Niki M. Dietz

Nitric oxide contributes to the rise in forearm blood flow during mental stress in humans.

1. Our aim was to determine whether the vasodilating substance nitric oxide (NO) contributes to the rise in forearm blood flow observed during mental stress in humans. We also determined whether the NO might be released as a result of cholinergic stimulation of the vascular endothelium. 2. Blood flow was measured in both forearms using plethysmography during several 3‐5 min bouts of a colour word test. In one forearm the nitric oxide synthase blocker NG‐monomethyl‐L‐arginine (L‐NMMA) and other drugs were infused via a brachial artery catheter. The contralateral forearm served as a control. 3. When L‐NMMA was given prior to mental stress it blunted the rise in blood flow in the treated forearm almost completely. The normal blood flow response returned during a second bout of stress conducted after a wash‐out period. During a third bout of mental stress, administration of more L‐NMMA again blunted the blood flow responses to mental stress. 4. When atropine was given prior to mental stress, the increases in blood flow were reduced in the treated forearm. Subsequent administration of both atropine and L‐NMMA caused a somewhat greater reduction in the blood flow responses than those observed with atropine alone. 5. These data demonstrate that NO plays a role in forearm vasodilatation during mental stress in humans. It is likely that most of the NO is released by cholinergic stimulation of the vascular endothelium.

Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation

Large, reproducible interindividual differences exist in resting sympathetic nerve activity among normotensive humans with similar arterial pressures, resulting in a lack of correlation between muscle sympathetic nerve activity (MSNA) and arterial pressure among individuals. Although it is known that the arterial pressure is the main short‐term determinant of MSNA in humans via the arterial baroreflex, the lack of correlation among individuals suggests that the level of arterial pressure is not the only important input in regulation of MSNA in humans. We studied the relationship between cardiac output (CO) and baroreflex control of sympathetic activity by measuring MSNA (peroneal microneurography), arterial pressure (arterial catheter), CO (acetylene uptake technique) and heart rate (HR; electrocardiogram) in 17 healthy young men during 20 min of supine rest. Across individuals, MSNA did not correlate with mean or diastolic blood pressure (r < 0.01 for both), but displayed a significant negative correlation with CO (r=−0.71, P= 0.001). To assess whether CO is related to arterial baroreflex control of MSNA, we constructed a baroreflex threshold diagram for each individual by plotting the percentage occurrence of a sympathetic burst against diastolic pressure. The mid‐point of the diagram (T50) at which 50% of cardiac cycles are associated with bursts, was inversely related to CO (r=−0.75, P < 0.001) and stroke volume (SV) (r=−0.57, P= 0.015). We conclude that dynamic inputs from CO and SV are important in regulation of baroreflex control of MSNA in healthy, normotensive humans. This results in a balance between CO and sympathetically mediated vasoconstriction that may contribute importantly to normal regulation of arterial pressure in humans.

Role of nitric oxide in exercise hyperaemia during prolonged rhythmic handgripping in humans.

1. We sought to determine whether the vasodilating molecule nitric oxide (NO) contributes to the forearm hyperaemia observed during prolonged rhythmic handgripping in humans. 2. Two bouts of exercise were performed during experimental protocols conducted on separate days. During each protocol the subject performed a 10 min and a 20 min bout of rhythmic (30 min‐1) handgripping at 15% of maximum. Two exercise bouts were required to facilitate pharmacological interventions during the second protocol. Blood flow in the exercising forearm was measured every minute with plethysmography during brief pauses in the contractions. During both exercise bouts in the first protocol, forearm blood flow increased 2‐ to 3‐fold above rest after 1 min of handgripping and remained constant at that level throughout the exercise. 3. During the 10 min bout of exercise in the second protocol, acetylcholine was given via a brachial artery catheter at 16 micrograms min‐1 for 3 min to evoke NO release from the vascular endothelium. This caused forearm blood flow to increase above the values observed during exercise alone. 4. During the 20 min trial of handgripping in the second protocol, the NO synthase blocker NG‐monomethyl‐L‐arginine (L‐NMMA) was infused in the exercising forearm via the brachial catheter after 5 min of handgripping. The L‐NMMA was infused at 4 mg min‐1 for 10 min. 5. L‐NMMA during exercise caused forearm blood flow to fall to values approximately 20‐30% lower than those observed during exercise alone. When ACh was given during exercise after L‐NMMA administration the rise in blood flow was also blunted, indicating blockade of NO synthase. These data suggest NO plays a role in exercise hyperaemia in humans.

Aging and Forearm Postjunctional α-Adrenergic Vasoconstriction in Healthy Men

Background—Muscle sympathetic vasoconstrictor nerve activity increases with age in healthy humans but does not result in an augmented forearm vasoconstrictor tone. We tested the hypothesis that this is due to a reduction in postjunctional &agr;-adrenergic responsiveness to endogenous norepinephrine (NE) release and determined whether this was specific to &agr;1- or &agr;2-adrenergic receptors. Methods and Results—Forearm blood flow (FBF, by strain-gauge plethysmography) responses to local intra-arterial infusions of tyramine (which evokes endogenous NE release), phenylephrine (selective &agr;1-agonist), and clonidine (&agr;2-agonist) were determined in 10 young (aged 26±1 [mean±SEM] years) and 10 older (aged 65±1 years) healthy normotensive men after local &bgr;-adrenergic blockade with propranolol. Basal forearm vascular tone was not different in young men and older men. The percentage reduction in FBF in response to the highest dose of tyramine was blunted in older men compared with young men (−37±3% versus −49±3%, respectively;P <0.01) despite a greater increase in deep venous NE concentration in older men (910±103 versus 565±69 pg/mL, respectively;P <0.001). Maximal reductions in FBF to phenylephrine were also blunted in older men (−47±2% versus −58±3% in young men, P <0.05). In contrast, the reductions in FBF (−36±7% versus −40±3% for older versus young men, respectively) and also in venous NE concentration (−79±24 versus −84±13 pg/mL for older versus young men, respectively) to clonidine were similar in the 2 groups. Finally, forearm sympathetic &agr;-adrenergic vasoconstrictor tone (assessed via nonselective &agr;-blockade with phentolamine) was significantly lower in older men. Conclusions—Our results indicate that human aging is associated with a reduction in forearm postjunctional &agr;-adrenergic responsiveness to endogenous NE release and that this might be specific to &agr;1-adrenergic receptors. Furthermore, the contribution of sympathetic &agr;-adrenergic vasoconstriction to basal forearm vascular tone is reduced with age in healthy men.

Forearm sympathetic withdrawal and vasodilatation during mental stress in humans

1 In humans, mental stress elicits vasodilatation in the muscle vascular beds of the forearm that may be neurally mediated. We sought to determine the extent to which this vasodilatation is due to sympathetic withdrawal, active neurogenic vasodilatation, or β‐adrenergically mediated vasodilatation. 2 We simultaneously measured forearm blood flow and muscle sympathetic nerve traffic to the forearm during mental stress in humans. In a second study, we measured forearm blood flow responses to mental stress after selective blockade of α‐adrenergic neurotransmission in one forearm. In a final study, we measured forearm blood flow responses to mental stress after unilateral anaesthetic blockade of the stellate ganglion, alone or in combination with selective β‐adrenergic receptor blockade of the forearm. 3 During mental stress, muscle sympathetic nerve activity decreased from 5113 ± 788 to 1509 ± 494 total integrated activity min− (P < 0.05) and forearm vascular resistance decreased from 96 ± 29 to 33 ± 7 mmHg (dl of tissue) min ml− (P < 0.05). Considerable vasodilatation was still elicited by mental stress after selective blockade of α‐adrenergic neurotransmission. Vasodilatation also occurred during mental stress after stellate ganglion blockade. This dilatation was reduced by selective blockade of β‐adrenergic receptors in the forearm. 4 Our results support a role for both sympathetic withdrawal and β‐adrenergic vasodilatation as the major causes of the forearm vasodilatation during mental stress in humans.

Blood substitutes : fluids, drugs, or miracle solutions ?

Oxygen-carrying volume-expanding solutions that can sustain life in the absence of red blood cells have been developed. Concerns about side effects, sources of hemoglobin, and the ultimate demonstration of efficacy will have to be satisfactorily addressed before anesthesiologists routinely administer such solutions in place of red cells during surgery.

Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans

In humans, sympathetic nerve activity (SNA) at rest can vary several‐fold among normotensive individuals with similar blood pressures. We recently showed that a balance exists between SNA and cardiac output, which may contribute to the maintenance of normal blood pressures over the range of resting SNA levels. In the present studies, we assessed whether variability in vascular adrenergic responsiveness has a role in this balance. We tested the hypothesis that forearm vascular responses to noradrenaline (NA) and tyramine (TYR) are related to SNA such that individuals with lower resting SNA have greater adrenergic responsiveness, and vice‐versa. We measured multifibre muscle SNA (MSNA; microneurography), arterial pressure (brachial catheter) and forearm blood flow (plethysmography) in 19 healthy subjects at baseline and during intrabrachial infusions of NA and TYR. Resting MSNA ranged from 6 to 34 bursts min−1, and was inversely related to vasoconstrictor responsiveness to both NA (r= 0.61, P= 0.01) and TYR (r= 0.52, P= 0.02), such that subjects with lower resting MSNA were more responsive to NA and TYR. We conclude that interindividual variability in vascular adrenergic responsiveness contributes to the balance of factors that maintain normal blood pressure in individuals with differing levels of sympathetic neural activity. Further understanding of this balance may have important implications for our understanding of the pathophysiology of hypertension.

β2‐Adrenergic receptor polymorphism and nitric oxide‐dependent forearm blood flow responses to isoproterenol in humans

Polymorphisms in the gene encoding the β2‐adrenoceptor have been associated with interindividual differences in blood pressure and the diagnosis of hypertension. A common polymorphism resulting in a change from arginine to glycine at amino acid 16 (Arg16 → Gly) enhances agonist‐promoted downregulation of receptor expression in vitro. It is unknown whether genotype‐dependent differences in nitric oxide generation contribute to differences in vasodilator responses to β2‐agonists in vivo. To address this question, venous occlusion plethysmography was used to measure forearm blood flow responses to graded brachial artery infusions of the β‐agonist isoproterenol in 41 healthy normotensive Caucasian adults (mean age (±s.d.) = 29 ± 6 years), who were either Arg16 (n= 18) or Gly16 (n= 23) homozygotes. Compared to Arg16 homozygotes, Gly16 homozygotes demonstrated significantly greater blood flow responses to isoproterenol (P= 0.02). After inhibition of nitric oxide synthase by Nγ‐monomethyl‐l‐arginine, blood flow responses did not differ significantly between genotype groups (P= 0.27). Consequently, effects of the Arg16 → Gly polymorphism on forearm blood flow responses to isoproterenol appear to be dependent on differences in endothelial generation of nitric oxide. In contrast to previous reports based on systemic infusions of β2‐agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes.

Evidence for nitric oxide‐mediated sympathetic forearm vasodiolatation in humans.

1. Our aim was to determine if sympathetic vasodilatation occurs in the human forearm, and if the vasodilating substance nitric oxide contributes to this dilatation. We also sought to determine if the nitric oxide might be released as a result of cholinergic stimulation of the vascular endothelium. 2. Blood flow was measured in the resting non‐dominant forearm with venous occlusion plethysmography. To increase sympathetic traffic to the resting forearm, rhythmic handgrip exercise to fatigue followed by post‐exercise ischaemia was performed by the dominant forearm. A brachial artery catheter in the non‐dominant arm was used to selectively infuse drugs. 3. During control conditions, there was mild vasodilatation in the resting forearm during exercise followed by constriction during post‐exercise ischaemia. When exercise was performed after brachial artery administration of bretylium (to block noradrenaline release) and phentolamine (an alpha‐adrenergic antagonist), profound vasodilatation was seen in the resting forearm during both exercise and post‐exercise ischaemia. 4. When the nitric oxide synthase blocker NG‐monomethyl‐L‐arginine (L‐NMMA) was administered in the presence of bretylium and phentolamine prior to another bout of handgripping, little or no vasodilatation was seen either during exercise or post‐exercise ischaemia. Atropine also blunted the vasodilator responses to exercise and post‐exercise ischaemia after bretylium and phentolamine. 5. These results support the existence of active sympathetic vasodilatation in the human forearm and the involvement of nitric oxide in this phenomenon. They also suggest nitric oxide might be released as a result of cholinergic stimulation of the vascular endothelium.

Effects of respiratory muscle work on blood flow distribution during exercise in heart failure

Heart failure (HF) patients have a reduced cardiac reserve and increased work of breathing. Increased locomotor muscle blood flow demand may result in competition between respiratory and locomotor vascular beds. We hypothesized that HF patients would demonstrate improved locomotor blood flow with respiratory muscle unloading during activity. Ten patients (ejection fraction = 31 ± 3%) and 10 controls (CTL) underwent two cycling sessions (60% peak work). Session 1 (S1): 5 min of normal breathing (NB), 5 min respiratory muscle unloading with a ventilator, and 5 min of NB. Session 2 (S2): 5 min NB, 5 min of respiratory muscle loading with inspiratory resistance, and 5 min of NB. Measurements included: leg blood flow (LBF, thermodilution), cardiac output , and oesophageal pressure (Ppl, index of pleural pressure). S1: Ppl was reduced in both groups (HF: 73 ± 8%; CTL: 60 ± 13%, P < 0.01). HF: increased (9.6 ± 0.4 vs. 11.3 ± 0.8 l min−1, P < 0.05) and LBF increased (4.8 ± 0.8 vs. 7.3 ± 1.1 l min−1, P < 0.01); CTL: no changes in (14.7 ± 1.0 vs. 14.8 ± 1.6 l min−1) or LBF (10.9 ± 1.8 vs. 10.3 ± 1.7 l min−1). S2: Ppl increased in both groups (HF: 172 ± 16%, CTL: 220 ± 40%, P < 0.01). HF: no change was observed in (10.0 ± 0.4 vs. 10.3 ± 0.8 l min−1) or LBF (5.0 ± 0.6 vs. 4.7 ± 0.5 l min−1); CTL: increased (15.4 ± 1.4 vs. 16.9 ± 1.5 l min−1, P < 0.01) and LBF remained unchanged (10.7 ± 1.5 vs. 10.3 ± 1.8 l min−1). These data suggest HF patients preferentially steal blood flow from locomotor muscles to accommodate the work of breathing during activity. Further, HF patients are unable to vasoconstrict locomotor vascular beds beyond NB when presented with a respiratory load.