Mechanisms of choroidal blood flow autoregulation during isometric exercise

Research project P 14219 Mechanisms choroidal autoregulation Michael WOLZT 06.03.2000 Title: Mechanisms of choroidal blood flow autoregulation during isometric exercise Investigators: Dr. Michael Wolzt, Prof. Dr. Leopold Schinetterer, Dr. Oliver Findl, Dr. Elzbieta Polska, Departments of Clinical Pharmacology and Ophthalmology, Institute of Medical Physics Clinical Investigator: Prof. Dr. Hans-Georg Eichler, Department of Clinical Pharmacology Background: Autoregulation is the ability of a vascular bed to maintain blood flow despite changes in perfusion pressure. For a long time it had been assumed that the choroid is a strictly passive vascular bed, which shows no autoregulation. However, recently several groups have identified some autoregulatory capacity of the rabbit and human choroid. In the brain and the retina the mechanism underlying myogenic autoregulation is most likely linked to changes in transmural pressure. In this model arterioles change their vascular tone depending on the pressure inside the vessel and ` outside the vessel. However, the mechanism behind choroidal autoregulation in humans remains unclear. In the present study squatting will be performed during administration of drugs, which may potentially alter the pressure-flow relationship. These drugs include a nitric oxide (NO) synthase inhibitor, an a-receptor agonist, an ACE inhibitor, an endothelin A-receptor antagonist, a muscarinic receptor antagonist, and a non specific P- adrenoceptor antagonist. These drugs were chosen on the basis of previous animal experiments, as the systems, which are specifically influenced by these substances, are likely to be involved in choroidal autoregulation during isometric exercise. Study objectives: To identify mechanisms behind choroidal blood flow autoregulation during isometric exercise. Study design: Study A: Randomized double masked, placebo-controlled three way cross-over study with phenylephrine (a-receptor agonist), NG-monomethyl-L-arginine (NO-synthase inhibitor) or placebo Study B: Randomized double masked, placebo-controlled three way cross-over study with BQ-123 (endothelinA- receptor antagonist), enalapril (ACE inhibitor) or placebo Study C: Randomized double masked, placebo-controlled three way cross-over study with propanolol (P 1 - receptor antagonist), atropine (muscarinic-receptor antagonist) or placebo Study population: 18 healthy male volunteers per study Age 19-35 yrs., nonsmokers Medication: Study A: Phenylephrine (Neosynephrineg, Winthrop Breon Laboratories New York, NY, USA) dose: I pg.kg- I.min- 1, infusion period 20 minutes NG-monomethyl-L-arginine (L-NNUVIA, Clinalfa, Laufelfingen, Switzerland) dose: bolus 6mg/kg over 5 minutes followed by a continuous infusion of 60pg/kghnin over 15 minutes Study B: Enalapril (RenitecO, MSD, Haarlem, Netherlands) dose: 4 mg over 60 minutes BQ-123 (Clinalfa, Laufelfingen, Switzerland) dose: 60[tg/min over 60 minutes Study C: Propanolol (Inderal@, Astra Zeneca, Macclesfield, United Kingdom) dose: bolus 80 gg/kg, followed by a continuous infusion of I gg/kg/min over 20 minutes Atropine (Atropinsulfat Lannacher, Lannach, Austria) dose: bolus 15pg/kg, followed by a continuous infusion of 0. 15~tg/kgftin over 20 minutes Topically administered medication: Oxybuprocainhydrochloride (Benoxinat@, Agepha, Vienna), dose: I drop per eye MethodsLaser Doppler flowmetry using a compact confocal laser Doppler device Non-invasive measurement of systemic blood pressure and pulse rate Measurement of intraocular pressure with applanation tonometry Main outcome variableschoroidal pressure-flow relationship

Autoregulation is the ability of a tissue to maintain blood flow despite changes in perfusion pressure. It has been assumed that the choroid is a strictly passive vascular bed without autoregulatory properties. Recent animal and humans experiments have suggested that the choroid can employ autoregulation in response to changes in ocular perfusion pressure. However, the mechanism of choroidal autoregulation was unclear. The aim of the present study was to investigate the mechanisms of choroidal blood flow regulation in healthy subjects. In the present experiments the ocular perfusion pressure was transiently increased by isometric exercise or different drugs and the effects on the perfusion pressure - blood flow relationship studied. Ocular perfusion pressure was determined from changes in arterial blood pressure and intraocular pressure. Choroidal blood flow was measured using a confocal laser Doppler flowmeter. The results of our study confirm the potent autoregulatory capacity of the choroid at ocular perfusion pressures changes of up to 50 % above baseline. Inhibition of the NO- or endothelin-system, which is involved in the counterregulatory responses, has a marked influence on the autoregulatory capacity. Several ocular diseases are associated with impaired ocular blood flow, such as glaucoma, diabetic retinopathy, or age-related macular degeneration,. In some of these conditions, alterations in the NO- and/or endothelin-system have been demonstrated. The present study therefore contributes to the understanding of choroidal blood flow regulation in the physiology and the pathophysiology of the eye. Further studies are necessary to investigate the mechanisms of choroidal autoregulation when perfusion pressure is decreased. Moreover, the findings have to be extended to patients with different eye diseases in order to assess potential treatment modalities.