Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR

Abstract

Abstract-We demonstrated recently that a significant reduction in both the molecular synthesis and functional expression of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor outflow, underlies the augmented sympathetic vasomotor tone during hypertension. This study further evaluated the hypothesis that this downregulation of basal iNOS at the RVLM during hypertension is innate. In adult spontaneously hypertensive rats (SHR) treated for 4 weeks with the antihypertensive captopril to normalize elevated blood pressure or in young prehypertensive SHR, the significantly lower iNOS mRNA and protein levels at the ventrolateral medulla under basal conditions or on activation by microinjection bilaterally into the RVLM of lipopolysaccharide (10 ng) remained unaltered. The retarded efficacy of lipopolysaccharide (10 ng) to elicit cardiovascular depression (hypotension, bradycardia, and reduction in sympathetic vasomotor tone) also persevered in captopril-treated adult or young normotensive SHR. On the other hand, compared with Wistar-Kyoto normotensive rats, the magnitude of cardiovascular depression induced in adult SHR by local administration into the RVLM of the NO precursor L-arginine (40 nmol) was significantly smaller. In addition, microinjection bilaterally into the RVLM of a selective iNOS inhibitor, aminoguanidine (125 or 250 pmol), was discernibly less efficacious in unmasking hypertension, tachycardia, and the increase in sympathetic vasomotor tone in adult SHR. We conclude that a predisposed reduction in molecular synthesis and functional expression of basal iNOS in the RVLM is associated with the sympathetic vasomotor overactivity during hypertension. Key Words: nitric oxide synthase Ⅲ hypertension, essential Ⅲ nitric oxide Ⅲ blood pressure Ⅲ heart rate Ⅲ nervous system, autonomic W hereas the notion that hypertension in human patients 1,2 and animal models 3-5 is attributable to an augmented central sympathetic outflow to the heart or peripheral vasculature is well accepted, the mechanism that underlies sympathetic overactivity during hypertension requires further delineation. Recent studies 6 -8 implicate an abnormality of the nitric oxide (NO) system in the brain in hypertension. Originally identified as an endothelium-derived vascular relaxing factor, 9 NO is now known to play an active role in central cardiovascular regulation. 6,7 In the rostral ventrolateral medulla (RVLM), where premotor neurons that provide the tonic sympathetic vasomotor drive are located, 10 we demonstrated 11 recently that whereas small amounts of NO generated by neuronal NO synthase (nNOS) in the RVLM promote sympathoexcitation, large amounts of NO produced by inducible NOS (iNOS) elicit sympathoinhibition. Under physiological conditions, the prevalence of nNOS over iNOS activity and the associated dominance of sympathoexcitation over sympathoinhibition are responsible for the maintenance of neurogenic vasomotor tone and stable arterial pressure elici...

Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon

“…In the cerebral cortex and brain stem, Cadependent NOS activity was decreased at 3-4 wk, although by 13-14 wk this was increased in the hypothalamus and brain stem compared with WKY rats (118). However, at 8 -10 wk functional expression and synthesis of iNOS (which is Ca independent) were reduced in the brain stem (RLVM) in SHR (25), which was associated with sympathetic vasomotor hyperactivity (24).…”

Relativizing innateness: innateness as the insensitivity of the appearance of a trait with respect to specified environmental variation

“…An ethologist's claim that a variety of birdsong is innate means something very different from an immunologist's claim that an antimicrobial peptide is innate or a medical researcher's claim that the downregulation of an enzyme is innate in rats with hypertension (Boman 1998;Chan et al 2003). The ethologist may be interested in birdsong's response to variations in exposure to the behaviour of conspecifics; the immunologist interested in whether an organism's production of the peptide varies depending on previous exposure to the relevant pathogen; and the medical researcher interested in whether the level of the enzyme is affected by the hypertensiveness of the rat.…”

Mitochondrial Respiratory Enzyme Complexes in Rostral Ventrolateral Medulla as Cellular Targets of Nitric Oxide and Superoxide Interaction in the Antagonism of Antihypertensive Action of eNOS Transgene

“…Overexpression of NO in the RVLM by eNOS gene transduction was proposed for treatment of neurogenic hypertension (Zanzinger, 1999) because NO deficiency in the RVLM contributes to the neural mechanisms of hypertension in SHR (Kagiyama et al, 1998;Chan et al, 2003;TandaiHiruma et al, 2005). The eNOS transgene, however, fails to provide sustained depressor effect (Kishi et al, 2002;Tai et al, 2005) and is followed by rebound hypertension (Tai et al, 2005).…”

“…One brain region in which NO is of pivotal importance in this regulatory machinery is the rostral ventrolateral medulla (RVLM) (Chan et al, 2001;Mayorov, 2005), which provides tonic sympathetic outflow for the maintenance of vasomotor tone (Dampney, 1994). Accumulating evidence suggests that NO deficiency in the RVLM may underlie sympathetic overexcitation (Kagiyama et al, 1998;Chan et al, 2003; TandaiHiruma et al, 2005) or impaired baroreflex regulation (Kishi et al, 2003) during hypertension. Accordingly, overproduction of NO by gene transduction of endothelial nitric-oxide…”