Animal studies have indicated that nitric oxide is usually a key signalling molecule involved in the tonic restraint of central sympathetic outflow from your brainstem. activity (SNA) which is not CP-640186 under baroreceptor control. Healthy normotensive humans were analyzed before during a 60 min intravenous infusion of the NOS inhibitor < 0.05) and remained significantly elevated for the remainder of the experiment (Δ18 ± 3 mmHg; < 0.05). Similarly systemic NOS inhibition produced time-dependent raises in pores and skin SNA such that pores and skin SNA was elevated at the end of the l-NAME infusion (total activity 200 ± 22% baseline; < 0.05). Importantly pores and skin SNA remained unchanged during time and hypertensive (phenylephrine) control experiments. These findings show that pharmacological inhibition of NOS causes sympathetic activation and support a role of nitric oxide in central sympathetic control in humans. Introduction An estimated one billion people worldwide are hypertensive (Kearney 2005) CP-640186 with greater than 90% of reported instances being classified as idiopathic hypertension (i.e. no identifiable cause) (Korner 2007 While a multitude of factors have been implicated in the pathogenesis of hypertension neurogenic mechanisms have been well recorded. Indeed improved sympathetic nerve activity (SNA) has been reported in CP-640186 both animal and human being hypertension (Grassi 2004 Fisher 2009). However the mechanism(s) traveling sympathetic overactivity in hypertensive conditions remains to be elucidated. It is widely recognized that nitric oxide (NO) produced via the oxidation of l-arginine by nitric oxide synthase (NOS) in the vasculature is an important signalling molecule involved in CP-640186 the local control CP-640186 of blood flow (Moncada & Higgs 1993 This classic pathway of endothelium-dependent vasodilatation and its impact on blood pressure has been well recorded (Cardillo & Panza 1998 Less appreciated is the growing body of animal literature that has offered strong evidence that centrally derived NO is an important component of the transmission transduction pathway that tonically restrains sympathetic outflow from your brainstem placing a brake on α-adrenergic vasoconstriction and subsequent raises in blood pressure (Sander 1995 1997 Sander & Victor 1999 Zucker & Liu 2000 Thomas 2001; Zucker 2004). To day cardiovascular studies in humans have primarily focused on the peripheral effects of NO with little regard for a role of NO in the central nervous system. The conceptual platform establishing a major neurogenic part for NO in blood pressure control was derived from acute studies in anaesthetized animals in which administration of NOS inhibitors into known sites of sympathetic rules within the brainstem elicited raises in SNA and blood pressure (Zanzinger 1995; Zhang & Patel 1998 Further support for any central action of NO to restrain SNA was acquired in conscious animals in which systemic NOS inhibition produced a biphasic SNA response: an initial transient decrease in SNA followed by a sustained increase in SNA (Sakuma 1992; Augustyniak 2006). Importantly when the confounding influence of baroreflex activation was eliminated by sino-aortic baroreceptor denervation intravenous NOS inhibition gradually improved SNA (Sakuma 1992; Augustyniak 2006). These data show that systemic infusion of NOS inhibitors causes central sympathoexcitation that can be offset by activation of the arterial baroreflex. A key question is the degree to which these findings in experimental animals can be translated to humans. Although the results of a few human studies have suggested that pharmacologically induced hypertension caused by systemic NOS inhibition may be partially mediated from the sympathetic nervous system (Owlya 1997; Lepori 1998; Sander 1999) results have been equivocal (Hansen 1994; Spieker 2000) and conclusions have been based on indirect indices of SNA (e.g. α-adrenergic blockade) or on direct measurements AIS of SNA confounded by arterial baroreflex buffering. As such a direct inhibitory action of NO on central sympathetic outflow has been difficult to demonstrate in humans. The purpose of this study was to test the hypothesis that NO is definitely involved in the tonic restraint of central sympathetic outflow in humans. This was accomplished by directly measuring pores and skin SNA before during and following systemic infusion of a NOS inhibitor. Cutaneous recordings of SNA were used because CP-640186 pores and skin SNA is not influenced from the arterial baroreflex in normothermic conditions (Delius 1972; Wallin 1975; Wilson 2001; Cui 2004 2006 whereas it is highly responsive to alterations in central sympathetic outflow (Vissing 1991;.