Oxidative Stress Induced Vasoconstrictions: Mechanisms of Protection and Clinical Implications

Abstract

Purpose: : Oxidative Stress occurs in many wide spread ocular diseases and may interact with vascular regulation. Aim of the present study is to study the effects of free radicals on arterial tone and to identify potential protective strategies.

Methods: : Isolated ciliary arteries from pigs and perfused rat ophthalmic arteries were studied in a myograph and pressure myograph system resp.. Hydroxyl radical exposure was done by a previously evaluated system using H2O2 and Fe3+ (Fenton reaction). Prior to radical exposure the preparations were pre-contracted by partial depolarization to a Nernst potential of -41mV for K+. Clinical examination was done using color Doppler imaging with a Siemens Elegra and an applicator type 7.5L40 at a frequency of 7.5MHz.

Results: : In isolated ciliary artery ring preparations vascular tone increased by 68±8% (N=11; P<0.001) after radical exposure. Comparable to that, radicals caused a decrease in vessel diameter in perfused pre-contracted ophthalmic arteries (diameter change -7.7±1.2%; N=11; P<0.001). Adding the strong hydroxyl radical scavenger pyruvate radical induced vasoconstriction was reduced by 57±7% (N=14; P<0.001) and by 51±9% in presence the ß-adrenoceptor-antagonist nebivolol, which is also thought to have scavenging properties (N=11; P<0.001). After blocking blocking sodium calcium exchanger reverse mode by KB-R7943 5/11 vessels showed absolutedly no vasoconstriction compared to 11/11 without KB-R7943. Average diameter derease was 4.5±3.2% with KB-R7943 (N=11; N.S.) vs. 7.7±1.2% without KB-R7943 (N=11; P<0.001). The approach to stabilize ocular perfusion by a treatment with nebivolol was assessed in a brief clinical study with glaucoma patients. Nebivolol lead to an increase of retrobulbar blood flow velocities in the short posterior ciliary artery (PSV: 8.9±2.9 vs. 10.9±3.8cms-1 EDV: 2.0±0.6 vs. 2.5±0.9cms-1; N=23 pat.; P<0.01).

Conclusions: : Pre-contracted arteries respond to free radicals with an increase of vascular tone. This increase may be attenuated in part by free radical scavengers. In addition blocking sodium calcium exchanger reverse mode stabilizes vascular tone after free radical injury. This implies calcium influx in the arterial smooth muscle cells to contribute signifantly to radical induced vasoconstriction. A translation of the in vitro results in a clinical trial showed stabilizing effects of nebivolol in glaucoma patients.

Clinical Trial: : EUDRACT NUMBER: 2004-004862-33

Keywords: oxidation/oxidative or free radical damage • blood supply • calcium