Angiotensin-Converting Enzyme Inhibitors and AT1-Receptor Antagonist Restore Nitric Oxide Synthase (NOS) Activity and Neuronal NOS Expression in the Adrenal Glands of Spontaneously Hypertensive Rats

Abstract

ABSTRACT-During development of hypertension in spontaneously hypertensive (SHR) rats, the activity of adrenal nitric oxide synthase (NOS) was investigated. SHR and Wistar-Kyoto (WKY) rats were studied at different ages: 3 -4, 7 -8 and 12 -13 weeks after birth. Basal NOS activity was measured by the ability of homogenate to convertAt all ages, SHR rats exhibited 50 -60% reduction in NOS activity when compared to age-matched WKY rats. In a following study, SHR rats (12 -13 weeks) were treated chronically with the angiotensin I-converting enzyme inhibitors (ACE-I) captopril or enalapril, or the AT1-receptor antagonist losartan (2´25, 10 and 60 mg/kg per day for 10 days, respectively). The total NOS activity and protein expression of NOS isoenzymes from adrenals were determined. The basal NOS activity and protein expression of neuronal NOS (nNOS) was significantly increased in treated SHR rats when compared to control rats. The isoforms endothelial NOS and inducible NOS were undetectable. We conclude that impaired NO synthesis in the adrenal glands of SHR rats may contribute to the onset and maintenance of hypertension. The upregulation of nNOS protein in the adrenal glands may be one of the mechanisms by which ACE inhibitors and AT1-receptor antagonists by restoring the NO synthesis, mediate their antihypertensive effects.Keywords: Nitric oxide synthase, Spontaneously hypertensive rat, Adrenal gland, Angiotensin-converting enzyme inhibitor, LosartanNeuronal nitric oxide synthase (nNOS) has been localized immunohistochemically in different central and peripheral organs including the medulla of rat adrenal glands (1 -3). Considerable evidence demonstrates that nonneuronal mediators such as endothelin-1, prostaglandins or NO modulate sympathetic neurotransmission. Recently, it has been reported that chromaffin cells isolated from bovine adrenals possess an autocrine NO /cGMP pathway tonically controlling the release of catecholamines (4). This was further supported by the fact that in isolated and perfused canine adrenal glands treatment with N G -monomethyl-L-arginine, an inhibitor of NOS, increased the basal efflux of noradrenaline, adrenaline and dopamine, whereas the effects of N G -monomethyl-L-arginine were reversed in the presence of L-arginine, the substrate of NOS (5). Therefore, it has been suggested that constitutive synthesis of NO within the adrenal medulla may modulate the release of catecholamines into the circulation, thereby playing an important role in the maintenance of blood pressure (BP) at physiological levels. We therefore hypothesized that an impaired synthesis of NO within the adrenal medulla in spontaneously hypertensive (SHR) rats may be one of the crucial factors contributing to the development and maintenance of hypertension. Furthermore, the reduction in BP following treatment with angiotensin-converting enzyme inhibitors (ACE-I) or AT1-receptor antagonists may affect the NO production within the adrenal gland. In the present study, we investigated the activities of NOS with respect to di...

Control of systemic and pulmonary blood pressure by nitric oxide formed through neuronal nitric oxide synthase

“…Similar findings were also obtained about the mechanisms underlying the hypotensive action of losartan in rats of the phenol-injury model [108]. The basal NOS activity and protein expression of nNOS were increased in adrenal glands of SHR chronically treated with losartan, captopril, or enalapril when compared with control rats; eNOS and iNOS were undetectable, suggesting that the upregulation of nNOS protein in adrenals may be one of the mechanisms of action of these antihypertensives [109].…”

Effect of diabetes on aortic nitric oxide synthesis in spontaneously hypertensive rats; does captopril modulate this effect?

“…However, we could not rule out the effect of captopril on NO in other tissues. It has been reported that administration of captopril to SHR did not affect the protein expression of NOS-2 and NOS-3 but upregulated NOS-1 in the adrenal glands (Qadri et al, 2001).…”

Altered function of nitrergic nerves inhibiting sympathetic neurotransmission in mesenteric vascular beds of renovascular hypertensive rats

“…Furthermore, the immunohistochemical study showed that the density of nNOS-immunopositive nerve fibers was markedly reduced in the mesenteric arteries of 2K1C-RHRs, supporting the present findings that neuronal NO modulation in adrenergic neurotransmission is decreased in 2K1C-RHRs. It has been reported that nNOS expression is decreased in the adrenal glands of SHR 31 and that soluble guanylate cyclase, the key precursor of NO cyclic guanosine monophosphate-dependent effects, is downregulated in the aorta 32 and atria 33 of SHRs. The reninangiotensin system is strongly augmented in 2K1C-RHRs.…”

“…The active substance of renin-angiotensin system, angiotensin II, is a potent vasoconstrictor, having strong effects on vascular tone regulation, facilitating sympathetic neurotransmission 34 and reducing the bioavailability of NO as a result of increasing oxidative stress. 28,3,31 Furthermore, it has been reported that high blood pressure causes increased oxidative stress in the vasculature. 35 Therefore, it is very likely that the acute increase in renin-angiotensin system and high blood pressure in 2K1C-RHRs blunts the inhibitory modulation of NO-containing nerves in adrenergic neurotransmission and thereby leads to further facilitation of adrenergic neurotransmission.…”