Adaptation to 5 weeks of intermittent local vascular pressure increments; mechanisms to be considered in the development of primary hypertension?

The aims were to study effects of iterative exposures to moderate elevations of local intravascular pressure on arterial/arteriolar stiffness and plasma levels of vasoactive substances. Pressures in the vasculature of an arm were increased by 150 mmHg in healthy men (n = 11) before and after a 5-wk regimen, during which the vasculature in one arm was exposed to fifteen 40-min sessions of moderately increased transmural pressure (+65 to +105 mmHg). This vascular pressure training and the pressure-distension determinations were conducted by exposing the subjects' arm versus remaining part of the body to differential ambient pressure. During the pressure-distension determinations, venous samples were simultaneously obtained from pressurized and unpressurized vessels. Pressure training reduced arterial pressure distension by 40 ± 23% and pressure-induced flow by 33 ± 30% (P < 0.01), but only in the pressure-trained arm, suggesting local adaptive mechanisms. The distending pressure-diameter and distending pressure-flow curves, with training-induced increments in pressure thresholds and reductions in response gains, suggest that the increased precapillary stiffness was attributable to increased contractility and structural remodeling of the walls. Acute vascular pressure provocation induced local release of angiotensin-II (ANG II) and endothelin-1 (ET-1) (P < 0.05), suggesting that these vasoconstrictors limited the pressure distension. Pressure training increased basal levels of ET-1 and induced local pressure release of matrix metalloproteinase 7 (P < 0.05), suggesting involvement of these substances in vascular remodeling. The findings are compatible with the notion that local intravascular pressure load acts as a prime mover in the development of primary hypertension.NEW & NOTEWORTHY Adaptive responses to arterial/arteriolar pressure elevation have typically been investigated in cross-sectional studies in hypertensive patients or in longitudinal studies in experimental animals. The present investigation shows that in healthy individuals, fifteen 40-min, carefully controlled, moderate transmural pressure elevations markedly increase in vivo stiffness (i.e. reduce pressure distension) in arteries and arterioles. The response is mediated via local mechanisms, and it appears that endothelin-1, angiotensin-II, and matrix metalloproteinase 7 may have key roles.

Elevations of local intravascular pressures release vasoactive substances in humans.

The wall stiffness of arteries and arterioles adapts to the long-term demands imposed by local intravascular pressure. We investigated whether substances capable of inducing acute and long-term effects on arterial wall stiffness are released locally into the bloodstream in response to an acute marked increase in local intravascular pressure in the blood vessels of the human arm. Experiments were performed on ten subjects positioned in a pressure chamber with one arm extended through a hole in the chamber door and kept at normal atmospheric pressure. Intravascular pressure was increased in the arm, by a stepwise increase in chamber pressure up to +150 mmHg. Diameter and flow were measured in the brachial artery by Doppler ultrasonography. Blood samples were drawn simultaneously from both arms before, during, immediately after and 2 h after the release of the chamber pressure. Plasma levels of endothelin-1 (ET-1), vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and angiotensin II (Ang-II) were measured. Elevation of chamber pressure by 150 mmHg increased local arterial distending pressure to about 220-260 mmHg, resulting in an increase in brachial artery diameter of 9% and flow of 246%. The pressure stimulus increased the plasma levels of ET-1 and Ang-II, but not of VEGF-A or FGF-2 in the test arm. The local release of the vasoconstrictors ET-1 and Ang-II in response to markedly increased distending pressure may reflect one mechanism behind adaptation to acute and long-term changes in intravascular pressure.

Baroreflex impairment during rapid posture changes at rest and exercise after 120 days of bed rest.

Orthostatic intolerance is common after space flight and head-down tilt (HDT) bed rest. We hypothesized that HDT-induced impairments of arterial blood pressure (AP) control would be more marked during exercise and that recovery of baroreflex function after very long-term HDT would be delayed. Six subjects were studied before (BDC) during (day 60, D60; D113) and after (recovery day 0, R0; R3; R15) 120 days of HDT. Supine resting subjects were exposed to repeated 1 min passive tilts to upright at 3-min interval. During 50 W steady-state exercise corresponding tilt had a 2-min duration at 4-min interval. The amplitudes of the tilt-induced transient beat-by-beat deviations in AP and rate (HR) were determined during the gravity transients. At rest these deviations did not change over time, but during exercise the total peak-to-nadir range of deviations in systolic AP (SAP) at up-tilt and down-tilt increased to 168+/-16% (mean+/-SEM) of BDC at D113 with no clear recovery upto and including R15. Counter-regulatory HR responses were not increased proportionally and especially not tachycardic responses to up-tilt, resulting in a reduction of baroreflex sensitivity (deltaRR-interval/deltaSAP) by 55+/-9% of BDC at D113 with no recovery upto and including R15. We conclude that prolonged bed rest cause long-lasting impairments in AP control and baroreflex function in exercising humans.

Effects of gravity on lung diffusing capacity and cardiac output in prone and supine humans.

Both in normal subjects exposed to hypergravity and in patients with acute respiratory distress syndrome, there are increased hydrostatic pressure gradients down the lung. Also, both conditions show an impaired arterial oxygenation, which is less severe in the prone than in the supine posture. The aim of this study was to use hypergravity to further investigate the mechanisms behind the differences in arterial oxygenation between the prone and the supine posture. Ten healthy subjects were studied in a human centrifuge while exposed to 1 and 5 times normal gravity (1 G, 5 G) in the anterioposterior (supine) and posterioanterior (prone) direction. They performed one rebreathing maneuver after approximately 5 min at each G level and posture. Lung diffusing capacity decreased in hypergravity compared with 1 G (ANOVA, P = 0.002); it decreased by 46% in the supine posture compared with 25% in the prone (P = 0.01 for supine vs. prone). At the same time, functional residual capacity decreased by 33 and 23%, respectively (P < 0.001 for supine vs. prone), and cardiac output by 40 and 31% (P = 0.007 for supine vs. prone), despite an increase in heart rate of 16 and 28% (P < 0.001 for supine vs. prone), respectively. The finding of a more impaired diffusing capacity in the supine posture compared with the prone at 5 G supports our previous observations of more severe arterial hypoxemia in the supine posture during hypergravity. A reduced pulmonary-capillary blood flow and a reduced estimated alveolar volume can explain most of the reduction in diffusing capacity when supine.

Impaired pressor response after spaceflight and bed rest: evidence for cardiovascular dysfunction.

We hypothesized that impaired cardiovascular responses to isometric muscle action contribute to the cardiovascular deconditioning that occurs after space flight (SF) and head-down-tilt bed rest (HDT). Six subjects were studied before, during and after 120 days of -6 degrees HDT, and four subjects were studied before, during (two subjects) and after 179-389 days of SF. Subjects performed a sustained handgrip (SHG) at a force equivalent to 30% of maximum contraction force for 2 min, and heart-rate (HR) and pressor (mean arterial pressure, deltaMAP) responses were recorded. At the same relative force, both deltaHR and deltaMAP were significantly reduced during the first days after HDT (-54%, P<0.05 and -43%, P<0.05). In two subjects studied within 24 h after their return from SF, deltaMAP was practically absent (-79%, P<0.05) whereas in four subjects studied 1-4 days after return from SF, deltaMAP was reduced by 35% (P<0.05). deltaHR was not significantly changed. Our finding of attenuated pressor responses to SHG after HDT and SF supports the notion of impairments at both the neurocirculatory control and effector organ levels.

Haemodynamic and baroreflex responses to whole-body tilting in exercising men before and after 6 weeks of bedrest.

We sought to determine whether the cardiovascular deconditioning that occurs in exercising men after prolonged (42 days) bedrest in the head-down tilt (HDT) position is primarily related to mechanical changes in the heart or to an impaired arterial-cardiacchronotropic baroreflex. Seven subjects were studied before (C, control) and repeatedly after HDT with rapid tilting between the upright and supine positions during steady-state 50-W dynamic leg exercise. Ventricular interdependence was assumed to be an index of cardiac size; it was assessed on the basis of the initial dip of arterial pulse pressure (PP) induced by a sudden tilt from the upright to the supine position (down-tilt). Arterialcardiac-chronotropic baroreflex sensitivity (ABS) was assessed as the ratio between tilt-induced heart rate transients and the preceding (and reciprocal) transient in arterial pressure. On the first day of recovery, the initial PP dip was -4 (2) mmHg (where 1 mmHg is 0.13 kPa), less than half of the control value; on subsequent recovery days, the initial PP dip was not significantly different from the control value. When tilting from the upright to the supine position, mean ABS ranged from 1.02 to 1.06 bpm/mmHg during three separate control sessions. Tilts in the opposite direction gave lower ABS values because of the more sluggish HR response and ranged from 0.43 to 0.45 bpm/mmHg in the control situations. ABS did not change after HDT. Our results indicate that impairments of the cardiovascular system after long-term bedrest are of haemodynamic rather than baroreflex origin.

Short-term cardiovascular responses to rapid whole-body tilting during exercise.

Our objective was to characterize the responses of heart rate (HR) and arterial blood pressure (BP) to changes in posture during concomitant dynamic leg exercise. Ten men performed dynamic leg exercise at 50, 100, and 150 W and were rapidly and repeatedly tilted between supine (0 degrees ) and upright (80 degrees ) positions at 2-min intervals. Continuous recordings of BP and HR were made, and changes in central blood volume were estimated from transthoracic impedance. Short-lasting increases in BP were observed immediately upon tilting from the upright to the supine position (down-tilt), averaging +18 mmHg (50 W) to +31 mmHg (150 W), and there were equally short-lasting decreases in BP, ranging from -26 to -38 mmHg upon tilting from supine to upright (up-tilt). These components occurred for all pressure parameters (systolic, mean, diastolic, and pulse pressures). We propose that these transients reflect mainly tilt-induced changes in total peripheral resistance resulting from decreases and increases of the efficiency of the venous muscle pump. After 3-4 s (down-tilt) and 7-11 s (up-tilt) there were large HR transients in a direction opposite to the pressure transients. These HR transients were larger during the down-tilt (-15 to -26 beats. min(-1)) than during the up-tilt (+13 to +17 beats. min(-1)), and increased in amplitude with work intensity during the down-tilt. The tilt-induced HR fluctuations could be modelled as a basically linear function of an arterial baroreflex input from a site half-way between the heart and the carotid sinus, and with varying contributions of fast vagal and slow sympathetic HR responses resulting in attenuated tachycardic responses to hypotensive stimuli during exercise.

Cardiovascular responses to upright and supine exercise in humans after 6 weeks of head-down tilt (-6 degrees).

Seven healthy men performed steady-state dynamic leg exercise at 50 W in supine and upright postures, before (control) and repeatedly after 42 days of strict head-down tilt (HDT) (-6 degrees) bedrest. Steady-state heart rate (fc), mean arterial blood pressure, cardiac output (Qc), and stroke volume (SV) were recorded. The following data changed significantly from control values. The fc was elevated in both postures at least until 12 days, but not at 32 days after bedrest. Immediately after HDT, SV and Qc were decreased by 25 (SEM 3)% and 19 (SEM 3)% in supine, and by 33 (SEM 5)% and 20 (SEM 3)% in upright postures, respectively. Within 2 days there was a partial recovery of SV in the upright but not in the supine posture. The SV and Qc during supine exercise remained significantly decreased for at least a month. Submaximal oxygen uptake did not change after HDT. We concluded that the cardiovascular response to exercise after prolonged bedrest was impaired for so long that it suggested that structural cardiac changes had developed during the HDT period.

Oxygen-conserving effects of apnea in exercising men.

We sought to determine whether apnea-induced cardiovascular responses resulted in a biologically significant temporary O(2) conservation during exercise. Nine healthy men performing steady-state leg exercise carried out repeated apnea (A) and rebreathing (R) maneuvers starting with residual volume +3.5 liters of air. Heart rate (HR), mean arterial pressure (MAP), and arterial O(2) saturation (Sa(O(2)); pulse oximetry) were recorded continuously. Responses (DeltaHR, DeltaMAP) were determined as differences between HR and MAP at baseline before the maneuver and the average of values recorded between 25 and 30 s into each maneuver. The rate of O(2) desaturation (DeltaSa(O(2))/Deltat) was determined during the same time interval. During apnea, DeltaSaO(2)/Deltat had a significant negative correlation to the amplitudes of DeltaHR and DeltaMAP (r(2) = 0.88, P < 0.001); i.e., individuals with the most prominent cardiovascular responses had the slowest DeltaSa(O(2))/Deltat. DeltaHR and DeltaMAP were much larger during A (-44 +/- 8 beats/min, +49 +/- 4 mmHg, respectively) than during R maneuver (+3 +/- 3 beats/min, +30 +/- 5 mmHg, respectively). DeltaSa(O(2))/Deltat during A and R maneuvers was -1.1 +/- 0.1 and -2.2 +/- 0.2% units/s, respectively, and nadir Sa(O(2)) values were 58 +/- 4 and 42 +/- 3% units, respectively. We conclude that bradycardia and hypertension during apnea are associated with a significant temporary O(2) conservation and that respiratory arrest, rather than the associated hypoxia, is essential for these responses.

Arterial baroreflex control during mild-to-moderate nitrous oxide narcosis.

We hypothesized that light-to-moderate inert gas narcosis might play a role in bradycardia in divers by altering sensitivity or response dynamics of arterial baroreflexes. Carotid-cardiac and carotid-mean arterial pressure (MAP) baroreflex response curves were generated by applying multiple levels of neck pressure and suction. Seven healthy volunteers were studied during air breathing (control) and during inhalation of 39% nitrous oxide (N2O). Baseline (pre-stimulus) heart rate (HR) and MAP were not altered by N2O. Range, threshold level, saturation level, and delay of responses did not differ between conditions. For hypertensive stimuli, sensitivity of responses did not differ between air control and N2O inhalation, but for hypotensive stimuli, maximal response gain for HR tended to be reduced with N2O inhalation (P = 0.054). Our results speak against inert gas narcosis as a primary mechanism for hyperbaric bradycardia, but it remains possible that an attenuation of tachycardic responses to hypotensive stimuli plays a role.

Human carotid baroreflex during isometric lower arm contraction and ischemia.

Our aim was to determine the roles of somatomotor activation and muscle ischemia for the tachycardia and hypertension of isometric arm contraction. Carotid-cardiac and carotid-mean arterial pressure (MAP) baroreflex response curves were determined in 10 men during rest, during isometric arm contraction at 30% of maximum, and during postcontraction ischemia. Carotid distending pressure (CDP) was changed by applying pressure and suction in a neck chamber. Pressures ranged from +40 to -80 mmHg and were applied repeatedly for 15 s during the three conditions. Maximum slopes and ranges of the response curves did not differ among conditions. The heart rate (HR) curve was shifted to a 14 +/- 1.8 (mean +/- SE) beats/min higher HR and a 9 +/- 5.7 mmHg higher CDP during contraction and to a 14 +/- 5.9 mmHg higher CDP during postcontraction ischemia with no change of HR compared with rest. The MAP curve was shifted to a 20 +/- 2.8 mmHg higher MAP and to a 18 +/- 5.4 mmHg higher CDP during contraction, and the same shifts were recorded during postcontraction ischemia. We conclude that neither somatomotor activation nor muscle ischemia changes the sensitivity of arterial baroreflexes. The upward shift of the MAP response curve, with no shift of the HR response curve during postexercise ischemia, supports the notion of parallel pathways for MAP and HR regulation in which HR responses are entirely caused by somatomotor activation and the pressor response is mainly caused by muscle ischemia.

Slowing of carotid-cardiac baroreflex with standing and with isometric and dynamic muscle activity.

We hypothesized that the carotid-cardiac baroreflex becomes slowed in conditions with increased sympathetic activity. Changes in heart rate (HR) and blood pressure in response to 10-s trains of 50-mmHg pulses of neck suction (NS) were studied in six male subjects during supine rest, upright rest, isometric arm exercise at 30% of maximum voluntary contraction, and dynamic leg exercise at 100 W in the sitting position. Estimated mean carotid distending pressure increased by approximately 20 mmHg with 50-mmHg, QRS-triggered, pulsatile NS. Repeated NS sequences were performed in each condition. The amplitude of the bradycardic response was highly variable among the subjects and did not differ significantly between conditions, mean values ranging from 0.3 to 0.6 beats.min-1.mmHg-1. In supine rest, the full bradycardic response appeared within < 1 s, i.e., during or immediately after the R-R interval of the first NS pulse. In the other conditions it took significantly longer, 2-3 s or three to seven R-R intervals, for the full HR responses to develop. Our results support the notion that the carotid-cardiac baroreflex in humans becomes slowed under conditions of concurrent sympathetic stimulation.

Influence of apnea on cardiovascular responses to neck suction during exercise.

Short-lasting neck suction (NS) is a common method to assess the carotid-cardiac baroreflex, and NS is usually applied during apnea to avoid breath-synchronous variations of heart rate (HR) and blood pressure. We hypothesized that the apnea might provoke cardiovascular effects that could confound the HR and blood pressure responses to NS. HR and blood pressure responses to 10-s trains of 50-mmHg pulses of NS were studied in six male subjects during supine rest, upright rest, isometric arm exercise at 30% of maximal voluntary contraction, and dynamic leg exercise at 100 W in the sitting position. Repeated NS sequences were performed during apnea preceded by a relaxed expiration to functional residual capacity and during eupnea. Initial HR responses to NS were similar during eupnea and apnea in all conditions. However, during isometric and dynamic exercise, recordings made under eupneic and apneic conditions differed during the second half of the NS period. During apneic isometric arm contraction, the elevation of mean carotid distending pressure (MCDP) (arterial pressure at carotid level minus NS pressure) was maintained at a 25-35% higher level than during eupneic isometric exercise over the last half of the NS period. In dynamic exercise, mean arterial pressure and MCDP started to increase after 3-5 s of apneic NS, whereas they were maintained during eupnea. One to three seconds later, HR started to drop markedly in apneic subjects, reaching values 20 beats/min lower than those in eupneic subjects at the end of the NS. We conclude that cardiovascular effects of apnea may appear after only 8 s of apnea in dynamic exercise and therefore could confound responses to NS.