Mechanisms of Blunted Muscle Vasodilation During Peripheral Chemoreceptor Stimulation in Heart Failure Patients

Abstract

Abstract-We described recently that systemic hypoxia provokes vasoconstriction in heart failure (HF) patients. We hypothesized that either the exaggerated muscle sympathetic nerve activity and/or endothelial dysfunction mediate the blunted vasodilatation during hypoxia in HF patients. Twenty-seven HF patients and 23 age-matched controls were studied. Muscle sympathetic nerve activity was assessed by microneurography and forearm blood flow (FBF) by venous occlusion plethysmography. Peripheral chemoreflex control was evaluated through the inhaling of a hypoxic gas mixture (10% O 2 and 90% N 2 ). Basal muscle sympathetic nerve activity was greater and basal FBF was lower in HF patients versus controls. During hypoxia, muscle sympathetic nerve activity responses were greater in HF patients, and forearm vasodilatation in HF was blunted versus controls. Phentolamine increased FBF responses in both groups, but the increase was lower in HF patients. Phentolamine and N G -monomethyl-L-arginine infusion did not change FBF responses in HF but markedly blunted the vasodilatation in controls. FBF responses to hypoxia in the presence of vitamin C were unchanged and remained lower in HF patients versus controls. In conclusion, muscle vasoconstriction in response to hypoxia in HF patients is attributed to exaggerated reflex sympathetic nerve activation and blunted endothelial function (NO activity). We were unable to identify a role for oxidative stress in these studies. (Hypertension. 2012;60:669-676.) • Online Data Supplement Key Words: heart failure � chemoreceptors � vasodilation � sympathetic nervous system � endothelium R esting sympathetic nerve activity is increased in patients with chronic systolic heart failure (HF), and patients with the greatest sympathetic activation have the highest mortality.1,2 Many potential mechanisms underlying the sympathetic excitation in HF have been proposed, including blunted baroreceptor control of central sympathetic outflow.3,4 Augmented peripheral chemoreceptor sensitivity in HF has also been described, which may also underlie the augmented central sympathetic outflow. 5,6 In healthy humans, hypoxia leads to increased blood flow directed to skeletal muscle, and this vasodilatation is mediated by NO release. 7 In a recent study, we reported that, paradoxically, the peripheral chemoreceptor stimulation resulted in skeletal muscle vasoconstriction in HF patients. 6 This unexpected vascular response led us to hypothesize that either the exaggerated sympathetic outflow attributable to chemoreceptor stimulation or the blunted endothelially mediated vasodilatation results in this muscle vasoconstriction during hypoxia in HF patients. In the present study, we describe muscle blood flow responses during peripheral chemoreceptor stimulation with local blockade of postsynaptic ␣-adrenergic receptors and in association with blockade of endothelial NO production in patients with severe HF and in healthy controls. In addition, we describe the effects of vitamin C, an antioxidant, alone, and an ant...

Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure

“…In contrast, L-NMMA infusion did not change the muscle vasodilation responses during hypoxia in patients with HF. 18 Together, these findings are consistent with an impaired endothelial response during chemoreceptors stimulation in HF patients with SDB. Finally, it is likely that the increased sympathetic nerve activity directed to skeletal muscle during peripheral and central chemoreceptors stimulation restrains the muscle vasodilatation in HF patients with SDB.…”

“…17 Compared with healthy individuals, patients with HF have blunted muscle vasodilation response and exaggerated enhancement in MSNA response during peripheral chemoreceptors stimulation. 17,18 This study extends the knowledge about the chemoreflex control in patients with HF and SDB. In fact, it clarifies that the adverse hemodynamic response is significantly greater in patients with HF who have SDB compared with those without SDB, which seems to be independent of diabetes mellitus and dyslipidemia.…”

“…20,44,45 Third, altered endothelium-mediated responses during hypoxia in patients with HF has been reported. 18 In this last study, intra-arterial infusion of L-NMMA (N G -monomethyl L-arginine), an inhibitor of nitric oxide synthase, completely abolished the muscle vasodilator responses in healthy individuals. In contrast, L-NMMA infusion did not change the muscle vasodilation responses during hypoxia in patients with HF.…”

“…18,40,41 Second, previous observational studies show that repeated episodes of hypoxia and reoxygenation decrease endothelial nitric oxide production 42,43 and increase oxidative stress. 20,44,45 Third, altered endothelium-mediated responses during hypoxia in patients with HF has been reported.…”

“…17 More recently, we demonstrated that the reduced muscle blood flow was because of both endothelial dysfunction and exaggerated sympathetic nerve activity. 18 However, whether these physiological sequelae of chemoreceptor stimulation were present in the subpopulation with SDB was not determined but is critical because it is this subpopulation that experiences repetitive chemoreceptor activation during recurrent sleep apneic episodes. Intermittent hypoxic cycles (oxygen desaturation and reoxygenation) during the sleep apnea periods in non-HF populations lead to endothelial dysfunction [20][21][22] and increase in sympathetic nerve activity.…”