Impaired Neuronal Nitric Oxide Synthase–Mediated Vasodilator Responses to Mental Stress in Essential Hypertension

Abstract

Abstract-Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress.To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 μmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the α-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events. (Hypertension. 2015;65:903-909.

The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase

“…In the present study, SMTC reduced basal coronary flow, as previously documented ( 32 , 33 ), and substantially attenuated the mental stress-induced increase in blood flow. The degree of attenuation in stress-induced vasodilation is similar to that previously observed in the forearm ( 20 ), although it should be noted that subject characteristics were significantly different between these studies. The present study by necessity was undertaken in patients undergoing diagnostic coronary angiography and, therefore, included older patients with multiple risk factors for coronary disease and on oral medications.…”

Cyclic nucleotide regulation of cardiac sympatho‐vagal responsiveness

“…Similarly, Zanzinger et al (1997) also reported that inhibition of nNOS in the paraventricular nucleus could drive central sympathetic outflow, suggesting an important role of NO in the cardiac sympathetic neural axis (reviewed by Paton et al 2002;Danson et al 2009). Since then, it has gradually been recognized that NO dysregulation may play a major role in the aetiology of sympathetic hyperactivity in hypertension and other cardiovascular pathologies (Hamilton Gamboa et al 2012;Zhang et al 2014;Khan et al 2015). However, a detailed understanding of the cellular pathways underpinning the action of cyclic nucleotides and protein kinase regulation on cardiac neurotransmission in disease is still relatively poorly understood.…”

“…; Khan et al . ). However, a detailed understanding of the cellular pathways underpinning the action of cyclic nucleotides and protein kinase regulation on cardiac neurotransmission in disease is still relatively poorly understood.…”

Forearm vasodilator responses to environmental stress and reactive hyperaemia are impaired in young South Asian men

“…The forearm vasodilatation of mental stress is highly dependent on shear stress-induced release of NO and the β 2 -adrenoceptor effect of adrenaline, which is NO-dependent (Dietz et al 1994 ; Halliwill et al 1997 ; Seddon et al 2008 ). The NO-dependent component of stress-induced forearm vasodilatation was impaired in those with hypertensive parents, in hypertensives and in black African Americans (Cardillo et al 1998a , b ; Schlach et al 2002 ; Khan et al 2015 ). Thus, it is reasonable to propose that the majority of young SA men showed forearm vasoconstriction because their NO-dependent, and β 2 -adrenoceptor mediated dilatation was blunted.…”