The Effect of Chronic NO Synthase Inhibition on the Vasoactive and Structural Properties of Thoracic Aorta, NO Synthase Activity, and Oxidative Stress Biomarkers in Young SHR

Abstract

Although the role of nitric oxide (NO) in essential hypertension is still unclear, the effects of long-term NO deficiency have not yet been investigated during the critical juvenile period in spontaneously hypertensive rats (SHR). We aimed to analyze the effects of chronic NO synthase (NOS) inhibition on systolic blood pressure (sBP), vasoactivity, morphological changes and superoxide level in the thoracic aorta (TA), NOS activity in different tissues, and general biomarkers of oxidative stress in plasma of young SHR. Four-week-old SHR were treated with NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, p.o.) for 4-5 weeks. L-NAME treatment induced a transient sBP increase only, and surprisingly, slightly inhibited endothelium-dependent relaxation of TA. Hereby, the inhibition of NOS activity varied from tissue to tissue, ranging from the lowest in the TA and the kidney to the highest in the brain stem. In spite of an increased sensitivity of adrenergic receptors, the maximal adrenergic contraction of TA was unchanged, which was associated with changes in elastin arrangement and an increase in wall thickness. The production of reactive oxygen species in the TA was increased; however, the level of selected biomarkers of oxidative stress did not change. Our findings proved that the TA of young SHR responded to chronic NO deficiency by the development of adaptive mechanisms on the functional (preserved NO-derived vasorelaxation, unincreased contraction) and molecular (preserved NOS activity) level.

Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches

“…The NO-deficiency impairs vascular homeostasis, alters the endothelium permeability and consequently leads to inflammatory and fibrotic processes, which are responsible for structural alterations, including vascular hypertrophy and increased vascular resistances. Consistently, chronic administration of NOS inhibitors causes sustained hypertension in several pre-clinical models [20] , [21] .…”

Aortic Stiffness in L-NAME Treated C57Bl/6 Mice Displays a Shift From Early Endothelial Dysfunction to Late-Term Vascular Smooth Muscle Cell Dysfunction

“…Although the results demonstrated constantly reduced basal NO production, impaired ACh-induced NO responses were only observed after short-term (1-4 weeks) but not long-term (8-16 weeks) L-NAME treatment. Although some studies describe the absence of endothelial dysfunction after chronic L-NAME treatment (Desai et al, 2006;Fitzgerald et al, 2007;Balis et al, 2010), others describe persistence of endothelial dysfunction (De Gennaro Colonna et al, 2005;Qu et al, 2010;Li et al, 2016;Berenyiova et al, 2018). These dissimilarities might be due to a difference in the studied animal model (e.g., C57Bl/6 mice (Fitzgerald et al, 2007), Wistar rats (Paulis et al, 2008), spontaneously hypertensive [SHR] rats (Berenyiova et al, 2018)), treatment dose (from 0.3 to 100 mg/kg (Fitzgerald et al, 2007;Balis et al, 2010), ~110 mg/kg in the current study), or treatment duration (from 5 to 10 weeks (Balis et al, 2010;Berenyiova et al, 2018)).…”

Influence of Age on Anticontractile Effect of Perivascular Adipose Tissue in Normotensive and Hypertensive Rats

“…However, the interaction of so many factors is difficult to consider simultaneously, and simplification is needed. Nevertheless, it is appropriate to mention some of the available literary data as well as some of our previous observations which suggest that, e.g., the endothelium-dependent relaxant responses are well established and equal between 5-week-old WKY rats and SHR [20], whereas in older individuals, these responses were found to be impaired [12] or preserved [21] in hypertensive comparing to normotensive rats. The regulatory influence of endothelium and PVAT on vascular smooth muscle seems to be largely independent, although several authors brought some evidence that substances released from PVAT could provoke or block the release and impact of some vasoactive factors from endothelium and vice versa [22, 23].…”