Attenuation of reflex forearm vasoconstriction by alpha-human atrial natriuretic peptide in men

This study examined whether atrial natriuretic peptide (ANP) modulates reflex forearm vasoconstriction in humans. Synthetic alpha-human ANP (alpha-hANP) was infused at a rate of 0.03 microgram/kg/min in 8 healthy men (mean age 23 +/- 0.7 years, mean +/- SEM). The alpha-hANP decreased systolic blood pressure and central venous pressure (CVP) but did not significantly alter resting heart rate and forearm vascular resistance (FVR). The magnitudes of reflex increases in FVR during lower body negative pressure (LBNP) at -110, -20, and -40 mm Hg were less during infusion of alpha-ANP than those magnitudes during infusion of saline solution. The slope of the regression line relating changes in CVP and those in FVR was less during infusion of alpha-hANP than the slope during infusion of saline solution. Forearm vascular responses to intra-arterial infusion of norepinephrine at doses of 100, 200, and 500 ng/min did not significantly differ during infusion of alpha-hANP and saline solution. These results suggest that alpha-hANP attenuates cardiopulmonary baroreflex control of FVR in normal men.     

Atrial natriuretic factor potentiates forearm reflex vasoconstriction induced by cardiopulmonary receptor deactivation in man

Previous evidence suggests that atrial natriuretic factor (ANF) interferes with the autonomic control of circulation. In the present study we investigated whether ANF modulates forearm vasoconstriction reflexly induced by cardiopulmonary receptor unloading in man. For this purpose, the hemodynamic response to -20 mm Hg lower body negative pressure (LBNP) was assessed under control conditions and during the constant infusion of alpha-human ANF (0.5 micrograms/kg bolus followed by 0.05 micrograms/kg/min) in seven normal subjects. ANF infusion resulted in a slight reduction in blood pressure and right atrial pressure, did not modify heart rate or forearm vascular resistance, but significantly potentiated the reflex increase in forearm vascular resistance during LBNP (+25 +/- 9% under control conditions vs +40 +/- 12% during ANF, p less than .05). In an attempt to clarify the mechanisms underlying the enhanced reflex vasoconstriction during infusion of ANF, in five additional subjects we demonstrated that there was a comparable vascular reflex response to LBNP under control conditions and during nitroglycerin infusion at a dose that induced a reduction in atrial pressure comparable to that observed during ANF. Finally, in seven additional subjects we found that ANF infusion did not alter the reflex hemodynamic responses elicited by carotid baroreceptor unloading induced by a +60 mm Hg increase in external neck pressure. We conclude that during the infusion of a pharmacologic dose of ANF the reflex forearm vasoconstriction in response to selective cardiopulmonary receptor unloading is potentiated. This effect does not seem to be related to the hemodynamic actions of the peptide or to interference with the sympathetic control of peripheral circulation.     

Blunted sympathetic response to cardiopulmonary receptor unloading in hypertensive patients with left ventricular hypertrophy. A possible compensatory role of atrial natriuretic factor

To investigate whether or not hypertension with left ventricular hypertrophy (LVH) modifies the mechanisms underlying the vascular adjustments to orthostatic stress, we evaluated the hemodynamic and hormonal effects of graded lower-body negative pressure (LBNP) (-10 and -40 mm Hg) before and after sympathetic blockade in 10 hypertensive patients with LVH and in five age- and sex-matched normotensive subjects. In control conditions, LBNP elicited comparable vasoconstrictor responses in the forearm in the two groups. In normotensive subjects, graded increases in plasma norepinephrine and plasma renin activity (PRA) and reductions in plasma immunoreactive atrial natriuretic factor (irANF) were recorded. In hypertensive patients, a significant increase in plasma norepinephrine and plasma renin activity was obtained only with the higher level of LBNP, whereas irANF plasma levels decreased progressively. In both groups, sympathetic blockade abolished the increase in plasma renin activity and did not modify the changes in plasma irANF induced by both levels of LBNP in control conditions. The vascular response to -10 mm Hg LBNP remained unchanged after sympathetic blockade in both groups. However, after sympathetic blockade, the vasoconstrictor response to -40 mm Hg LBNP in normal subjects was no longer different from that elicited by -10 mm Hg LBNP, whereas in hypertensive patients the vasoconstrictor response was still significantly higher than that induced by -10 mm Hg LBNP. Direct correlations between the percent changes in forearm vascular resistance and those in plasma norepinephrine and plasma renin activity were found only in normal subjects in control conditions but were not observed after sympathetic blockade. On the contrary, the inverse correlation between changes in irANF plasma levels and in forearm vascular resistance found in control conditions in both groups was still observed after sympathetic blockade. In a separate group of hypertensive patients with left ventricular hypertrophy, exogenous infusion of ANF induced an increase in venous irANF plasma levels of the same magnitude of the decrease evoked by LBNP and significantly reduced forearm vascular resistance. These data show that in hypertensive patients with left ventricular hypertrophy, sympathetic activation does not contribute to the vascular response to cardiopulmonary receptor unloading (-10 mm Hg LBNP). They also suggest that in these patients inhibition of ANF secretion may play a role in the response to a low level of LBNP so that the peripheral vasoconstriction induced by cardiopulmonary receptor unloading is comparable to that observed in normal subjects despite the lack of appropriate sympathetic reflex vasoconstriction.     

Neurohumoral and hemodynamic effects of lower body negative pressure in patients with congestive heart failure

Baroreflex modulation of forearm vascular resistance (FVR) has been reported to be abnormal in patients with congestive heart failure (CHF). However, the neurohumoral mechanisms for this impairment are not defined. We assessed the responses of arterial pressure, FVR, plasma norepinephrine, and plasma renin activity to lower body negative pressure in 29 patients with compensated CHF (New York Heart Association class III and IV) and in 11 normal age-matched control subjects. Baseline mean arterial pressure (83 +/- 2 vs 84 +/- 2 mm Hg) and mean arterial pressure during LBNP (-10, -20, and -40 mm Hg) were not significantly different in the two groups. Basal FVR (43.7 +/- 4 vs 27 +/- 2 units), plasma norepinephrine (605 +/- 81 vs 155 +/- 8 pg/ml), and plasma renin activity (8.3 +/- 1.7 vs 1.2 +/- 0.2 ng/ml/hr) were significantly (p less than 0.01) higher in patients with CHF. The relative increases in FVR responses during LBNP of -10, -20, and -40 mm Hg (10 +/- 4% vs 70 +/- 12%, 17 +/- 6% vs 106 +/- 21%, and 24 +/- 9% vs 152 +/- 28%) were markedly attenuated in patients with CHF compared to control subjects. Plasma norepinephrine and plasma renin activity responses during LBNP were also attenuated in patients with heart failure. Our results suggest that baroreflex control of FVR and plasma norepinephrine and plasma renin activity is impaired in CHF because of the inability of the cardiopulmonary baroreceptors to alter sympathetic outflow.     

Impaired responsiveness of the ventricular sensory receptor in hypertensive patients with left ventricular hypertrophy

We studied the control of forearm vascular resistance (FVR) by cardiopulmonary receptors in seven patients with hypertension and left ventricular hypertrophy (LVH) and in seven normotensive control subjects. Increasing levels of lower body negative pressure (LBNP) (-10 and -40 mm Hg) induced a progressive decrease in central venous pressure (CVP) and an increase in FVR. The changes in these two variables were correlated both in normal subjects and patients with hypertension (slope for normal subjects = -29.9, for patients with hypertension = -40.3, NS). After propranolol, there was a significant reduction in the increase in FVR induced by -40 mm Hg LBNP in normal subjects (+107 +/- 5 vs +129 +/- 15 mm Hg/ml/sec, p less than .05) but not in patients with hypertension. Consequently, the slope of the delta CVP/delta FVR regression was reduced in normal subjects (-20.6, p less than .01) but not in patients with hypertension. In another seven normal subjects and seven patients with hypertension and LVH we assessed the effects of -10 and -40 mm Hg LBNP on left ventricular filling pressure (LVFP). LBNP induced similar changes in CVP, LVFP, and total peripheral resistance both in normal subjects and in patients with hypertension. Propranolol failed to modify the effects of LBNP on CVP and LVFP in both groups and reduced the response of total peripheral resistance to -40 mm Hg LBNP only in normal subjects. Propranolol did not reduce the response of FVR to the cold pressor test and sustained handgrip or the arterial baroreflex response to the injection of phenylephrine and increased neck tissue pressure. Thus, hypertension-induced LVH seems to be associated with a selective impairment of the left ventricular sensory receptors.     

Norepinephrine and forearm vascular resistance responses to tilt and cold pressor test in essential hypertension: effects of aging

Heart rate, blood pressure, forearm vascular resistance (FVR), and catecholamine and renin responses to head-up tilt at 80 degrees and cold pressor test were investigated in 15 hypertensive men aged less than fifty-five (mean 44 +/- 7 years; M +/- SD) and 13 similarly hypertensive men aged more than fifty-five (mean 62 +/- 4 years; M +/- SD). Baseline plasma norepinephrine levels, as well as norepinephrine responses to tilt and cold pressor stress, were similar in the two groups, suggesting a lack of age-related increase in plasma norepinephrine (NE) responses in patients with essential hypertension. Normalized FVR responses (% change) to tilting (28 +/- 21 vs 95 +/- 36; M +/- SE) and cold pressor test (33 +/- 12 vs 64 +/- 21; M +/- SE) were significantly less (p less than 0.01) in older hypertensives. These results, but not the plasma NE responses to reflex sympathetic activation by tilt and cold pressor testing in older hypertensives, suggest an impaired forearm vasoconstriction.     

Desipramine blocks augmented neurogenic vasoconstrictor responses to epinephrine

The forearm vasoconstrictor response to lower body negative pressure (LBNP), a reflex stimulus to norepinephrine release, can be augmented by a prior brachial artery infusion of epinephrine. We wished to determine whether this sustained aftereffect of epinephrine could be replicated by systemic infusion and, if so, whether it could be prevented by prior uptake-1 blockade with desipramine. Eight normal men (mean age 30 years) were studied on two separate study days at least 1 week apart, 2.5 hours after taking, at random, either desipramine (125 mg p.o.) or placebo. Forearm vascular resistance was measured at rest and at the end of 6 minutes of LBNP at -40 mm Hg. This was done both before and 30 minutes after a 60-minute infusion of epinephrine (1.5 micrograms/min i.v.). From similar baselines, the forearm vasoconstrictor response to LBNP was significantly augmented 30 minutes after epinephrine on the placebo day (+17 +/- 4 vs. +12 +/- 3 resistance units, mean +/- SEM, p less than 0.01) but not on the desipramine day (+14 +/- 2 vs. +16 +/- 3 resistance units). The heart rate response to LBNP was also greater after epinephrine on the placebo day (+20 +/- 3 vs. +16 +/- 2 beats/min, p less than 0.05). Mean arterial pressure was higher after epinephrine infusion on the placebo (p less than 0.01) but not on the desipramine day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced Cardiopulmonary Baroreflex Sensitivity in Patients With Hypertrophic Cardiomyopathy

Objectives. We sought to assess baroreflex function in patients with hypertrophic cardiomyopathy (HCM).Background. We have previously demonstrated a specific abnormality in the afferent limb of the cardiopulmonary baroreflex in patients with vasovagal syncope. Patients with HCM exhibit abnormal control of their vasculature during exercise and upright tilt; we therefore hypothesize a similar abnormality in the afferent limb of the cardiopulmonary baroreflex arc.Methods. We investigated 29 patients with HCM and 32 control subjects. Integrated baroreceptor sensitivity was assessed after administration of phenylephrine. Cardiopulmonary baroreceptor sensitivity was assessed by measuring forearm vascular resistance (FVR) during lower body negative pressure (LBNP). Carotid artery baroreflex sensitivity was assessed by measuring the in RR interval during manipulation of carotid artery transmural pressure. The integrity of the efferent limb of the reflex arc was determined by studying responses to both handgrip and peripheral alpha-receptor sensitivity.Results. During LBNP, FVR increased by only 2.36 ± 9 U in patients, compared with an increase of 12.3 ± 8.76 U in control subjects (p = 0.001). FVR paradoxically fell in eight patients, but in none of the control subjects. Furthermore, FVR fell by 4.9 ± 5.6 U in patients with a history of syncope, compared with an increase of 4.7 ± 7.2 U in those without syncope (p = 0.014). Integrated and carotid artery baroreflex sensitivities were similar in patients and control subjects (14 ± 7 vs. 14 ± 6 ms/mm Hg, p = NS and −3 ± 2 vs. −4 ± 2 ms/mm Hg, p = NS, respectively). Similarly, handgrip responses and the dose/response ratio to phenylephrine were not significantly different.Conclusions. This study suggests that patients with HCM have a defect in the afferent limb of the cardiopulmonary reflex arc.     

Inhibitory effects of procainamide on sympathetic nerve activity in humans

In experimental animals, procainamide causes hypotension and reductions in efferent vasoconstrictor sympathetic outflow that may result from ganglionic blockade or central nervous system sympathetic inhibition. To test the hypothesis that procainamide decreases sympathetic nerve activity (SNA) in humans, we recorded postganglionic SNA in seven normal subjects in the baseline state and during infusions of procainamide HCl at 50 mg/min (loading) and 8 mg/min (maintenance). At the end of the loading infusion, mean arterial pressure (MAP) had decreased from 88.5 +/- 2.4 (mean +/- SEM) to 81.5 +/- 3.2 mm Hg (p less than 0.05), central venous pressure from 6.7 +/- 0.7 to 5.4 +/- 0.9 mm Hg (p less than 0.05), forearm vascular resistance (FVR) from 28 +/- 4.8 to 22.3 +/- 5.1 resistance units (p less than 0.05), and SNA from 259 +/- 47 to 94 +/- 26 units/min (p less than 0.05). These changes persisted during the maintenance infusion. Increased levels of SNA, FVR, and MAP provoked by the cold pressor test were reduced significantly by intravenous procainamide. In eight other subjects, intravenous procainamide HCl (15 mg/kg at 50 mg/min) caused dose-dependent inhibition of SNA that reversed as blood concentrations fell during drug washout. To determine if procainamide causes direct vasodilation, in nine subjects, graded infusions were delivered into the brachial artery at doses that produced no systemic effect. Ipsilateral FVR tended to increase during local intra-arterial infusion of procainamide. These data show that intravenous procainamide causes hypotension, vasodilation, and sympathetic withdrawal. Vasodilation does not result from a direct vasorelaxant effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic angiotensin II infusion decreases renal norepinephrine overflow in conscious dogs

Sympathetic nerve activity and in particular renal sympathetic nerve activity were monitored in six conscious dogs subjected to 6 days of intravenous angiotensin (ANG II) infusion (20 ng/kg/min). This was accomplished by measurement of both arterial and renal venous plasma catecholamine concentration. During the initial 4 hours of ANG II infusion, mean arterial pressure (MAP) increased 35 +/- 8 mm Hg from a control value of 101 +/- 4 mm Hg. Although there were no significant changes in arterial plasma norepinephrine (NE) concentration at this time (control = 148 +/- 40 pg/ml), arterial plasma epinephrine (E) concentration increased threefold (control 42 +/- 15 pg/ml). After 24 hours of ANG II infusion, MAP remained elevated (132 +/- 5 mm Hg), but plasma E concentration returned to control levels. From Days 2 through 6 of ANG II infusion, MAP was elevated approximately 40 mm Hg, but there were no chronic increases in either arterial plasma E or NE concentrations. In contrast to arterial plasma catecholamine concentration, renal vein plasma NE concentration (control = 216 +/- 27 pg/ml) actually decreased during both the acute (122 +/- 12 pg/ml) and chronic (103 +/- 26 pg/ml) phases of ANG II infusion. Moreover, renal NE overflow (renal venous plasma NE concentration-arterial plasma NE concentration X effective renal plasma flow), an index of renal sympathetic nerve activity, was depressed during the chronic phase of ANG II hypertension. These results, therefore, do not support the contention that the sympathetic nervous system mediates the hypertension produced by elevated plasma levels of ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.     

Relation between sympathetic outflow and vascular resistance in the calf during perturbations in central venous pressure. Evidence for cardiopulmonary afferent regulation of calf vascular resistance in humans

Vascular studies in humans have advanced the concept that, during orthostatic stress, cardiopulmonary afferents reflexly regulate vascular resistance in the forearm but exert surprisingly little if any effects on vascular resistance in the calf. In contrast, neurophysiological studies have indicated that unloading of cardiopulmonary afferents during lower body negative pressure evokes comparable increases in sympathetic outflow to the muscles of both the forearm and the calf. The aim of this study, therefore, was to determine if alterations in central venous pressure over the physiological range trigger reflex changes in muscle sympathetic outflow that not only are statistically significant but also are large enough to alter vascular resistance in the calf. To accomplish this aim, we measured calf blood flow with plethysmography and simultaneously performed microelectrode recordings of sympathetic outflow to calf muscles in conscious humans during maneuvers designed to alter the loading conditions of the cardiopulmonary afferents. We found that calf vascular resistance increased by 33 +/- 7% (mean +/- SEM, p less than 0.05) during decreases in central venous pressure produced by nonhypotensive lower body negative pressure (LBNP) and decreased by 26 +/- 5% (p less than 0.05) during increases in central venous pressure produced by nonhypertensive infusion of normal saline. These changes in calf resistance were at least as large as the changes in forearm resistance evoked by these maneuvers and were accompanied by parallel changes in peroneal muscle sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Sympathoinhibitory effects of atrial natriuretic factor in normal humans

In rats, atrial natriuretic factor (ANF) reduces sympathetic nerve activity (SNA) reflexively by sensitizing cardiac mechanoreceptors with inhibitory vagal afferents. We performed three series of experiments in 26 normal young men to document whether ANF inhibits SNA in humans and if so, to determine potential mechanisms for this phenomenon. First, we recorded muscle SNA before and during brief infusions of ANF, vehicle (saline solution), and sodium nitroprusside, titrated to achieve reductions similar to those produced by ANF in diastolic pressure and central venous pressure, and we also assessed the effect of ANF on sympathetic nerve responses to a cold pressor test (CPT). Second, we determined the effect of ANF on Doppler-derived measurements of cardiac output and responses to hypotensive (-40 mm Hg) lower-body negative pressure (LBNP) and its sudden cessation. Third, we applied nonhypotensive (-15 mm Hg) LBNP to selectively unload cardiopulmonary baroreceptors, and we released LBNP to stimulate these inhibitory afferents during sequential infusions of nitroglycerin, vehicle (saline solution), and ANF. Our key findings were that 1) reductions in arterial and central venous pressures during ANF infusion were not accompanied by anticipated reflex increases in muscle SNA; 2) ANF blunted the increase in SNA with CPT; 3) ANF increased stroke volume and cardiac output; and 4) sympathoneural responses to both the application and the sudden cessation of nonhypotensive LBNP were attenuated, not augmented, by ANF. Changes in plasma norepinephrine concentrations reflected these sympathetic nerve responses to ANF. These results do not support the concept that ANF inhibits sympathetic outflow reflexively in humans by increasing discharge from cardiac mechanoreceptors with inhibitory vagal afferents but are consistent with either a central or a ganglionic sympathoinhibitory action of ANF. ANF could facilitate hypotension and natriuresis in humans by attenuating the reflex sympathetic response to baroreceptor deactivation.     

Pressure dependence of atrial natriuretic peptide during norepinephrine infusion in humans

The relative contribution of increased blood pressure (BP) or norepinephrine (NE), or both, to the stimulatory effect of an NE pressor infusion on circulating immunoreactive atrial natriuretic peptide (ANP) was evaluated in 10 healthy young men. They were studied during an infusion of NE, which was applied initially alone and then in combination with sodium nitroprusside. NE infusion rate was increased in four 30-minute intervals to a final dose of 200 ng/kg body weight per minute, leading to 12-fold higher plasma NE levels than were seen during control conditions. This increased mean BP (from a mean basal value of 94 +/- 3 to 119 +/- 4 [SEM] mm Hg; p less than 0.001) and plasma immunoreactive ANP (from 50 +/- 7 to 112 +/- 17 pg/ml; p less than 0.001), whereas heart rate decreased (p less than 0.001). The NE infusion was continued at the highest dose and an additional infusion of sodium nitroprusside was started to titrate mean BP in 30-minute intervals down to control values; a mean sodium nitroprusside dose of 0.95 micrograms/kg/min restored mean BP to 93 +/- 4 mm Hg (p less than 0.001), decreased plasma immunoreactive ANP to basal values (51 +/- 4 pg/ml; p less than 0.001), increased heart rate (p less than 0.001), and left plasma levels of NE largely unchanged. Plasma protein and hematocrit rose about 5 to 6% (p less than 0.001) during the NE infusion and then decreased about 3 to 4% (p less than 0.001 and p less than 0.01) when sodium nitroprusside was added.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nifedipine on baroreflex modulation of vascular resistance in man

Studies in animals have demonstrated that, in addition to their vascular effects, calcium channel blockers have important effects on baroreceptor function. We performed a series of experiments to determine if nifedipine, in doses employed clinically, alters baroreflex control of vascular resistance in normal humans. Forearm vasoconstrictor responses of 14 normal subjects to unloading of baroreceptors with lower body negative pressure (LBNP), to a cold pressor test and during intra-arterial infusions of norepinephrine were studied in the control state and following administration of nifedipine. Nifedipine had no effect on baseline mean arterial pressure or central venous pressure. Heart rate and forearm blood flow (FBF) increased significantly following nifedipine: heart rate = 59.7 +/- 2.4 bpm before and 72.6 +/- 4.4 bpm after nifedipine (mean +/- SE, p less than 0.001, n = 14); FBF = 4.6 +/- 0.4 ml X min-1 X 100 ml-1 before and 6.7 +/- 1.0 ml X min1 X 100 ml-1 after nifedipine (p less than 0.02, n = 14). Forearm vascular resistance (FVR) tended to decrease following nifedipine but the difference was not significant: FVR = 21.1 +/- 1.4 units before and 17.8 +/- 2.3 units after nifedipine (p = 0.07, n = 14). Nifedipine attenuated forearm vasoconstrictor responses to cold pressor stimulus: delta FVR during cold pressor test = +10.3 +/- 2.4 units before and +4.7 +/- 1.4 units after nifedipine (p less than 0.02, n = 14). Likewise, nifedipine depressed vasoconstrictor responses to intra-arterial infusion of norepinephrine: delta FVR during norepinephrine = +15.5 +/- 3.4 units before and +10.2 +/- 2.9 units after nifedipine (p less than 0.05, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of postural stimulation on systemic hemodynamics and sympathetic nervous activity in systemic hypertension

The contributions of the carotid sinus and cardiopulmonary baroreflexes to the interindividual variation in sympathetic nervous system activation caused by postural adaptation were indirectly assessed in 68 mild hypertensive subjects. Supine and upright plasma norepinephrine (NE), blood pressure (cuff) and cardiac output (acetylene rebreathing) were measured. Mean arterial pressure (MAP), carotid sinus pressure, stroke volume and systemic vascular resistance were calculated. Stroke volume was assumed to be proportional to the degree of stretch of cardiac mechanoreceptors, carotid sinus MAP was assumed to be proportional to carotid sinus stretch and plasma NE to reflect sympathetic nervous activity. Plasma NE correlated inversely with stroke volume (r = -0.62, p less than 10(-14] and estimated carotid sinus MAP (r = -0.33, p less than 0.0002) and positively with systemic vascular resistance (r = 0.59, p less than 10(-10]. Holding systemic vascular resistance constant by partial regression, the inverse relation between plasma NE and stroke volume remained (partial r = -0.36, p less than 0.02). Multiple linear regression yielded the equation: plasma NE (pg/ml) = 720 + 4.3 age - 5.1 stroke volume (ml) - 1.0 carotid sinus MAP (mm Hg). Substituting mean supine and upright values for stroke volume and carotid sinus MAP in this equation, it can be roughly estimated that changes in stroke volume account for as much as 60% of the postural variation in plasma NE in hypertensives, whereas only 15% of this variation is caused by changes in carotid sinus pressure. These findings suggest that cardiopulmonary baroreflexes are primary activators of the sympathetic nervous system during postural adaptation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympathomoderating influence of benazepril in essential hypertension.

OBJECTIVE: In essential hypertension, captopril attenuates forearm vasoconstriction reflexly induced by deactivation of cardiopulmonary and arterial baroreceptors, thus exerting a sympathomoderating effect. We investigated whether this is a common effect of angiotensin converting enzyme (ACE) inhibitors. METHODS AND DESIGN: Cardiopulmonary and arterial baroreceptors were deactivated by progressively reducing central venous pressure (CVP) through progressively greater lower body negative pressures in eight untreated mild essential hypertensives on a moderately low-sodium diet (50 mmol/l per day). This deactivation was performed after oral administration of the non-sulphidrylic ACE inhibitor benazepril (10 mg) and placebo according to a double-blind randomized crossover experimental design. RESULTS: After placebo, the reduction in CVP increased forearm vascular resistance (FVR; mean arterial pressure: plethysmographic forearm blood flow ratio). After benazepril, baseline blood pressure (beat-to-beat finger pressure) and FVR were significantly reduced whilst plasma angiotensin II was suppressed and PRA increased (both measured by radioimmunoassay). The FVR increases induced by progressive CVP reduction were less than after placebo administration, and the overall difference was statistically significant. Benazepril did not affect the reflex FVR reduction observed by increasing CVP through leg raising, nor the reflex changes in plasma norepinephrine measured by high-performance liquid chromatography accompanying the changes in FVR. CONCLUSIONS: Benazepril attenuates sympathetic vasoconstriction as does captopril. This effect (which is mainly operative during an increased sympathetic drive and exerted through a reduction of adrenoceptor responsiveness) is thus likely to be a class- rather than a compound-related feature.     

Baroreflex control of muscle sympathetic nerve activity in borderline hypertension

Patients with borderline hypertension have exaggerated vascular responses to orthostatic stress produced by tilt or lower body negative pressure (LBNP). It has been suggested that 1) in the supine position, these patients have augmented activity of cardiopulmonary baroreceptors that exerts an increased restraint on sympathetic vasoconstrictor tone; 2) withdrawal of this augmented inhibitory baroreceptor activity during orthostatic stress elicits augmented reflex sympathetic vasoconstrictor outflow; and 3) augmented cardiopulmonary baroreceptor activity may be secondary to impaired arterial baroreflex mechanisms. To test these hypotheses, we recorded muscle sympathetic nerve activity from the peroneal nerve in seven borderline hypertensive subjects and seven age-, sex-, and weight-matched normotensive subjects during three levels of nonhypotensive LBNP and infusions of phenylephrine and nitroprusside. During LBNP, reductions of central venous pressure were similar in borderline hypertensive and normotensive subjects, and arterial pressure and heart rate values were unchanged. Increases of sympathetic nerve activity, however, were significantly greater in borderline hypertensive than in normotensive subjects at each level of LBNP, indicating an augmented gain of the cardiopulmonary baroreflex. To determine whether this augmentation is related to impairment of arterial baroreflexes, we measured changes of sympathetic nerve activity during increases and decreases of arterial pressure produced with infusions of intravenous phenylephrine and nitroprusside. Central venous pressure was held at control levels by LBNP during phenylephrine and saline infusion during nitroprusside. Changes of sympathetic nerve activity during alterations of arterial pressure were similar in borderline hypertensive and normotensive subjects. These data show that cardiopulmonary baroreflex control of SNA is augmented in borderline hypertensive subjects and that this augmentation does not result from an attenuation of the arterial baroreflex.