[Contribution of L-arginine-derived nitric oxide to the structural integrity of coronary artery and cardiac interstitium, and to the regulation of sympathetic nerve activity: assessment using a rat model produced by chronic nitric oxide inhibition].

A chronic model of hypertension, induced by continuous inhibition of nitric oxide synthase (NOS), was used to examine whether chronic NOS inhibition is associated with the heightened sympathetic activity and how nitric oxide (NO) produced by NOS contributes to maintain structural integrity of coronary artery and myocardial interstitium. Osmotic pumps were implanted intraperitoneally for 4 or 8 weeks to male Wistar rats. Solution in the osmotic pumps contained 0.2 M L-NG-nitroarginine methylester (LNAME) [low dose (LD)] or 1 M LNAME [high dose (HD)], or saline (SA). Sproke-prone spontaneous hypertensive rats (SHRSP) served as hypertensive controls. After 4 weeks the pumps in some rats were exchanged to the ones containing same solution (SA-SA, LD-LD, and HD-HD), or LNAME was discontinued and replaced by SA (LD-SA, and HD-SA). After 4 weeks, blood pressure (BP) of the LNAME-treated rats gradually rose from 112 to 142 (LD) and 180 (HD) mmHg. When the LNAME treatment was continued for the next 4 weeks, BP remained high (140 mmHg) in LD-LD. When LNAME was discontinued, BP returned to control levels (LD-SA: 110 mmHg; HD-SA: 122 mmHg). Heart rate (HR) decreased soon after initiation of the LNAME treatment, and remained lower in LD and LD-LD for 8 weeks, while it was gradually elevated and reached to the control level in HD. Discontinuation of the LNAME treatment normalized HR (LD-SA and HD-SA). Plasma dopamine levels were lower in the LNAME-treated rats and the withdrawal of LNAME normalized them. Plasma norepinephrine levels were significantly higher in HD than SA and LD, and it returned to control level in 8 weeks. Plasma renin concentrations were unchanged throughout the study. Microscopic examination (ME) revealed more severe thickening of coronary arterioles and fibrosis of myocardial interstitium in HD than in SHRSP. ME also revealed severe histiocyte infiltration in HD rats, while no kidney damages. These results suggest that, in the chronic model of hypertension induced by sustained LNAME administration, not only NO derived from endothelial NOS (NOS-3), but also the heightened sympathetic drive caused by central NOS (NOS-1) inhibition modifies progression of the disease. Furthermore, NOS-2 induced by histiocyte infiltration and its inhibition by LNAME may have resulted in the severe structural changes in the lesions. Thus, various NOSs may take part in maintaining cardiovascular integrity.