrease in femoral, carotid, and ciliary artery blood pressure. There was a simultaneous decrease in uveal blood flow and a slight but probably insignificant reduction of uveal vascular resistance. When the common carotid artery teas ligated, distal carotid and ciliary artery blood pressure and uveal blood flow increased after sympathetic stimulation. In the cat, sympathetic stimulation increased femoral, carotid, and ciliary artery blood pressure. Anterior uveal blood flow increased simultaneously, although uveal vasctdar resistance was not significantly affected. Thes(^e£uks-JbxM.cxi£e*JhQL-^^ ^ f f l vascular

Key words: sympathetic stimulation, ocular hemodynamics, uveal blood flow, uveal vascular resistance, ciliary arteiy blood pressure, ciliary artery blood flow, vortex vein blood flow

D,

sympathetic nervous system in the control of ocular blood flow is unclear. Attempts to clarify this issue have been based primarily on measurements of changes in ocular vasomotor tone or blood flow after simulation of the ipsilateral cervical sympathetic nerve in animals. Thus, sympathetic stimulation has been found to increase the critical closing pressure of the intraocular circulation, reflecting an increase in vasomotor tone,3 and to reduce blood flow in the iris,4 ciliary body,5 and choroid.6 Analysis of these and similar studies7"9 has led to the conclusion that the reduction in ocular blood flow after ipsilateral cervical sympathetic stimulation is due to an increase in uveal vascular

"espite anatomic evidence of adrenergic innervation of iris, ciliary body, and choroidal blood vessels,1'2 the role of the

From the Department of Ophthalmology, New York Medical College, Center for Chronic Disease, Bird S. Coler Hospital, Welfare Island, New York, N. Y. Aided by United States Public Health Service Grant No. HE 13660-06 and Grant No. 69-869 from the American Heart Association. Manuscript submitted Jan. 17, 1972; revised manuscript accepted Feb. 28, 1972. Reprint requests to: Dr. Best, New York Medical College, Center for Chronic Disease, Bird S. Coler Hospital, Welfare Island, New York, N. Y. 10017.

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Fig. 1. Effect of cervical sympathetic stimulation (1.2 v., 0.5 msec, five per second) on femoral and ipsilateral common carotid artery blood pressure in the rabbit. A, Stimulus on; B, stimulus off. Note biphasic response of carotid blood pressure when the common carotid artery is patent.

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of vasoconstriction that increases uveal vascular resistance or occurred passively in response to alterations in ocular vascular perfusion pressure. This was accomplished by correlating ciliary artery and vortex vein blood flow with femoral, carotid, and ciliary artery blood pressure before and during sympathetic stimulation.

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Rabbits weighing between 2 and 3 Kg. and cats weighing between 3.5 and 5 Kg. were anesthetized by intravenous administration of 30 nig. per kilogram pentobarbital sodium. Through a ventral midline neck incision, a 5 cm. length of the common carotid artery was exposed and freed of its sheath. The cervical sympathetic nerve was isolated 1 cm. below the thyroid cartilage, and a stimulating electrode was attached to it at this point. Carotid blood pressure was measured by two techniques. In some animals a plastic T-tube was inserted into the common carotid artery in order to maintain blood flow, while blood pressure was measured from the sidearm with a Statham P23BB pressure transducer. In these experiments common carotid blood flow was measured simultaneously with an electromagnetic flow probe. After ligating the artery in other experiments, cannulas were inserted to measure blood pressure proximal and distal to the point of ligation. In the cat, ciliary artery blood pressure and flow were measured in the temporal long posterior ciliary artery after disinserting the lateral rectus muscle. Blood pressure was measured by cannulating the artery just posterior to its entrance into

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Fig. 2. Effect of cervical sympathetic stimulation (1.2 v., 0.5 msec, five per second) on femoral and ipsilateral distal common carotid artery blood pressure after ligating the common carotid in the rabbit. A, Stimulus on; B, stimulus off. Note sustained rise in distal carotid blood pressure despite fall in systemic blood pressure.

resistance. However, most of these studies have measured ocular blood flow by indirect methods and have not adequately considered the effect of alterations in vascular perfusion pressure to the eye after cervical sympathetic stimulation. This study was undertaken to determine whether the alterations in ocular blood flow after ipsilateral cervical sympathetic stimulation were due to an active process

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Sympathetic stimulation on ocular hemodynamics 213

Table I. Effects of cervical sympathetic stimulation on mean femoral and carotid blood pressure in the rabbit Blood pressure (mm. Hg) Carotid artery Ligated

Intensity of stimulus (v.)

Femoral artery

0.6

-10

0.9

-15

1.2

-30

1.9

-28

Patent Distal segment Biphasic—rises 6 mm. Hg above then 18 falls 15 mm. Hg below prestimulation base line Biphasic—rises 12 mm. Hg above then falls 20 mm. Hg below prestimulation base line

Proximal segment

20

-12

15

-20

Mean changes in blood pressure from prestimulation base line in experiments on five rabbits.

Table II. Effect of cervical sympathetic stimulation on ciliary artery pressure (CAP), vortex vein flow (I), and uveal vascular resistance in the rabbit Animal No.

Carotid artery

Stimulus intensity (v.)

CAP

Uveal vascular resistance During Before stimulation stimulation

1 2

Patent Patent

0.6 1.9

-24 -30

-21 -21

59.2 60.0

47.4 53.0

3

Patent

1.2

-26

-23

54.1

49.1

4

Occluded Occluded

0.6 1.2

CO O CO CO

14 28

5

Occluded Occluded

0.6 1.2

22 47

13 39

6

Occluded

1.2

17

35

"Values indicate per cent change from prestimulation base line.

the sclera with PE 10 polyethylene tubing attached to a pressure transducer. Blood flow was measured by cannulating the artery with PE 10 polyethylene cannulas at two points and connecting them to a differential pressure-type flowmeter.10 The flowmeter, which had a sensitivity of 5 fi\ and responded in a linear fashion to alterations in flow, was calibrated after each experiment with the use of a constant-flow infusion pump. In experiments in which ciliary artery blood pressure and flow were measured simultaneously, pressure was determined in the medial and flow in the temporal long posterior ciliary artery of the same eye. In the rabbit, vortex vein blood flow was measured by cannulating one vortex vein with a PE 10 polyethylene cannula pointing toward the eye. One end of a differential pressure-type flowmeter was connected to the vortex vein cannula,

the other end remaining open to air. Bill11 has demonstrated that total uveal blood flow may be determined as the flow from one opened vortex vein multiplied by the numbers of veins if intraocular pressure exceeds 10 to 15 mm. Hg. Since intraocular pressure was maintained at 20 mm. Hg in these experiments, total uveal blood flow was considered to equal four times the flowmeter measurement. Simultaneous measurements of ciliary artery blood pressure were obtained in the temporal long posterior ciliary artery as described above. In all animals, systemic blood pressure was monitored by cannulating one femoral artery. Cervical sympathetic stimulation was performed with an isolated dual stimulator that delivered a rectangular pulse of variable intensity and 0.1 msec, duration at a rate of five per second.


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Fig. 3. Simultaneous effects of stimulation of right cervical sympathetic nerve (A, 1.9 v., 0.5 msec, five per second; C, 0.6 v., 0.5 msec, five per second) on femoral and contralateral carotid artery blood pressure, ipsilateral carotid and long posterior ciliary artery blood pressure, and ipsilateral carotid and vortex vein blood flow in the rabbit. Both carotid arteries were patent, A and C, Stimulus on; B and D, stimulus off. Pupillary dilatation was used as an indication that the correct nerve was being stimulated. Intraocular pressure was measured by cannulating the anterior chamber at the limbus with a 23 gauge needle attached to a pressure transducer and recorder. In most experiments, intraocular pressure was maintained at 20 mm. Hg with a saline reservoir. Uveal vascular resistance (UVR) was defined as (CAP - IOP)/I, where CAP is blood pressure in the long posterior ciliary artery, IOP is intraocular pressure, and I is uveal blood flow. UVR reflects vascular resistance in the anterior uvea

when flow was measured in the ciliary artery (cats) and in the entire uvea when flow was measured from the vortex vein (rabbits). Since pressure in the effluent uveal veins, under most conditions, approximately equals intraocular pressure,12 the vascular tree that was investigated includes only intraocular blood vessels.

Results Femoral and carotid artery blood pressure. No effect on femoral or carotid artery blood pressure was observed when the

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Fig. 4. Simultaneous effects of stimulation of right cervical sympathetic nerve on femoral and contialateral carotid artery blood pressure and ipsilateial distal carotid artery and ciliary artery blood pressure in the rabbit. Ipsilateral common carotid artery is ligated. Stimulus on at A (0.6 v.); C (0.9 v.); E (1.2 v.); G (1.9 v.); I (2.4 v.). Stimulus off at B, D, F, H, and J. All stimulation intensities have 0.5 msec, duration and five per second rate.

Table III. Effect of cervical sympathetic stimulation on ciliary artery blood pressure (CAP), ciliary artery blood flow (I), and uveal vascular resistance in the cat

Animal No. 1 2 3 4

5 6 7 8

Stimulus intensity (v.) 0.6 0.6 0.9 1.2 0.6 0.6 1.2 0.6

Uveal vascular resistance During Before stimulation stimulation

CAP* 19 24 19 19 23 22 22 29

27 25 25 32 31 18 18 46

32.6 30.8 32.6 34.1 29.6 36.2 35.6 31.6

32.1 33.6 32.0 32.3 29.3 39.5 38.9 30.9

'Values indicate per cent change from prcstimulation base line.

cervical sympathetic nerve was stimulated with 250 mv. or less. The typical effect of greater amounts of stimulation in the rabbits is shown in Fig. 1. After a short latent period there was a rise in ipsilateral carotid blood pressure which occurred simultaneously with pupillary dilatation.

About three seconds later, femoral blood pressure and pulse pressure decreased. Simultaneously, carotid blood pressure decreased below the prestimulation level while pulse pressure increased. This biphasic effect on carotid blood pressure was observed only when the artery was patent.


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Fig. 5. Simultaneous effects of stimulation of right cervical sympathetic nerve (A, 0.9 v., 0.5 msec, five per second; C, 1.2 v., 0,5 msec, five per second) on femoral and contralateral carotid artery blood pressure, ipsilateral distal carotid artery and long posterior ciliary artery blood pressure, and ipsilateral vortex vein blood flow in the rabbit. Ipsilateral common carotid artery was ligated. A and C, Stimulus on; B and D, stimulus off.

When the carotid artery was ligated in the rabbit, cervical sympathetic stimulation had an opposite effect on the proximal and distal segments. Distally, carotid blood pressure increased markedly despite the presence of a significant fall in femoral blood pressure (Fig. 2). However, the proximal carotid segment reflected the decline in systemic blood pressure. Table I lists the mean changes in femoral and ipsilateral carotid blood pressure in the rabbit after cervical sympathetic stimulation of varying intensity. In the cat, cervical sympathetic stimula-


tion caused a simultaneous increase in femoral and carotid artery blood pressure. A biphasic response, typical of the rabbit, was not found in the cat. There was a direct relationship between the magnitude of the changes in femoral blood pressure and the stimulus intensity between 0.6 and 1.2 v. Stimulus intensities greater than 1.9 v. caused profound depression of systemic blood pressure and lack of an adequate steady state in many animals. In the remainder of the study, therefore, stimulus intensities between 0.6 and 1.9 v. were used. In both species, stimulation of the distal end of a divided cervical sympathetic nerve effected the changes in blood pressure described above, while stimulation of the central end had no effect. Division of the vagus nerve in the neck or the administration of 40 to 60 mg. of atropine intravenously in the rabbit did not alter the effects of cervical sympathetic stimulation on femora] or carotid blood pressure. Ciliary artery blood pressure and flow; vortex vein blood flow. Events in the long posterior ciliary artery reflected those in the carotid artery. When the carotid artery was patent in the rabbit, ipsilateral cervical sympathetic stimulation reduced femoral, carotid, and ciliary artery blood pressure while simultaneously reducing carotid artery and vortex vein blood flow (Fig. 3). Fig. 4 shows the effects of sympathetic stimulation when the ipsilateral common carotid artery was ligated in the rabbit. Femoral and contralateral carotid blood pressure were reduced in direct proportion to the intensity of the stimulus, while ipsilateral carotid and ciliary artery blood pressure were simultaneously increased. The increases in ciliary and carotid pressure were largest with stimulus intensities of 0.6 and 1.2 v. When greater voltages were applied to the cervical sympathetic nerve, the resulting profound fall in systemic blood pressure limited the increase in blood pressure that occurred in the ipsilateral distal carotid artery segment and

Sympathetic stimulation on ocuhr hemodynamics 217

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Fig. 6. Effects of left cervical sympathetic nerve stimulation (1.2 v., 0.5 msec, five per second) on femoral blood pressure and ipsilateral long posterior ciliary artery blood pressure and flow in the cat. A, Stimulus on; B, stimulus off.

ciliary artery. Vortex vein blood flow on the side of the ligated carotid artery increased simultaneously with ciliary artery blood pressure after ipsilateral cervical sympathetic stimulation (Fig. 5). Table II lists the effect of cervical sympathetic stimulation on ciliary artery blood pressure, vortex vein blood flow, and uveal vascular resistance in the rabbit. Steadystate values of vortex vein blood flow were obtained in three experiments with a patent carotid artery, and these indicated that cervical sympathetic stimulation reduced uveal vascular resistance to a slight extent. When the carotid artery was ligated, sympathetic stimulation increased vortex vein blood flow, but adequate steady-state values for calculation of uveal vascular resistance could not be obtained due to induced large variations in vortex vein blood flow which appeared to be related to alterations in respiratory pattern. In the cat, cervical sympathetic stimulation increased ipsilateral ciliary artery blood pressure and flow (Fig. 6). There was a simultaneous increase in femoral and ipsilateral carotid artery blood pressure and vortex vein blood flow (Fig. 7). The

results of eight experiments in cats are listed in Table III and demonstrate that sympathetic stimulation did not significantly alter uveal vascular resistance. Intraocular pressure. In most experiments, intraocular pressure was maintained at 20 mm. Hg with an open manometric system in order to analyze the effect of sympathetic stimulation on ocular hemodynamics independent of alterations in intraocular pressure. When intraocular pressure was not controlled, however, it changed in the same direction as ciliary artery blood pressure after sympathetic stimulation. Discussion Previous investigators have used various indirect methods to assess the effect of cervical sympathetic stimulation on uveal blood flow. Adler9 attributed a decrease in the rate of formation of aqueous humor and Greaves and Perkins7 a fall in intraocular pressure after sympathetic stimulation to constriction of intraocular blood vessels. Using the ascorbic acid clearance technique, Langham and Rosenthal5 showed that blood flow through the ciliary body


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Fig. 7. Effects of left cervical sympathetic nerve stimulation on fenioral and ipsilateral carotid and ciliary artery blood pressure and vortex vein blood flow in the cat. Stimulus on at A (0.9 v., 0.5 msec., five per second) and C (1.2 v,, 0.5 msec, five per second). Stimulus off at B and D.

was reduced as much as 50 per cent by sympathetic stimulation. By measuring vascular heat dissipation from the iris, Cole and Rumble4 similarly demonstrated a decrease in iris artery blood flow. Bill0 used a calorimetric technique to measure choroidal blood flow and estimated total uveal blood flow by measuring vortex vein outflow. He showed that both of these were reduced by ipsilateral cervical sympathetic stimulation. Although these studies indicate that sympathetic stimulation reduces ocular blood flow, the mechanism of this effect is not


apparent, because simultaneous measurements of alterations in vascular perfusion pressure to the eye were not obtained. Bill's0 demonstration of an increase in uveal and choroidal vascular resistance during sympathetic stimulation is open to question, since his calculations of vascular resistance were based on measurements of femoral instead of ciliary artery blood pressure. Since the pressure in the arteries entering the uvea is significantly lower than that in the femoral artery, his calculations of vascular resistance include a portion of the extraocular vessels as well as the uveal vessels. The present study demonstrates that cervical sympathetic stimulation has different effects on blood pressure in the two species studied. Femoral, carotid, and ciliary artery blood pressure were increased in the cat at all stimulus intensities studied. The reverse effect was found in rabbits in which sympathetic stimulation induced a biphasic response of femoral and carotid artery blood pressure characterized by a transitory increase followed by a prolonged decrease in pressure. The decline in ciliary artery pressure occurred simultaneously with the decrease in systemic blood pressure. When the carotid artery was ligated in the rabbit, however, sympathetic stimulation increased ciliary artery and distal carotid blood pressure, despite a simultaneous decrease in systemic blood pressure. This latter result confirms the findings in previous experiments in rabbits.s Blood flow in the ciliary artery and vortex veins varied directly with ciliary artery blood pressure. In the cat, therefore, sympathetic stimulation increased ipsilateral ciliary artery blood flow. This appears to occur in a passive manner, since there was no change in uveal vascular resistance. The calculation of vascular resistance in the anterior uvea of the cat in this study is based on measurements of blood flow through one long posterior ciliary artery. Although this does not represent total anterior uveal blood flow, it

Sympathetic stimulation on ocular hemochjnamics 219

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Fig. 8. Effects of left cervical sympathetic nerve stimulation (0.9 v., 0.5 msec, five per second) on ipsilateral femoral and long posterior ciliary artery blood pressure and flow. A, Stimulus on; B3 stimulus off.

probably represents a large majority of the flow, since blood was diverted from the opposite long posterior ciliary artery which was used for blood pressure measurements. In addition, the anterior ciliary artery contribution to anterior uveal blood flow was reduced by the disinsertion of the medial and lateral rectus muscles. Any alterations in uveal vascular resistance during cervical sympathetic stimulation, therefore, were probably accurately reflected in the measurements of ciliary artery pressure and flow performed in this study. The difference in responsiveness of the ocular and hindlimb vasculature to sympathetic stimulation in the cat is clearly demonstrated in Fig. 8. Sympathetic stimulation increased both ciliary and femoral artery blood pressure. Ciliary artery flow increased in a passive manner, while femoral artery flow simultaneously decreased presumably due to an increase in vascular resistance in the hindlimb circulation. In the rabbit, blood flow was measured

in one vortex vein with a differential pressure flowmeter, and total uveal blood flow was considered to equal four times this value. Cervical sympathetic stimulation decreased ipsilateral ciliary artery blood pressure and uveal blood flow in the rabbit when the carotid artery was patent. Uveal vascular resistance was simultaneously decreased to a slight but probably not significant extent. When the carotid artery was ligated, ciliary artery blood pressure and uveal blood flow increased simultaneously, but uveal vascular resistance could not be calculated because adequate steady-state values of vortex vein blood flow were not obtained. This study confirms previous findings that cervical sympathetic stimulation has marked effects on both systemic blood pressure and local ocular vascular perfusion pressure. It is essential to consider these effects in attempts to elucidate the mechanism by which sympathetic stimulation effects alterations of ocular blood flow.



The present results indicate that changes of ocular blood flow after ipsilateral cervical sympathetic stimulation occur passively in response to alterations of vascular perfusion pressure to the eye and that uveal vascular resistance is not altered significantly. Technical assistance was provided George Hiller.

5.

6. 7.

by Mr. 8.

REFERENCES 1. Laties, A. M., and Jacobowitz, D.: A comparative study of the autonomic innervation of the eye in money, cat, and rabbit, Anat. Rec. 156: 383, 1966. 2. Wolter, J.: Nerves of the normal human choroid, Arch. Ophthalmol. 64: 120, 1960. 3. Best, M., Blumenthal, M., Masket, S., and Galin, M. A.: Effect of sympathetic stimulation on critical closure of intraocular blood vessels, INVEST. OPHTHALMOL. 9: 911,

1970.

4. Cole, D. F., and Rumble, R.: Responses of iris blood flow to stimulation of the cervical sym-

9. 10.

11. 12.

pathetic in the rabbit, Exp. Eye. Res. 10: 183, 1970. Langham, M. E., and Rosenthal, A. R.: Role of cervical sympathetic nerve in regulating intraocular pressure and circulation, Am. J. Physiol. 210: 786, 1966. Bill, A.: Autonomic nervous control of uveal blood flow, Acta Physiol. Scand. 56: 70, 1962. Greaves, D. P., and Perkins, E. S.: Influence of the sympathetic nervous system on the intraocular pressure and vascular circulation of the eye, Br. J. Ophthalmol. 36: 258, 1952. Bill, A.: Effects of cervical sympathetic tone on blood pressure and uveal blood flow after carotid occlusion, Exp. Eye Res. 2: 203, 1963. Adler, F. H.: The local control of the ocular circulation, Arch. Ophthalmol. 53: 1, 1924. Macri, F. J., and Brown, J. G.: The constrictive action of acetazolamide on the iris arteries of the cat, Arch. Ophthalmol. 66: 570, 1961. Bill, A.: Quantitative determination of uveal blood flow in rabbits, Acta Physiol. Scand. 55: 101, 1962. Bill, A.: Aspects of the regulation of uveal venous pressure in rabbits, Exp. Eye Res. 1: 193, 1962.