Cyclic AMP elevating agents and nitric oxide modulate angiotensin II-induced leukocyte-endothelial cell interactions in vivo

1 Angiotensin (Ang-II) is a key molecule in the development of cardiac isch aemic disorders and displays proinflammatory activity in vivo. Since intrac ellular cyclic nucleotides elevating agents have proved to be effective mod ulators of leukocyte recruitment, we have evaluated their effect on Ang-II- induced leukocyte-endothelial cell interactions in vivo using intravital mi croscopy within the rat mesenteric microcirculation. 2 Pretreatment with iloprost significantly inhibited (1 nM) Ang-II-induced increase in leukocyte rolling flux, adhesion and emigration at 60 min by 96 , 92 and 90% respectively, and returned leukocyte rolling velocity to basal levels. Pretreatment with salbutamol or co-superfusion with forskolin exer ted similar effects. 3 When theophylline was administered, leukocyte rolling flux, adhesion and emigration elicited by Ang-II were significantly attenuated by 81, 89 and 7 1% respectively. Rolipram administration caused similar reduction of Ang-II -induced leukocyte responses. 4 Co-superfusion of Ang-II with the NO-donor, spermine-NO, or 8-Br-cyclic G MP, or pretreatment with a transdermal nytroglycerin patch, resulted in a s ignificant reduction of the leukocyte-endothelial cell interactions elicite d by Aug-II. 5 Salbutamol preadministration did not modify leukocyte-endothelial cell in teractions elicited by either L-NAME or L-NAME+Ang-II, indicating that the inhibitory leukocyte effects caused by cyclic AMP-elevating agents are medi ated through NO release. 6 In conclusion, we have provided evidence that cyclic AMP elevating agents and NO donors, are potent inhibitors of Ang-II-induced leukocyte-endotheli al cell interactions. Thus, they could constitute a powerful therapeutical tool in the control of the leukocyte recruitment characteristic of the vasc ular lesions that occur in cardiovascular disease states where Ang-II plays a critical role.