Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles

Abstract

Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with N G -nitro-L-arginine methyl ester (L-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively. Treatment was continued for 1-3 mo (8.3 ± 0.6 mg · kg −1 · day −1 ). In vitro EDD of coronary LADs and arterioles was assessed via responses to ADP (LADs only) and bradykinin (BK), and endothelium-independent function was assessed via responses to sodium nitroprusside (SNP). Chronic NOS inhibition diminished coronary artery EDD to ADP and BK. Incubating LAD rings with L-NAME decreased relaxation responses of LADs from control pigs but not from CNI pigs such that between-group differences were abolished. Neither indomethacin (Indo) nor sulfaphenazole incubation significantly affected relaxation responses of LAD rings to ADP or BK. Coronary arteries from CNI pigs showed enhanced relaxation responses to SNP. In contrast to coronary arteries, coronary arterioles from CNI pigs demonstrated preserved EDD to BK and no increase in dilation responses to SNP. L-NAME, Indo, and L-NAME + Indo incubation did not result in significant between-group differences in arteriole dilation responses to BK. These results suggest that although chronic NOS inhibition diminishes EDD of LAD rings, most likely via a NOS-dependent mechanism, it does not affect EDD of coronary arterioles. Keywords endothelium-dependent dilation; N G -nitro-L-arginine methyl esterA healthy vascular endothelium promotes arterial homeostasis; in contrast, an injured endothelium portends arterial dysfunction (28). Although the mechanisms by which endothelial dysfunction exacts vascular damage remain to be fully elucidated, it is thought that reduced nitric oxide (NO) production and/or scavenging play a crucial role (27).Chronically decreased NO production by nitric oxide synthase (NOS) inhibition results in significant hemodynamic alterations. Systemically, NOS inhibition via N G -nitro-L-argi-nine methyl ester (L-NAME) or other NOS inhibitor administration increases blood pressure and peripheral resistance while decreasing heart rate and cardiac output (4,11,18,21,24,29). The fact that chronic NOS inhibition causes increased mean arterial pressure in vivo could be Address for reprint requests and other correspondence: M. H. Laughlin, Department of Biomedical Sciences, W102 Veterinary Medicine, 1600 E. Rollins Rd., Univ. of Missouri, Columbia, MO 65211 (e-mail: laughlinm @missouri.edu). * D. G. Ingram and S. C. Newcomer contributed equally to this work. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript evidence that chronic NOS inh...

Changes in Adrenoceptors and G-Protein-Coupled Receptor Kinase 2 in <smlcap>L</smlcap>-NAME-Induced Hypertension Compared to Spontaneous Hypertension in Rats

“…Despite the chronic inhibition of NO formation, only a slight decrease in Ach response, which did not reach statistical significance, was observed in MRA from LNHR. This confirms the results of previous works showing that, instead of NO, the endothelium-derived hyperpolarizing factor(s) (EDHF) play(s) a major role in Ach-induced vasodilatation in the distal [30] and resistance mesenteric arteries [31,32] and agrees with data reported on the coronary arteries and arterioles of pigs [33] and in the carotid and mesenteric arteries of rats [20]. …”

Effects of Chronic Nitric Oxide Synthase Inhibition on Endothelium-Dependent and -Independent Relaxation in Arteries that Perfuse Skeletal Muscle of Swine

“…Brachial and femoral arteries were harvested, cleaned, measured, and set to the optimal point in the length tension relationship (L max ) as previously described (Newcomer et al 2007). Contractile responses of the brachial and femoral rings to KCl were performed prior to vasorelaxation studies.…”

“…The role of the nitric oxide synthase (NOS) pathway in the relaxation responses to endothelium-dependent and -independent vasodilators was assessed through the addition of L-NAME (300 µM) to the Krebs bicarbonate solution of one ring from the brachial and femoral artery 30 min before preconstriction with PGF 2α . This concentration of L-NAME has been utilized by our laboratory (McAllister and Laughlin 1997;Woodman et al 2003Woodman et al , 2005Ingram et al 2007) and derived from experiments performed in our laboratory, which demonstrate that higher concentrations were no more effective in the inhibition of NOS. Similarly, a ring from the brachial and femoral arteries was pretreated with indomethacin (INDO; 5 µM) to investigate the role of the cyclooxygenase (COX) pathway in relaxation responses to endothelium-dependent and -independent vasodilators.…”

“…Recently, we reported that chronic L-NAME treatment altered relaxation responses of conduit coronary arteries but not coronary arterioles from the same swine (Ingram et al 2007). It is unknown whether these findings from the coronary circulation are unique to this vascular bed or if these effects of chronic L-NAME treatment are generalized.…”

Effect of Nitric Oxide on Cardiac Functions: Review

“…74 Domuz kalbinde NO'nun NG-nitro-Larjinin metil ester (L-NAME) ile kronik inhibisyonunun koroner arterlerin endotel-bağımlı fonksiyonlarını bozduğu gösterilmiştir. 75 İzole perfüze kalp preparatlarında L-NMMA'nın bazal koroner damar direncini artırdığı ve ACh, bradikinin 79 Sürtünme stresi ile uyarılan vazodilatasyon yanıtının, hipertansif hastalarda zayıfladığı ya da ortadan kalktığı gözlenmiştir. Bunun nedeninin azalmış NO aktivitesi olduğu düşünülmektedir.…”