Alterations to the nitric oxide pathway in the spontaneously hypertensive rat

Nava, Eduardo; Farré, Antonio López; Moreno, Carol; Casado, Santos; Moreau, Pierre; Cosentino, Francesco; Lüscher, Thomas F.

doi:10.1097/00004872-199816050-00008

Cited by 81 publications

(45 citation statements)

References 15 publications

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“…Indeed, these findings of decreased arginase complement other studies indicating increased NOS activity in LVH (31,35). Other things being equal, these coordinated changes should serve to additively enhance NOdependent signaling in the compensated phase of pathological hypertrophy.…”

Section: Discussionsupporting

confidence: 80%

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Jung¹,

Kubo²,

Wilson³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Modulation of contractility by myocytederived arginase in normal and hypertrophied feline myocardium. Am J Physiol Heart Circ Physiol 290: H1756 -H1762, 2006. First published December 3, 2005 doi:10.1152/ajpheart.01104.2005.-L-Arginine, the sole substrate for the nitric oxide (NO) synthase (NOS) enzyme in producing NO, is also a substrate for arginase. We examined normal feline hearts and hearts with compensated left ventricular (LV) hypertrophy (LVH) produced by ascending aorta banding. Using Western blot analysis, we examined the abundance of arginase isozymes in crude homogenates and isolated cardiac myocytes obtained from the LVs of normal and LVH hearts. We examined the functional significance of myocyte arginase via measurement of shortening and intracellular calcium in isolated myocytes in the presence and absence of boronoethyl chloride (BEC), a specific pharmacological inhibitor of arginase. Both arginase I and II were detected in crude myocardial homogenates, but only arginase I was present in isolated cardiac myocytes. Arginase I was downregulated in LVH compared with normal. Inhibition of arginase with BEC reduced fractional shortening, maximal rate of shortening (ϩdL/dt) and relengthening (ϪdL/dt), and the peak of the free cytosolic calcium transient in normal myocytes but did not affect these parameters in LVH myocytes. These negative inotropic actions of arginase inhibition were associated with increases in cGMP generation. These studies indicate that only arginase I is present in cardiac myocytes where it tends to limit NO and cGMP production with the effect of supporting basal contractility. In experimental LVH induced by pressure overload, our studies demonstrate reduced arginase I expression and reduced functional significance, allowing greater arginine substrate availability for NO/cGMP signaling.arginase; hypertrophy; nitric oxide; guanosine 3Ј,5Ј-cyclic monophosphate; calcium AS IN THE VASCULATURE, nitric oxide (NO) synthase (NOS) regulates the generation of NO in cardiac myocytes by deaminating the amino acid substrate L-arginine to produce NO and citrulline. NO modulates cardiac contractility via activation of soluble guanylyl cyclase, inducing increases in cGMP. In turn, cGMP modulates contractility via the activation of certain phosphodiesterases, activation of protein kinase G, and by direct stimulation of calcium cycling proteins. On the other hand, there are reports that NO can alter contractility independent of cGMP by direct nitrosylation or acetylation of various channels and calcium cycling proteins.In the normal myocardium, the acute effects of increases in NO are bimodal, with a positive inotropic effect at low amounts of NO exposure but a negative one at higher amounts (28). NO donors have been shown to exhibit weak to moderate negative inotropic effects in nondiseased preparations (8,25,34). On the other hand, in pathological states, there is increasing evidence that upregulation of NOS and/or increased production of NO improves left ventricular (LV) performance and myocyt...

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Section: Discussionsupporting

confidence: 80%

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Jung¹,

Kubo²,

Wilson³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…27 Furthermore, increased oxidative stress has been shown to occur in hypertension, 28,29 and this increased oxidative stress causes a decrease in NO bioavailability. 30 Taken together, these studies and the present findings suggest that the decrease in NO availability at adrenergic nerve synapses in hypertension results in facilitated adrenergic neurotransmission and the reduced effect of L-NAME on PNSinduced vasoconstriction. Thus, it seems likely that the altered modulation of adrenergic neurotransmission caused by neuronal NO contributes to the onset and maintenance of hypertension in 2K1C-RHRs.…”

Section: Discussionsupporting

confidence: 78%

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

et al. 2010

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Neuronal nitric oxide (NO) has been shown to modulate perivascular adrenergic neurotransmission by inhibiting noradrenaline release from terminals in rat mesenteric arteries. This study was conducted to investigate changes in the inhibitory function of NO-containing nerves (nitrergic nerves) in mesenteric vascular beds of 2-kidney, 1-clip renovascular hypertensive rats (2K1C-RHR). Rat mesenteric vascular beds without endothelium were perfused with Krebs solution and the perfusion pressure was measured. In preparations from sham-operated rats (control) and 2K1C-RHRs, vasoconstriction induced by periarterial nerve stimulation (PNS; 2-8 Hz), but not vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol), was markedly facilitated in the presence of a nonselective NO synthase (NOS) inhibitor, N-x-nitro-L-arginine methyl ester (L-NAME) (100 lM). The facilitatory effect of L-NAME in preparations from 2K1C-RHR was smaller than that in control preparations. L-NAME augmented PNS-evoked noradrenaline release, which was smaller in 2K1C-RHRs than in controls. The expression of neuronal NO synthase (nNOS) measured by western blotting in mesenteric arteries from 2K1C-RHRs was significantly decreased compared with control arteries. Immunohistochemical staining of mesenteric arteries showed dense innervation of nNOSimmunopositive nerves that was significantly smaller in arteries from 2K1C-RHR than that in control arteries. Mesenteric arteries were densely innervated by tyrosine hydroxylase-immunopositive nerves, which coalesced with nNOS-immunopositive nerves. These results suggest that the inhibitory function of nitrergic nerves in adrenergic neurotransmission is significantly decreased in 2K1C-RHRs. This functional alteration based on the decrease in nNOS expression and nitrergic innervation leads to enhanced adrenergic neurotransmission and contributes to the initiation and development of renovascular hypertension.

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“…Moreover, the plasma concentrations of the oxidative product of NO metabolism, nitrate, are higher in hypertensive rats than in normotensive controls. 21 These results indicate that the basal release of NO is increased in hypertensive rats.…”

Section: Nitric Oxide In Experimental Hypertensionmentioning

confidence: 71%

“…Surprisingly, the NO pathway is paradoxically upregulated in the resistance circulation and the heart of spontaneously hypertensive rats (SHR). 21,22 Adult SHR possess a higher activity of eNOS than their normotensive counterparts. 23 Very young pre-hypertensive SHR have, in contrast, Figure 1 Endothelium-derived vasoactive substances.…”

Section: Nitric Oxide In Experimental Hypertensionmentioning

confidence: 99%

Working under pressure: the vascular endothelium in arterial hypertension

et al. 2000

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The vascular endothelium synthesizes and releases a spectrum of vasoactive substances like nitric oxide (NO) and endothelin (ET). In hypertension, the delicate balance of endothelium-derived factors is disturbed. ET acts as the natural counterpart to endothelium-derived NO, which exerts vasodilating, antithrombotic, and antiproliferative effects, and inhibits leukocyte-adhesion to the vascular wall. Besides its blood pressure rising effect also in man, ET induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. The derangement of endothelial function in hypertension is likely to be caused in part by genetic factors, but also due to elevated blood pressure itself. Due to its position between blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both target and mediator of arterial hypertension. Oxi-

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Alterations to the nitric oxide pathway in the spontaneously hypertensive rat

Cited by 81 publications

References 15 publications

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

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

Working under pressure: the vascular endothelium in arterial hypertension

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