Effects of mental and physical stress on central haemodynamics and cardiac sympathetic nerve activity during QT interval-sensing rate-responsive and fixed rate ventricular inhibited pacing

The effects of mental stress and dynamic exercise on central haemodynamic variables and cardiac sympathetic nerve activity were studied in 15 patients during both fixed rate ventricular-inhibited (VVI) and QT interval-sensing rate-responsive (TX) pacing. Haemodynamic measurements were made at rest, during a mental stress test and during supine exercise at 30 W. Cardiac sympathetic nerve activity was assessed by measuring the arterial and coronary sinus plasma concentrations of noradrenaline (NA) and adrenaline (ADR), the NA kinetics in arterial plasma (radiotracer infusion) and the overflow of NA into the coronary sinus. During exercise the paced ventricular rate increased by 47% with TX. TX provided a higher cardiac output than VVI despite a similar myocardial oxygen consumption and a lower level of cardiac sympathetic activity. Cardiac NA overflow based on 3H-NA extraction over the heart increased from 182 to 1046 pmol min-1 in the VVI mode (P less than 0.01) and from 178 to 793 pmol min-1 in the TX mode (P less than 0.001). The difference in cardiac NA overflow in response to exercise (P less than 0.05 by ANOVA) was not reflected in similar differences in arterial NA concentrations or spill over rates. During mental stress the ventricular rate increased in 12/14 patients. Noradrenaline overflow increased similarly in the two modes. Changes in cardiac NA overflow during mental stress and exercise were correlated with increases in TX pacing rate. This study confirms that both mental and physical stress cause significant changes in cardiac sympathetic nerve activity and central haemodynamic variables, and that the TX pacemaker responds by increasing its pacing rate in a physiological manner.     

Adrenaline infusion in man increases muscle sympathetic nerve activity and noradrenaline overflow to plasma

This study was conducted to determine if muscle sympathetic nerve activity (MSA) and/or the neuronal release of noradrenaline per impulse are modulated by adrenaline in the physiological plasma concentration range. We gave step-wise infusions of adrenaline (0.05-0.6 nmol/kg per min) to 10 healthy young men and measured: intra-arterial blood pressure; heart rate; central venous pressure (CVP); efferent MSA (microneurography in the peroneal nerve); arterial (brachial artery) and femoral venous plasma concentrations of noradrenaline, and the spillover of noradrenaline to arterial and venous plasma (radiotracer infusion). The infusion of adrenaline caused a fall in diastolic blood pressure and tachycardia, and was associated with increases in MSA and noradrenaline spillover. These observations suggest that part of the adrenaline-induced increase in transmitter release is due to enhanced nerve impulse activity, but such a conclusion rests on the absence of diffusion limitations from the site of noradrenaline infusion into the blood stream. After termination of adrenaline infusion the tachycardia and elevated plasma noradrenaline levels persisted, but these changes were probably due mainly to a profound increase in nerve activity. Concurrently, there was a reduction in CVP which may have triggered the increase in efferent sympathetic nerve activity. Infusions of adrenaline did not influence the clearance of noradrenaline from arterial plasma, but the fractional extraction over the leg was moderately reduced, indicating that more arterial noradrenaline is recovered in venous plasma during adrenaline infusion. The present data suggest that the reasons for the adrenaline-induced increase in noradrenaline release are complex, but they are consistent with the hypothesis that stress levels of adrenaline enhance sympathetic nerve activity, and that circulating adrenaline may modulate both haemodynamic and neural responses to stress.     

Evidence for functional alpha 2-adrenoceptors on vascular sympathetic nerve endings in the human forearm.

The role of alpha 2-adrenoceptors on vascular sympathetic nerve endings in modulating release of the sympathetic neurotransmitter norepinephrine (NE) in humans was examined by measuring the regional rate of appearance of NE in forearm venous plasma (forearm NE spillover [FSO]) in 32 healthy volunteers during intra-arterial infusion of drugs acting at adrenoceptors or directly on vascular smooth muscle. Simultaneous intra-arterial infusions of tracer amounts of [3H]NE were used to calculate the extraction rate of NE in the forearm. Methoxamine or propranolol with epinephrine (PRO + EPI) was used to stimulate alpha-adrenoceptors, yohimbine was used to inhibit alpha-adrenoceptors, and sodium nitroprusside (NIP) was used to produce increases in forearm blood flow directly. Sympathetic efferent activity was manipulated by systemic intravenous infusions of NIP or trimethaphan. Yohimbine and NIP increased and PRO + EPI and methoxamine decreased NE FSO, without effects on systemic blood pressure, heart rate, or arterial levels of catechols. Changes in FSO were flow dependent; therefore, the slope of the relation between the changes in FSO and forearm blood flow was used to evaluate the effects of each drug on regional sympathoneural activity. During administration of yohimbine, the mean slope of the relation between the change in estimated FSO and the change in forearm blood flow was about four times that of the mean slope during administration of NIP (F = 6.35, p less than 0.05). The slopes of the relations between changes in FSO and forearm blood flow were unaffected by systemic trimethaphan or NIP infusion, indicating that the activity of alpha 2-adrenoceptors was not altered during inhibition or reflexive stimulation of sympathetic outflow. The results suggest that alpha 2-adrenoceptors modulate release of NE from vascular sympathetic nerve endings in humans and that the function of these receptors is unchanged during acute changes in junctional NE concentrations.     

Total and renal sympathetic nervous system activity in alcoholic cirrhosis

Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.     

Rilmenidine sympatholytic activity preserves mental stress, orthostatic sympathetic responses and adrenaline secretion

BACKGROUND: Heightened central sympathetic nervous outflow is common in essential hypertension, contributing to hypertension development and possibly also to complications. Acute sympathetic nervous activation is a proven trigger for adverse cardiovascular events. Accordingly, antihypertensive drugs inhibiting sympathetic outflow represent a theoretically attractive therapeutic option. OBJECTIVES: To study the sympatholytic and blood pressure-lowering activity of the imidazoline binding agent rilmenidine at rest and during reflex sympathetic activation. DESIGN AND METHODS: We used a randomized, double-blind, 6-week cross-over study, with a 1-week placebo run-in period, two 2-week active treatment intervals (rilmenidine 1 mg twice daily or placebo) and intervening 1-week placebo washout. In 15 hypertensive patients, noradrenaline and adrenaline plasma kinetics and intra-arterial blood pressure measurements were performed at rest, after mental stress (difficult mental arithmetic) and during head-up tilting, at the end of the 2-week dosing periods. RESULTS: The noradrenaline spillover rate, indicative of whole body sympathetic activity, was reduced 35% by rilmenidine at rest (P < 0.01) and remained significantly lower during mental stress and tilting, although the increases in noradrenaline spillover with both stimuli were preserved. The effects on intra-arterial blood pressure ran in parallel, a fall in supine resting pressure, but no reduction in blood pressure rise during mental stress and a lack of fall in blood pressure with tilting. On placebo, adrenaline secretion was 0.88 +/- 0.15 nmol/min (mean +/- SE) at rest, increased by 0.42 +/- 0.23 nmol/min with mental stress (P = 0.019) and was unchanged with tilting. Rilmenidine left adrenaline secretion untouched under all conditions. CONCLUSIONS: The present study confirms a sympatholytic effect of rilmenidine during supine rest but preservation of sympathetic responses during mental stress and tilting, with the latter underlying a freedom from postural hypotension on the drug. The absence of suppression of reflexive sympathetic responses contrasts with the described effects of rilmenidine in experimental animals, and emphasizes the previously demonstrated unique importance in humans of suprabulbar noradrenergic neuronal projections from the brainstem in regulating tonic sympathetic activity, with these being inhibited by imidazoline binding agents. Sympathetic nervous inhibition with rilmenidine contrasted with an absence of suppression of adrenaline secretion, affirming that sympathetic nervous and adrenal medullary function can be disconnected.     

Norepinephrine removal and release in the forearm of healthy subjects

The relevance of local removal and release of norepinephrine (NE) for antecubital venous plasma NE concentration was studied in 22 healthy subjects. Arterial and venous plasma NE and forearm blood flow were measured during intra-arterial infusion of two doses of NE, intra-arterial NE infusion with two doses of sodium nitroprusside, intravenous infusion of NE with intra-arterial infusion of four doses of sodium nitroprusside, and lower body negative pressure of -20 mm Hg for 15 minutes. The venous plasma NE concentration-time curves during the infusions of the two doses of NE indicated first-order kinetics for forearm extraction: forearm NE extraction rate during the low dose infusion was 67 +/- 4.1% (SEM) and correlated with basal forearm blood flow (r = -0.64, p less than 0.03, n = 12). Local sodium nitroprusside-induced vasodilatation during the intra-arterial and intravenous NE infusions was accompanied by dose-dependent decreases in forearm extraction rates for NE and epinephrine. During lower body negative pressure, taking into account the high basal forearm extraction rate for NE, local and systemic release of NE was indicated by increases in arterial and venous plasma and the venous-arterial plasma NE concentration difference (p less than 0.05 for all). These data show that removal of NE from forearm circulation is a process with a high extraction ratio obeying first-order kinetics and that this extraction process inversely relates to forearm blood flow. Thus, antecubital venous plasma NE is likely to be derived mainly from local release and not from the arterial plasma NE input.     

Evidence for increased renal norepinephrine overflow during sodium restriction in humans

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.     

Does regional norepinephrine spillover represent local sympathetic activity?

Regional spillover of norepinephrine (NE), based on isotope dilution and single-compartment steady-state kinetics, is considered one of the best parameters for estimating organ sympathetic activity. However, the effects of local changes in clearance of NE on the spillover have not yet been investigated. We studied local NE kinetics and clearance in the forearm of 10 healthy subjects using intra-arterial infusions of NE, tritiated NE, the neuronal uptake inhibitor desipramine, and tyramine, which competes with NE for the neuronal uptake carrier. Before and during complete blockade of neuronal uptake by desipramine the venous concentration-time curves for tritiated NE and for NE released by tyramine were biexponential, consistent with the presence of (at least) two compartments for circulating tritiated NE and for locally released NE. The time constants for tyramine-induced release of NE and, in the same subjects during desipramine infusion, for tritiated NE were almost equal at the same level of forearm blood flow. This argues against possible diffusion or transport differences for NE to and from the circulation and the synapse. The regional intrinsic clearance capacity (a measure of the maximal ability of an organ to irreversibly remove drug by all pathways in the absence of any flow limitations) for NE decreased in the forearm by 65% (p less than 0.01) during neuronal uptake blockade by desipramine; the forearm clearance decreased by 59% (p less than 0.001), whereas the spillover rate of NE increased from 33 +/- 5 to 63 +/- 11 pmol.min-1 (p less than 0.05). Nitroprusside-induced increments in blood flow increased the spillover of NE from 18 +/- 4 to 35 +/- 6 pmol.min-1 (p less than 0.01); the clearance of circulating NE also increased (by 58%, p less than 0.05), and the intrinsic clearance capacity remained unchanged. This demonstrates that regional spillover of NE is markedly influenced by local changes in clearance and flow. The new parameter plasma appearance rate of NE is proposed. Although also derived from isotope dilution, this parameter may better approximate the regional entry of NE into the blood pool than spillover. This is corroborated by the nonsignificant changes of plasma appearance rate of NE during our desipramine and nitroprusside infusions.     

Coronary venous noradrenaline during coronary angioplasty

Coronary venous and arterial noradrenaline concentrations were measured during percutaneous transluminal coronary angioplasty in 14 patients. Coronary venous noradrenaline did not increase significantly during balloon inflation but was increased during early reperfusion in patients undergoing left anterior descending angioplasty (n = 8), from 157 +/- 38 pg/ml to 295 +/- 94 pg/ml (P less than 0.05). Coronary blood flow, measured by thermodilution in 7 further patients during left anterior descending angioplasty, was 69 +/- 9 ml/min, decreased to 80 +/- 3% of basal flow during balloon inflation (P less than 0.01) and increased to 135 +/- 5% during early reperfusion (P less than 0.01). It was estimated using these results that cardiac spillover of noradrenaline did not change during occlusion of the left anterior descending artery, but increased almost 3-fold during early reperfusion. During the period of balloon inflations, there was a modest increase in overall sympathetic tone, as assessed by total noradrenaline spillover to plasma (400 +/- 77 ng/min to 473 +/- 87 ng/min, P less than 0.01). These results, suggesting an increase in release of noradrenaline during early reperfusion following brief occlusion of the left anterior descending artery, may be relevant to the genesis of reperfusion arrhythmias.     

Long-term calcium antagonist treatment of human hypertension with mibefradil or amlodipine increases sympathetic nerve activity

OBJECTIVES: Calcium antagonists are vasodilating drugs, which may cause reflex activation of the sympathetic nervous system with potentially untoward effects. We studied the effects of long-term treatment with amlodipine, a long-acting dihydropyridine-type calcium antagonist, and mibefradil, a phenylalkylamine-type calcium antagonist, on sympathetic nerve activity. METHODS: Fourteen patients with primary hypertension participated in a double-blind, cross-over study comparing the effects of 6 weeks of treatment with mibefradil 100 mg daily and amlodipine 10 mg daily. Heart rate, direct arterial blood pressure and cardiac output by echocardiography were registered. Global sympathetic activity was estimated using a [3H]noradrenaline isotope dilution method with arterial and venous sampling; cardiac sympathetic activity was assessed indirectly by heart rate variability and tissue velocity echocardiography. RESULTS: Both drugs lowered mean arterial pressure; the decrease was more pronounced with mibefradil (from 118 +/- 3 to 99 +/- 2 mmHg, compared to 118 +/- 3 to 104 +/- 2 mmHg for amlodipine, P < 0.01 between drugs). Mibefradil decreased heart rate (66 +/- 2 to 57 +/- 2 bpm), whereas amlodipine caused a slight increase (66 +/- 2 to 70 +/- 2 bpm; P < 0.001 between drugs) and tended to increase cardiac output. Noradrenaline spillover increased similarly with the two drugs, from 3.44 +/- 0.27 to 5.20 +/- 0.48 nmol/min per m2(P < 0.01) during mibefradil and to 5.72 +/- 0.49 nmol/min per m2 (P < 0.001) during amlodipine. There were minor effects on cardiac sympatho-vagal balance, but systolic and diastolic myocardial velocities were increased similarly by both drugs. CONCLUSIONS: Mibefradil and amlodipine treatment increase global sympathetic nerve activity similarly during long-term treatment, despite opposite effects on heart rate. Increases in myocardial velocities suggest concomitant cardiac sympathetic activation.     

Direct neurohumoral evidence for isolated sympathetic nervous system activation to skeletal muscle in response to cardiopulmonary baroreceptor unloading

It has been postulated that cardiopulmonary baroreceptor unloading in humans results in nonuniform activation of the sympathetic nervous system. We reasoned that simultaneous measurements of arterial and venous norepinephrine (NE) spillover and clearance (using NE kinetics), muscle sympathetic neural activity (using microneurography), forearm blood flow (using plethysmography), and skin blood flow (using laser Doppler velocimetry) during lower body negative pressure at -15 mm Hg would isolate the location and extent of cardiopulmonary baroreceptor-mediated sympathetic nervous system activation. We exposed normal subjects (n = 8) to lower body negative pressure for 30 minutes, with measurements obtained at baseline, 5-10 minutes (EARLY), and 25-30 minutes (LATE). We found that arterial NE spillover, reflecting systemic sympathetic nervous system activation, did not increase significantly, whereas arterial NE clearance decreased significantly. In contrast, forearm venous NE spillover, reflecting skin and muscle sympathetic nervous system activation, increased by 17% and muscle sympathetic neural activity by 35% EARLY, whereas venous clearance did not change significantly. Although laser Doppler skin blood flow did not change, plethysmographic forearm blood flow (combined muscle and skin blood flow) decreased by 28%. All changes were sustained throughout 30 minutes of lower body negative pressure. Our data suggest that sympathetic vasoconstriction to muscle is greater than it is to skin in response to cardiopulmonary baroreceptor unloading. Moreover, our data suggest that reduced NE clearance in the arterial circulation is the primary mechanism by which arterial NE concentrations rise. Conversely, NE spillover appears to be the primary mechanism responsible for increasing venous NE concentrations measured from the forearm during cardiopulmonary baroreceptor unloading.     

Adenosine attenuates the response to sympathetic stimuli in humans

The effect of adenosine on the forearm vasoconstrictor response to alpha-adrenergic and sympathetic stimulation was studied in healthy volunteers. During a predilated state achieved by infusion of sodium nitroprusside into the branchial artery, subsequent infusion of norepinephrine induced a mean increase in forearm vascular resistance of 571%, whereas this response was only 270% when an equipotent vasodilator dose of adenosine was used instead of sodium nitroprusside (nitroprusside versus adenosine, p less than 0.05, n = 6). A comparable difference was found when the endogenous release of norepinephrine was stimulated by the local infusion of tyramine, with tyramine-induced increments in forearm vascular resistance of 438% during nitroprusside versus 93% during adenosine (n = 6, p less than 0.05). During these tyramine infusions a similar increase in the calculated forearm norepinephrine overflow occurred in the adenosine and the nitroprusside tests. In a third experiment, we demonstrated that adenosine also reduced the vasoconstrictor response to lower body negative pressure, an endogenous stimulus, of the sympathetic nervous system. During nitroprusside, lower body negative pressure induced an increase in forearm vascular resistance of 135%, whereas this was 39% during adenosine (n = 6, p less than 0.05). We conclude that adenosine attenuates the response to sympathetic nervous system-mediated vasoconstriction in humans, and that this effect may at least partly be explained by a postsynaptic inhibition of alpha-adrenergic vasoconstriction. Therefore, we think that adenosine may be an important endogenous modulator of sympathetic nervous system activity in humans.     

Influence of acute and chronic mineralocorticoid excess on endothelial function in healthy men

Aldosterone has rapid nongenomic effects in the human vasculature. However, data are not uniform and little is known about chronic effects of aldosterone. Therefore, we investigated acute and chronic effects of elevated aldosterone levels on endothelial function in the forearm vasculature of healthy men. In a first crossover study, the effects of arterial aldosterone infusion in ascending doses (3.3 to 55 pmol/min per 1000 mL forearm volume) on forearm blood flow were investigated in 8 healthy men (26+/-2 years). In a second study, endothelium-dependent (acetylcholine; 0.08, 0.275, and 2.75 micromol/min per 1000 mL) and endothelium-independent (sodium nitroprusside 0.02 micromol/min per 1000 mL) vasodilation and basal nitric oxide formation (forearm blood flow response to blockade by N(G)-monomethyl-l-arginine 8 micromol/min per 1000 mL) were tested in 10 healthy men (age 30+/-5 years) at baseline, during infusion of 55 pmol/1000 mL per min aldosterone (acute effects), and after 0.3 mg/d oral fludrocortisone for 2 weeks (chronic effects) on separate days. Forearm blood flow was assessed by venous occlusion plethysmography. No change in forearm blood flow was seen with aldosterone infusion alone. Acute coinfusion of aldosterone increased vasodilation to sodium nitroprusside by 93% (P<0.01) and to acetylcholine by 60% (P=0.14). Response to N(G)-monomethyl-l-arginine did not change. After 2 weeks of oral fludrocortisone, response to acetylcholine was enhanced by 72% compared with baseline (P=0.03). Additionally, response to N(G)-monomethyl-l-arginine was enhanced by 80% compared with baseline (P=0.05). Aldosterone acutely enhances vasodilation to exogenous nitric oxide whereas mineralocorticoid excess for 2 weeks enhances basal nitric oxide bioactivity and improves endothelium dependent, nitric oxide-mediated vasodilation in the forearm vasculature of healthy men.     

Arterial vasodilator effects of the dihydropyridine calcium antagonist amlodipine alone and in combination with verapamil in systemic hypertension

The arterial vasodilator properties of the dihydropyridine calcium antagonist amlodipine were compared with the effects of vascular muscle cyclic guanosine monophosphate production by sodium nitroprusside and with the effects of a combined infusion of amlodipine and the nondihydropyridine calcium antagonist verapamil in 8 untreated patients with primary hypertension. Arterial vasodilation was assessed by measurement of changes of forearm blood flow by mercury in Silastic strain-gauge plethysmography during brachial artery drug infusions. Forearm blood flow increased during amlodipine infusions (0.4 to 45 micrograms/min/100 ml forearm tissue) from 2.9 +/- 1.7 to a maximum of 23.6 +/- 7.6 ml/min/100 ml (687%), while sodium nitroprusside caused an increase from 3.0 +/- 1.8 to 16.2 +/- 5.4 ml/min/100 ml (449%), attesting to the importance of transmembrane calcium influx for the maintenance of vascular tone. The addition of verapamil 40 micrograms/min/100 ml to an infusion of amlodipine 44.5 micrograms/min/100 ml resulted in a further increase of forearm blood flow, from 23.6 +/- 7.6 to 34.4 +/- 9.8 ml/min/100 ml (p less than 0.05). The precise mechanisms of this finding have yet to be elucidated but may be due to interactions of the effects of the binding of these 2 chemically and pharmacologically different calcium antagonists to distinct binding sites at calcium channels. The clinical relevance of this observation for the treatment of coronary artery disease and systemic hypertension needs further study.     

Functional versus structural changes of forearm vascular resistance in hypertension

Structural changes in resistance vessels have been considered an important factor in triggering and maintaining chronic hypertension in humans and in experimental animals. To determine whether the increased forearm vascular resistance observed following vasodilator maneuvers in hypertensive patients is predominantly due to structural or to functional changes, we examined the influence of different vasodilator stimuli on forearm blood flow and blood pressure in 22 male patients with established essential hypertension and in 22 age-matched normotensive men (age range, 28-52 years). Blood pressure was measured directly, and blood flow was measured by venous occlusion plethysmography. The maneuvers applied were 1) arterial occlusion combined with handgrip exercise and local heating, 2) intra-arterial infusion of the calcium entry blocker nifedipine, 3) intra-arterial infusion of the nonspecific vasodilator sodium nitroprusside, 4) arterial occlusion initiated after intra-arterial infusion of nifedipine. Vascular resistance during vasodilation induced by arterial occlusion or infusion of nifedipine or sodium nitroprusside remained significantly higher in the hypertensive than in the normotensive subjects. However, the maximal vasodilation achieved by the combination of arterial occlusion and nifedipine resulted in a similar resistance in both groups (1.6 +/- 0.2 in the hypertensive vs 1.4 +/- 0.2 mm Hg/ml/min/100 ml tissue in the normotensive subjects. These data suggest that there is an important functional component of the elevated resistance in patients with essential hypertension.     

Volume-pressure analysis of reflex changes in forearm venous function. A method by mental arithmetic stress and radionuclide plethysmography

Mental arithmetic stress is known to cause forearm arterial dilation, but the venous responses, including possible changes in the volume-pressure relation, have not been defined. Hence, 10 apparently normal subjects, eight men and two women, mean age 46 +/- 9 years, were studied before and during mental arithmetic stress. Changes in forearm venous volume were estimated with 99mTc blood pool scintigraphy. Group variability of this measurement technique was 1.8 +/- 2.3%. A brachial blood pressure cuff was used to obtain venous occluding pressures of 0, 10, 20, and 30 mm Hg. Mental arithmetic stress increased group systolic and diastolic blood pressure from 126 +/- 12 to 152 +/- 20 mm Hg and from 83 +/- 8 to 93 +/- 15 mm Hg, respectively (p less than 0.001). Heart rate increased from a mean of 75 +/- 15 to 85 +/- 17 beats/min (p less than 0.01). There was no evidence of interaction between or nonlinearity of the volume-pressure plots. Linear regression then yielded the equations V = 99.8 + 0.96P before and V = 86.3 + 0.96P during mental arithmetic stress, which represents a 13.5 +/- 1.6% decrease in forearm vascular volume (p less than 0.001). We conclude that 1) a linear relation exists between forearm venous volume and pressure at physiologic pressures before and during mental arithmetic stress; 2) mental arithmetic stress causes forearm venoconstriction; and 3) such venoconstriction takes place by a parallel shift in the volume-pressure relation (i.e., a shift in unstressed venous volume).     

Interaction of neuropeptide Y and the sympathetic nervous system in vascular control in man

BACKGROUND. There is increasing evidence that neuropeptide Y (NPY) contributes to the autonomic control of the circulation. NPY coexists with noradrenaline in perivascular nerve terminals, may be released during sympathetic stimulation, and is a potent constrictor of the human coronary circulation and other vascular beds. In vitro studies show that NPY can act either directly on vascular smooth muscle or indirectly by modulation of the presynaptic release or the postsynaptic actions of noradrenaline. It is unclear to what extent these mechanisms operate in vivo. METHODS AND RESULTS. The effect on forearm blood flow of intra-arterial NPY was studied in six volunteers during coinfusion of noradrenaline and during reflex sympathetic stimulation induced by lower-body negative pressure. NPY alone induced a dose-dependent reduction of forearm blood flow in all subjects studied, to a maximum of 49 +/- 6.1%. The reduction of flow during infusion of noradrenaline alone was 42 +/- 8%. The response to noradrenaline was unaffected by coinfusion of a threshold constrictor dose of NPY (50 pmol/min). Furthermore, the reflex sympathetic vasoconstrictor response to 20 cm H2O of lower-body negative pressure was similar in both the infused and control arms during the infusion of 50 pmol/min NPY. The response to noradrenaline was abolished by alpha-blockade with phentolamine, but the flow reduction induced by NPY was unaffected by alpha-blockade. CONCLUSIONS. NPY is a potent constrictor of human forearm resistance vessels and has a direct effect independent of alpha-receptors. NPY has no detectable modulating effect in vivo on the action of endogenous or infused noradrenaline.     

Effects of L-arginine on forearm vessels and responses to acetylcholine.

This study was designed to investigate the effects of L-arginine (the substrate of endothelium-derived nitric oxide) in human forearm vessels. We examined whether intra-arterial infusion of L-arginine dilated forearm vessels and augmented vasodilatory responses to acetylcholine in young, healthy humans. The left brachial artery was cannulated for drug infusions and direct measurement of arterial pressure. Forearm blood flow was measured by a strain gauge plethysmograph. Intra-arterial infusions of L-arginine at 10, 20, 40, and 60 mg/min increased forearm blood flow from 4.7 +/- 0.6 to 4.9 +/- 0.5, 5.7 +/- 0.5, 7.2 +/- 0.8, and 8.2 +/- 0.9 ml.min-1.100 ml-1, respectively (n = 8, p less than 0.01), whereas D-arginine at the same doses did not alter forearm blood flow (n = 7). Intra-arterial infusions of acetylcholine (n = 7) (4, 8, 16, and 24 micrograms/min) and sodium nitroprusside (n = 5) (0.2, 0.4, 0.8, and 1.2 micrograms/min) increased forearm blood flow dose dependently (p less than 0.01 for both). Arterial pressure was not altered with infusions of these drugs. Responses to acetylcholine were augmented with simultaneous intra-arterial infusion of L-arginine at 10 mg/ml (p less than 0.01) but not with D-arginine. Responses to sodium nitroprusside were not altered by L-arginine. These results in human forearm resistance vessels support the notion that vasodilation induced by acetylcholine is a result of the conversion from L-arginine to endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympathetic activity in major depressive disorder: identifying those at increased cardiac risk?

BACKGROUND: Evidence exists linking major depressive disorder (MDD) with clinical cardiovascular events. The importance of the sympathetic nervous system in the generation of cardiac risk in other contexts is established. OBJECTIVE: To examine the importance of the sympathetic nervous system in the generation of cardiac risk in patients with major depressive disorder (MDD). METHODS: Studies were performed in 39 patients meeting the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for MDD and in 76 healthy subjects. Treatment for patients consisted of selective serotonin reuptake inhibition (SSRI) for 12 weeks. Whole body and cardiac sympathetic activity were examined using noradrenaline isotope dilution methodology and sympathetic nerve recording techniques. Measurement of the extraction of infused tritiated noradrenaline by the heart, and estimation of cardiac dihydroxyphenylglycol production provided direct quantification of neuronal noradrenaline reuptake. RESULTS: Sympathetic activity, particularly in the heart and for the whole body, in patients with MDD followed a bimodal distribution. Elevated values were observed in patients with co-morbid panic disorder (P = 0.006). Consistent with a defect in noradrenaline reuptake, the cardiac extraction of tritiated noradrenaline (0.80 +/- 0.01 versus 0.56 +/- 0.04%, P < 0.001) and cardiac dihydroxyphenylglycol overflow (109 +/- 8 versus 73 +/- 11, P = 0.01) were reduced in patients with MDD. SSRI therapy abolished the excessive sympathetic activation, with whole body noradrenaline spillover falling from 518 +/- 83 to 290 +/- 41 ng/min (P = 0.008). CONCLUSIONS: We have identified a subset of patients with MDD in whom sympathetic nervous activity is extraordinarily high, including in the sympathetic outflow to the heart. Treatment with an SSRI may reduce sympathetic activity in a manner likely to reduce cardiac risk.     

Rilmenidine sympatholytic activity preserves mental and orthostatic sympathetic response and epinephrine secretion

BACKGROUND: Heightened central sympathetic nervous outflow is common in essential hypertension, contributing to hypertension development and perhaps also to complications. Acute sympathetic nervous activation is a proven trigger for adverse cardiovascular events. Accordingly, antihypertensive drugs inhibiting sympathetic outflow represent a theoretically attractive therapeutic option. OBJECTIVES: To study the sympatholytic and blood pressure lowering activity of the imidazoline binding agent rilmenidine at rest and during reflex sympathetic activation. DESIGN AND METHODS: The HERA study (Hyperium Effect on the sympathetic Reflex activation and Adrenaline) is a randomised, double-blind, 6-week cross-over trial, with a 1-week placebo run-in period, two 2-week active treatment intervals (rilmenidine 1 mg bid, placebo) and intervening one week placebo wash-out. In 15 hypertensive patients, noradrenaline and adrenaline plasma kinetics and intra-arterial blood pressure measurements were performed at rest, after mental stress (difficult mental arithmetic) and during head-up tilting, at the end of the 2-week dosing periods. RESULTS: The noradrenaline spillover rate, indicative of whole body sympathetic activity, was reduced 35% by rilmenidine at rest (p<0.01) and remained significantly lower during mental stress and tilting, although the increases in noradrenaline spillover with both stimuli were preserved. The effects on intraarterial blood pressure ran in parallel, a fall in supine resting pressure, but no reduction in BP rise during mental stress and a lack of fall in BP with tilting. On placebo, adrenaline secretion was 162 +/- 27 ng/min (mean, SE) at rest, increased by 77 +/- 42 ng/min with mental stress (p=0.019) and was unchanged with tilting. Rilmenidine left adrenaline secretion untouched under all conditions. CONCLUSIONS: This study confirms a sympatholytic effect of rilmenidine during supine rest but demonstrates that sympathetic responses during mental stress and tilting are preserved, the latter underlying a perhaps surprising absence of postural hypotension on the drug. The absence of suppression of reflexive sympathetic responses contrasts with the effects of rilmenidine in experimental animals, and emphasises the previously demonstrated unique importance in humans of suprabulbar noradrenergic neuronal projections from the brainstem, which are inhibited by imidazoline binding agents, in regulating tonic sympathetic activity in essential hypertension. Sympathetic nervous inhibition with rilmenidine contrasted with an absence of suppression of the secretion of adrenaline affirming that here, as elsewhere, sympathetic nervous and adrenal medullary function can be disconnected.