Abstract-We examined the contribution of the renal nerves to mean arterial pressure (MAP) during 5-week chronic infusion of angiotensin II (Ang II; 50 ng/kg per minute SC) in conscious rabbits. Basal MAP was 68Ϯ1 mm Hg, and the maximum depressor response to ganglion blockade was Ϫ20Ϯ2 mm Hg. MAP increased by 25Ϯ2 mm Hg after 1 week and remained stable over the next 4 weeks. Depressor responses to pentolinium (6 mg/kg IV) were similar to control during the first week of hypertension but thereafter became increasingly greater in Ang II-treated rabbits but not vehicle-treated rabbits. After 5 weeks, the fall in MAP was 54% greater in Ang II-than in vehicle-treated rabbits (Ϫ34Ϯ2 versus Ϫ22Ϯ2 mm Hg), but renal sympathetic nerve activity was similar in both groups. Renal denervation produced a small fall in MAP in all of the vehicle-treated rabbits after 4 days (Ϫ6Ϯ2 mm Hg; Pϭ0.01), but there was no consistent effect in hypertensive rabbits. The depressor response to ganglion blockade was enhanced in vehicle-treated but not Ang II-treated rabbits. The finding that renal sympathetic nerve activity is not altered by Ang II hypertension nor is the hypertension altered by renal denervation suggests that renal sympathetic nerves do not contribute to the hypertension. The greater depressor effect of acute ganglion blockade in hypertensive rabbits suggests that the sympathetic nervous system exerts increased vasoconstriction in the peripheral vasculature in Ang II-induced hypertension. (Hypertension. 2008;51:878-883.)Key Words: Ang hypertension Ⅲ sympathetic nervous system Ⅲ ganglion blockade Ⅲ renal denervation Ⅲ rabbits Ⅲ blood pressure Ⅲ heart rate E levated sympathetic activity has long been associated with the development of essential hypertension, 1 but whether this is also the case in hypertension induced by chronic infusion of angiotensin (Ang) II has yet to be established. Evidence to date suggests that the responses to ganglionic blockade and sympatholytic agents are enhanced in Ang II-induced hypertension in rats 2,3 and rabbits. 4,5 Collectively, these observations suggest that there may be greater sympathetic nervous system (SNS)-mediated vasoconstrictor activity, but this does not necessarily mean that activation of the SNS initiates or maintains Ang II-induced hypertension.However, the precise role of the renal nerves in the pathogenesis of Ang II hypertension is still somewhat controversial. Previous renal denervation has been observed to delay or blunt the development of hypertension during chronic infusion of Ang II in rats, 6 -9 although this is not a universal finding. 10 Furthermore, a 7-day infusion of Ang II reduced renal sympathetic nerve activity (RSNA) measured directly in rabbits 11 and renal spillover of norepinephrine in dogs. 12 Furthermore, the renal nerves appear to promote sodium excretion in Ang II-induced hypertension in dogs via a baroreflex-dependent mechanism. [13][14][15] Collectively, these observations suggest that the renal nerves may make little contribution to hypertension induced...
Our results suggest that low-dose AngII-treatment results in marked sympathetic activation at rest and during stress and hypoxia, due to activation of specific hypothalamic pathways. These mechanisms may contribute to sympathetic activation in conditions associated with chronic activation of the renin-angiotensin system such as obesity or renovascular disease.
BPH/2J mice are a genetic model of hypertension which were selectively bred for elevated blood pressure (BP) in the 1970s alongside a normotensive strain (BPN/3J).1 Recent studies suggest that the hypertension in BPH/2J mice is caused by enhanced activation of the sympathetic nervous system (SNS) because ganglion blockade causes a greater depressor response in BPH/2J mice compared with BPN/3J controls. 2,3 Importantly, cardiovascular regulatory forebrain regions within the hypothalamus and amygdala display markedly greater neuronal activity in BPH/2J compared with BPN/3J mice during the dark-active period of the 24-hour light cycle.2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.A gene array approach has been used to identify differential expression of genes in the hypothalamus between BPH/2J and BPN/3J mice. 5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons. Indeed, orexin is capable of increasing BP, heart rate (HR), and SNS activity.8 Orexinergic neurons originate in the hypothalamus and project to a wide range of brain regions, but in terms of sympathetic control of BP, the Abstract-BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system.Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/ kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively; P<0.001 compared with vehicle). However, when almorexant (100 mg/ kg, IP) was administered during the light-inactive pe...
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