Karin Strenn

Role of NO in the O2 and CO2 responsiveness of cerebral and ocular circulation in humans

It is well known that changes in PCO2 or PO2 strongly influence cerebral and ocular blood flow. However, the mediators of these changes have not yet been completely identified. There is evidence from animal studies that NO may play a role in hypercapnia-induced vasodilation and that NO synthase inhibition modulates the response to hyperoxia in the choroid. Hence we have studied the effect of NO synthase inhibition by NG-monomethyl-L-arginine (L-NMMA, 3 mg/kg over 5 min as a bolus followed by a continuous infusion of 30 micrograms.kg-1.min-1) on the changes of cerebral and ocular hemodynamic parameters elicited by hypercapnia and hyperoxia in healthy young subjects. Mean flow velocities in the middle cerebral artery and the ophthalmic artery were measured with Doppler ultrasound, and ocular fundus pulsation amplitude, which estimates pulsatile choroidal blood flow, was measured with laser interferometry Administration of L-NMMA reduced ocular fundus pulsation. (-19%, P < 0.005) but only slightly reduced mean flow velocities in the larger arteries. Hypercapnia (PCO2 = 48 mmHg) significantly increased mean flow velocities in the middle cerebral artery (+26%, P < 0.01) and fundus pulsation amplitude (+16%, P < 0.005) but did not change mean flow velocity in the ophthalmic artery. The response to hypercapnia in the middle cerebral artery (P < 0.05) and in the choroid (P < 0.05) was significantly blunted by L-NMMA. On the contrary, L-NMMA did not affect hyperoxia-induced (PO2 = 530 mmHg) hemodynamic changes. The hemodynamic effects of L-NMMA (at baseline and during hypercapnia) were reversed by coadministration of L-arginine. The present study supports the concept that NO has a role in hypercapnia induced vasodilation in humans.It is well known that changes in [Formula: see text] or[Formula: see text] strongly influence cerebral and ocular blood flow. However, the mediators of these changes have not yet been completely identified. There is evidence from animal studies that NO may play a role in hypercapnia-induced vasodilation and that NO synthase inhibition modulates the response to hyperoxia in the choroid. Hence we have studied the effect of NO synthase inhibition by N G-monomethyl-l-arginine (l-NMMA, 3 mg/kg over 5 min as a bolus followed by a continuous infusion of 30 μg ⋅ kg-1 ⋅ min-1) on the changes of cerebral and ocular hemodynamic parameters elicited by hypercapnia and hyperoxia in healthy young subjects. Mean flow velocities in the middle cerebral artery and the ophthalmic artery were measured with Doppler ultrasound, and ocular fundus pulsation amplitude, which estimates pulsatile choroidal blood flow, was measured with laser interferometry. Administration ofl-NMMA reduced ocular fundus pulsations (-19%, P < 0.005) but only slightly reduced mean flow velocities in the larger arteries. Hypercapnia ([Formula: see text] = 48 mmHg) significantly increased mean flow velocities in the middle cerebral artery (+26%, P < 0.01) and fundus pulsation amplitude (+16%, P < 0.005) but did not change mean flow velocity in the ophthalmic artery. The response to hypercapnia in the middle cerebral artery ( P < 0.05) and in the choroid ( P < 0.05) was significantly blunted by l-NMMA. On the contrary,l-NMMA did not affect hyperoxia-induced ([Formula: see text] = 530 mmHg) hemodynamic changes. The hemodynamic effects ofl-NMMA (at baseline and during hypercapnia) were reversed by coadministration ofl-arginine. The present study supports the concept that NO has a role in hypercapnia-induced vasodilation in humans.

Nitric Oxide and Ocular Blood Flow in Patients With IDDM

Endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disorders such as diabetic retinopathy. We hypothesized that either local endogenous nitric oxide (NO) synthesis or local reactivity to endogenous NO might be impaired in patients with IDDM and that this may contribute to the development of diabetic retinopathy. Ten otherwise healthy patients with long-standing IDDM and ten healthy control subjects were studied according to an open randomized two-way cross-over design. Subjects received intravenous infusions of either NG-monomethyl-L-arginine, an inhibitor of NO-synthase, or L-arginine, the precursor of NO synthesis, on two separate study days. Ocular hemodynamics were assessed by laser interferometric measurement of fundus pulsations and Doppler sonographic measurement of blood flow velocity in the ophthalmic artery. NG-monomethyl-L-arginine decreased fundus pulsations and blood flow velocity in the ophthalmic artery and increased blood pressure in healthy subjects. The responses to NO-synthase inhibition were significantly less in diabetic subjects. In contrast, L-arginine caused a comparable increase in fundus pulsations and decrease in blood pressure in both cohorts. These results indicate that systemic and ocular hemodynamic reactivity to NO-synthase inhibition is reduced in patients with long-standing IDDM, compared with healthy control subjects. Thus, this study indicates that either NO-synthase activity is increased or NO sensitivity is decreased in patients with IDDM and supports the concept of an involvement of the Larginine–NO system in the pathophysiology of diabetic retinopathy.

Reproducibility and sensitivity of scanning laser Doppler flowmetry during graded changes in Po2

AIMS/BACKGROUND Recently a commercially available scanning laser Doppler flowmeter has been produced, which provides two dimensional maps of the retinal perfusion. The aim of the present study was to investigate the reproducibility and the sensitivity of these measurements. METHODS 16 healthy subjects were randomised to inhale different gas mixtures of oxygen and nitrogen in a double blind crossover study. The following gas mixtures of oxygen and nitrogen were administered: 100% oxygen + 0% nitrogen, 80% oxygen + 20% nitrogen, 60% oxygen + 40% nitrogen, 40% oxygen + 60% nitrogen, 30% oxygen + 70% nitrogen, 20% oxygen + 80% nitrogen, 15% oxygen + 85% nitrogen, and 10% oxygen + 90% nitrogen. Retinal haemodynamic variables and systemic haemodynamics were measured during all inhalation periods. Recordings under resting conditions were performed three times to calculate intraclass coefficients. RESULTS In two subjects we did not obtain technically adequate results. A dose dependent change in retinal blood flow during graded oxygen breathing was observed (p < 0.001). During 100% oxygen breathing blood flow decrease was between 29% and 33%, whereas blood flow increase was between 28% and 33% during inhalation of 10% oxygen + 90% nitrogen. CONCLUSIONS Scanning laser Doppler flowmetry has an acceptable reproducibility and is appropriate for description of the effect of graded changes in Po 2 on retinal haemodynamics. The main problems with the system are the large zero offset, the fixation during retinal scanning, and the neglect of blood flow changes during the cardiac cycle.

Effects of antiglaucoma drugs on ocular hemodynamics in healthy volunteers

There is evidence that ocular blood flow plays a critical role in the clinical course of glaucoma. Hence a reduction in ocular blood flow due to topical antiglaucoma treatment should be avoided. The purpose of this study was to characterize the effect of antiglaucoma drugs on ocular hemodynamics.

Capsular bag shrinkage after implantation of an open-loop silicone lens and a poly(methyl methacrylate) capsule tension ring

Purpose: To quantify the dynamics of capsular bag shrinkage after cataract surgery. Setting: University Eye Hospital, Vienna, Austria. Methods: Nineteen eyes in 13 patients had clear corneal cataract surgery with implantation of a foldable, open‐loop, silicone posterior chamber intraocular lens (IOL) (AMO SI‐30). At the same time, an open, poly(methyl methacrylate) capsule tension ring (Morcher type 14 or 14A) was inserted to allow measurement of capsular bag circumference and diameter. After surgery, capsular bag shrinkage was quantified by measuring anterior chamber depth (ACD), iris‐lens distance (ILD), and distance between the eyelets of the capsule tension ring using optical methods. Capsular bag circumference (CBC) was deduced from these measurements, which were taken 1 day (baseline), 1 week, and 1 and 3 months postoperatively. Results: Between 1 day and 3 months, all three parameters decreased significantly. During the first postoperative week, ACID and ILD did not change, while both parameters decreased between 1 week and 1 month. After 1 month, ACID did not decrease further; ILD continued to decrease. The CBC decreased during the entire postoperative period. Conclusion: Besides ACID and ILD, CBC significantly decreased during the first 3 months after cataract surgery with in‐the‐bag posterior chamber IOL implantation. The CBC can be calculated from the distance between the ends of the capsule tension ring, which can be measured gonioscopically. From this, the diameter of the capsular bag can be calculated in the living eye. The influence of the capsule tension ring itself on capsular bag shrinkage remains to be established.

Renal and Ocular Hemodynamic Effects of Insulin

There is evidence that the vasodilator action of insulin is mediated by the release of nitric oxide (NO). We hypothesized that euglycemic hyperinsulinemia might increase renal and ocular blood flow, and that the vasodilator capacity of insulin might be NO-dependent. Euglycemic insulin clamps were performed in 10 healthy subjects. Sixty minutes after the start of insulin administration, an intravenous coinfusion of N-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, or of norepinephrine (NE), an endothelium-independent vasoconstrictor, was started. Renal plasma flow was measured by para-aminohippurate (PAH) clearance method. Ocular hemodynamics were assessed by laser interferometric measurement of fundus pulsations and Doppler sonographic measurement of blood flow velocity in the ophthalmic artery. Renal plasma flow and ocular fundus pulsations were increased by insulin, L-NMMA almost completely abolished the vasodilative effects of insulin, whereas the effects of combined infusion of insulin and NE were approximately the sum of the hemodynamic changes induced by each agent alone. The results show that during euglycemic hyperinsulinemia, renal and ocular blood flow are increased, which may be mediated either by a local vasodilator effect or a systemic increase in flow. The hemodynamic effects of insulin in the kidney and the eye are at least partially dependent on NO synthesis. Because the insulin plasma levels we obtained are in the high physiological range, it may be assumed that insulin plays a role in renal and ocular blood flow regulation.

Reversal of endothelin‐1—induced ocular hemodynamic effects by low‐dose nifedipine in humans

There is evidence that calcium channel blockers may be useful in patients with normal tension glaucoma and vasospastic reactions. We therefore hypothesized that calcium channel blockers may increase ocular blood flow and that there may be a functional antagonism between endothelin‐1 (ET‐1) and calcium channel blockers in the ocular vasculature.

Age Dependence of Choroidal Blood Flow

OBJECTIVE: To investigate the age dependence of choroidal blood flow.

High-altitude retinopathy and retinal vascular dysregulation.

Purpose (a) To show that high-altitude retinopathy (HAR) is common at high altitudes even in well-acclimatised climbers and that it should not be regarded as part of the spectrum of benign mountain sickness but rather as a clinical sign with a separate aetiology. (b) To test the hypothesis that HAR could be interpreted as a clinical expression of ‘ocular vascular dysregulation.Methods Both eyes of the 8 mountaineers of the First Vienna Himalayan Expedition in May/June 1996 were examined 2 weeks before departure to and 2 weeks after descent from a high altitude. Retinal blood flow was measured in the right eyes of 7 climbers, using the Heidelberg Retina Flowmeter (HRF).Results Two of the 8 climbers had bilateral retinal haemorrhage after the expedition. In 5 climbers chronic hypoxic exposure caused an increase in retinal blood flow between +18% and +96%, and in 2 climbers a decrease in retinal blood flow between -21% and -31%. The 2 climbers (climbers 1 and 2) with bilateral retinal haemorrhage showed a significant increase in HRF parameters.Conclusions HAR may be a clinical sign of mountaineers with a tendency towards ocular vascular dysregulation. The pronounced increase in all haemodynamic parameters in the 2 climbers with retinal haemorrhage combined with a dilated epipapillary network 2 weeks after the exposure reflects a retinal vessel configuration, as might be expected at high altitudes under acute hypoxic stress. An inadequate autoregulatory response of the retinal circulation under conditions of chronic hypoxia may play an important part in the pathogenesis of HAR.

Surgically induced astigmatism following a 4.0 mm sclerocorneal valve incision

Purpose: To determine whether sutureless small incision cataract surgery reduces induced astigmatism over the long term. Setting: University Eye Hospital, Vienna, Austria. Methods: In a prospective study, we investigated surgically induced astigmatism in 63 cases of no‐stitch, small incision cataract surgery with a 4.0 mm square sclerocorneal tunnel and implantation of a flexible intraocular lens. Follow‐up was 4 to 5 years. Keratometry was measured with a Zeiss keratometer preoperatively and after 1 day, 1 week, 1, 3, and 9 months, and a median of 4.4 years. In 21 nonoperated eyes, we investigated the natural course of astigmatism over 5 years. Results: The mean keratometric cylinder stabilized at 0.8 diopter (D) after 1 week and slightly increased to 1.0 D after 4 to 5 years. Cravy’s vector analysis showed an immediate against‐the‐rule (ATR) shift of ‐0.2 D that remained relatively stable until 9 months. Between 9 months and 4.4 years postoperatively, there was a statistically significant increase in ATR induced astigmatism from ‐0.2 to ‐0.5 D. The natural course of astigmatism in the nonoperated eyes showed an ATR shift of ‐0.1 D for the same period. Conclusion: The results show a small, though statistically significant amount of postoperatively induced astigmatism 4 to 5 years after no‐stitch, small incision cataract surgery.