INTRODUCTION

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ARTERIAL PULSE PRESSURE can modulate plasma antidiuretic hormone concentration in dogs through changes in pulsatile carotid baroreceptor activity (23). Furthermore, a decrease in arterial pulse pressure in humans without changes in mean arterial pressure is accompanied by an increase in heart rate (10) and release of arginine vasopressin (AVP) (17). Because arterial pulse pressure increases simultaneously with an increase in cardiac filling pressures during water immersion in humans (1, 8, 24), this increase could account for the suppression of AVP release by pulsatile stimulation of aortic and carotid baroreceptors (15, 22). Therefore, the generally accepted notion that suppression of AVP release is induced solely by stimulation of low-pressure receptors might not be correct (18).

Arterial pressures have only once been measured invasively during water immersion to the neck in humans (1) and concentrations of neuroendocrine mediators measured in venous plasma. Therefore, no information is available regarding the relationship between arterial pulse pressure determined by accurate invasive measurements and arterial plasma concentration of AVP during graded water immersion in humans.

The hypothesis was tested that an increase in arterial pulse pressure is the determinant of inhibition of AVP release. Previous results from our laboratory (8) have shown that water immersion to the xiphoid process induces a similar increase in arterial pulse pressure as water immersion to the neck, whereas stimulation of low-pressure receptors by cardiac distension is gradually augmented. Therefore, we anticipated that if the hypothesis is correct, further cardiac distension during water immersion to the neck compared with during immersion to the xiphoid process would not cause further suppression of AVP release.

	METHODS

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Eight male subjects [mean age 23.8 yr (range 22-26 yr), height 181 ± 1 cm (means ± SE), weight 76.3 ± 3 kg] participated in the experiment. Ten subjects originally entered the study, but two subjects developed symptoms of vasovagally mediated presyncope during the experiment, and the data of these subjects are therefore not presented. No other complications occurred. All had a negative history of cardiovascular and kidney diseases and were healthy as indicated by medical history, physical examination, arterial blood pressure (<140/90 mmHg) and unipolar electrocardiogram (ECG) recording. Informed consent was obtained and the experimental protocol approved by the Ethics Committee of Copenhagen (KF 01-048/98) and was in compliance with the principles of the Declaration of Helsinki.

The subject was instructed to abstain from eating and drinking from 2100 the day before the experiment and until its termination. The subject arrived at the laboratory at 2200 the evening before the experiment started, slept at the laboratory, and was awakened at 0730. After emptying the bladder, he was placed in the supine position.

During local anesthesia (Lidocaine 20 mg/ml, Sammenslutningen of Apotekere i Danmark, Copenhagen, Denmark) and ECG surveillance, the arterial catheter was introduced into the brachial artery of the nondominant arm, and the subject was then seated upright for at least 30 min. The subject then underwent the following: 1) a 15-min seated control period followed by 2) 15 min of either seated control or water immersion to the xiphoid process or the neck and 3) 15 min of recovery. The sequence of immersion to the xiphoid process, immersion to the neck, and control, respectively, was performed in a randomized balanced order. Water temperature was kept at 34.6 ± 0.05 to 34.8 ± 0.05°C (means ± SE). The variation between different experimental days of air temperature was 26.7 ± 0.1 to 27.9 ± 0.2°C and of relative humidity 43 ± 0.3 to 65 ± 0.2%.

Arterial pressures were measured by an indwelling arterial cannula (Viggo venflon, 18 gauge; BOC Ohmeda, Helsingborg, Sweden) in a brachial artery connected to a pressure transducer (BOC Ohmeda DT-XX, with resonance overshoot eliminator, BOC Ohmeda) through a fluid-filled tube system with the reference point set at the level of the sternal border of the 4th intercostal space. The transducer was connected to an amplifier (S&W PS 021), and the pressure signal was continuously sampled on a computer and stored for later analysis. The arterial pressure signal was analyzed by beat-to-beat determinations of systolic, diastolic, and mean arterial pressures and subsequently averaged over 15-min periods. The pressure recording system (cannula, tubing, and transducer) has previously been tested and demonstrated to accurately transmit frequencies up to 11 Hz (17).

Heart rate was determined from the arterial pressure curve from the R-R interval (beat to beat) and averaged over 15-min periods.

Echocardiographic recordings (model SSD 500; Aloka, Tokyo, Japan) of left atrial diameter were obtained using the parasternal long-axis view in M-mode according to the criteria of Feigenbaum (7). Left atrial diameter was determined from the average of three recordings that were subsequently blinded and analyzed by the same investigator.

Cardiac output was determined by measurements of pulmonary blood flow utilizing a noninvasive inert gas rebreathing technique as previously described in detail (4). Briefly, a closed system containing a rebreathing gas mixture of 1% SF₆, 5% N₂O, and 50% O₂ in N₂ in a 4-liter antistatic rubber bag connected to an infrared photoacoustic gas analyzer (AMIS 2001; Innovision, Odense, Denmark) was used. Rebreathing was performed over 34 s with a gas volume of 30% of the calculated vital capacity (2), a breathing rate of 14/min, and gas continuously sampled for analysis. Pulmonary blood flow was determined from the uptake rate into the blood of N₂O (determined from the gas concentration tracings corrected for system volume changes calculated from the SF₆ blood insoluble gas concentration tracings). From these measurements, stroke volume was calculated by dividing cardiac output with heart rate during rebreathing.

Blood samples were drawn from the brachial artery and immediately transferred to chilled tubes and centrifuged at 3,700 rpm at 4°C for 10 min. The plasma was then frozen and stored at 25°C for later determinations of plasma concentrations of AVP, norepinephrine, and epinephrine. After each sampling, the amount of blood was substituted with the same amount of isotonic saline. Plasma AVP concentrations were measured by means of a radioimmunoassay with average recovery of 87 ± 3% (11), whereas norepinephrine and epinephrine were measured by a radioenzymatic assay as previously described (12). The AVP concentration values were not corrected for incomplete recovery.

Plasma osmolality was measured in triplicate on thawed samples by freezing point depression (osmometer model 3MO; Advanced Instruments, Needham Heights, MA).

Analysis of variance (ANOVA) for repeated measurements with time and subject as factors with a post hoc multiple- range test (Newman-Keuls) was applied to detect changes within each of the three series of the experiment and differences across the experimental series (between values of the two immersion procedures and of the seated control). Logarithmic transformation of AVP values was performed before the statistical analysis. Data are presented as means ± SE, and the level of statistical significance was chosen at 0.05.

	RESULTS

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Left atrial diameter (Fig. 1) exhibited a graded increase in response to the two levels of water immersion from 28 ± 1 to 34 ± 1 mm (xiphoid process, P < 0.05) and from 27 ± 1 to 36 ± 1 mm (neck, P < 0.05 vs. xiphoid immersion), with a prompt return to baseline values during recovery. Left atrial diameter did not change during the seated control (28 ± 1 mm). Arterial pulse pressure (Fig. 1) promptly increased (P < 0.05) to the same extent in response to both immersion procedures from 44 ± 1 to 51 ± 2 mmHg (xiphoid process) and 42 ± 1 to 52 ± 2 mmHg (neck) and varied insignificantly between 43 ± 2 to 45 ± 2 mmHg during seated control. Arterial pulse pressure remained elevated (P < 0.05) during recovery from immersion to the neck. Mean arterial pressure (Table 1) was unchanged during seated control and immersion to the xiphoid process but increased during immersion to the neck from 77 ± 2 to 84 ± 2 mmHg (P < 0.05). During immersion to the xiphoid process and neck, heart rate (Table 1) decreased (P < 0.05) to the same extent from 69 ± 2 to 60 ± 2 and 71 ± 2 to 63 ± 2 beats/min, respectively. Heart rate varied insignificantly between 68 ± 1 and 69 ± 2 beats/min during the seated control.

View larger version (14K): [in this window] [in a new window]   Fig. 1.   Arterial pulse pressure (PP), arterial plasma concentration of arginine vasopressin (AVP), and left atrial diameter (LAD) before (B), during (WI-C), and following (R) 15 min of thermoneutral water immersion to the xiphoid process, to the neck, or seated control. Values are means ± SE of n = 8. *Statistical significant difference (P < 0.05) from B. Statistical significant difference (P < 0.05) between immersion levels at same points in time.

Cardiac output (Table 1) increased in response to water immersion to the xiphoid process from 4.6 ± 0.2 to 6.1 ± 0.2 l/min (P < 0.05) and further during immersion to the neck from 4.4 ± 0.2 to 7.0 ± 0.3 l/min (P < 0.05 vs. xiphoid process). Cardiac output did not change during the seated control (4.2 ± 0.2 to 4.6 ± 0.2 l/min). Stroke volume (Table 1) exhibited a similar pattern of change as cardiac output and increased from 63 ± 2 to 95 ± 5 ml/beat during immersion to the xiphoid process (P < 0.05) and further (P < 0.05) from 62 ± 3 to 104 ± 4 ml/beat during immersion to the neck. During recovery from immersion to the neck, stroke volume remained elevated compared with baseline. Stroke volume exhibited a minor decrease at the end of the seated control from 65 ± 3 to 60 ± 3 ml/beat (P < 0.05).

Plasma concentrations of AVP (Fig. 1) did not change during the seated control (2.5 ± 0.9 to 2.6 ± 0.8 pg/ml). During immersion to the xiphoid process, plasma concentrations of AVP decreased from 2.5 ± 0.7 to 1.8 ± 0.5 pg/ml (P < 0.05) with a more pronounced decrease during immersion to the neck (P < 0.05) from 2.4 ± 0.8 to 1.4 ± 0.5 pg/ml. During immersion to the xiphoid process and the neck, plasma norepinephrine concentrations (Table 1) were suppressed (P < 0.05) to similar levels from the respective baseline values. Changes in plasma epinephrine concentrations (Table 1) could not be detected during immersion to the xiphoid process but exhibited a decrease during immersion to the neck (P < 0.05). A statistical significant difference of the epinephrine levels could not be detected, comparing immersion to the xiphoid process with immersion to the neck.

Plasma osmolality varied insignificantly between 289 ± 1 and 291 ± 1 mosmol/kgH₂O during all of the interventions.

	DISCUSSION

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This is the first time that arterial pressures have been obtained by direct invasive measurements in humans during graded water immersion simultaneously with measurements of arterial plasma concentrations of neuroendocrine mediators. Graded central volume expansion by water immersion to the xiphoid process and neck, respectively, induced a graded increase in left atrial distension, whereas arterial pulse pressure increased to the same extent. Simultaneously, arterial plasma concentration of AVP exhibited a graded suppression. Therefore, the hypothesis that arterial pulse pressure alone determines the suppression of AVP release during water immersion was not confirmed. The results indicate that either increased cardiopulmonary low-pressure receptor stimulation alone or additional arterial baroreceptor stimulation through increased mean arterial pressure accounted for the further suppression of AVP release during immersion to the neck compared with immersion to the xiphoid process.

It has long been debated whether cardiopulmonary low- or arterial high pressure reflexes constitute the primary mechanism of the nonosmotic changes in AVP release during orthostatic and antiorthostatic maneuvers in humans (15, 18, 26). During water immersion to the neck, central venous pressure and arterial pulse pressure increase in parallel, and AVP release is suppressed (5, 6, 9, 14, 16). We have previously observed that changes in arterial pulse pressure might govern the release of AVP in humans during lower body negative pressure (17). Therefore, it is conceivable that an increase in arterial pulse pressure is a determinant of the suppression of AVP release during water immersion to the xiphoid process. In contrast, the additional suppression of AVP release during water immersion to the neck cannot be explained by changes in arterial pulse pressure, which was similar during immersion to the xiphoid process. Because immersion to the neck induced a more pronounced distension of the left atrium compared with immersion to the xiphoid process, increased loading of cardiopulmonary baroreceptors might have been responsible for the further inhibition of AVP release.

The speculation that cardiac distension modulates AVP release during immersion to the xiphoid process or the neck may appear in contrast with results of a previous investigation (17), where reductions in cardiac filling pressures in supine humans did not elicit an increase in plasma AVP except when a decrease in arterial pulse pressure also occurred. This ostensible discrepancy may be explained by the different postures of the subjects. In the present investigation we investigated subjects in the upright seated position, whereas in the study by Norsk et al. (17), the subjects were supine. The supine position per se suppresses the release of AVP (21), which may attenuate the responsiveness of AVP release compared with the seated position. Therefore, the seated position in this study might account for an effect of cardiac distension on AVP release.

During immersion to the neck, mean arterial pressure increased by 7 mmHg, whereas it was unchanged during immersion to the xiphoid process. This increase might have induced the additional suppression of AVP secretion through stimulation of arterial baroreceptors, comparing immersion to the xiphoid process with immersion to the neck. In a previous investigation (8), however, we observed that water immersion to the neck increased intrathoracic pressure by ~6 mmHg. Therefore, it is possible that the increase in mean arterial pressure during immersion to the neck did not reflect an increase in transmural aortic pressure. If transmural aortic pressure in fact did not increase, then static aortic baroreceptor stimulation could not have contributed to suppression of plasma AVP during immersion.

It is a possibility that the 7-mmHg increase in mean arterial pressure caused an increase in carotid baroreceptor loading and thus participated in suppression of AVP release. Results of a recent investigation from our laboratory (21), however, demonstrate that a selective increase in transmural carotid sinus pressure by 10 mmHg does not suppress venous plasma AVP. Therefore, it is doubtful whether the increase in mean arterial pressure by only 7 mmHg accounted for the additional suppression of AVP release, comparing immersion to the neck with immersion to the xiphoid process.

Stroke volume increased in a graded manner concomitant with the increase in cardiac distension. It is conceivable that the difference in stroke volume, comparing the two immersion procedures, induced different levels of arterial filling. Increased arterial filling may suppress AVP release through arterial baroreceptor stimulation. Therefore, the graded increase in stroke volume could theoretically have contributed to the graded suppression of AVP release, but since arterial pulse pressure was unchanged, this notion seems unlikely unless changes in brachial artery pressure do not accurately reflect those of the aorta.

As previously observed (14), norepinephrine concentration in arterial plasma was suppressed during immersion to the xiphoid process and the neck from their respective baseline levels, but a statistical significant difference could not be detected in the absolute norepinephrine levels, comparing the two immersion procedures. This observation suggests that the major part of the inhibition of sympathetic nervous activity occur during immersion to the xiphoid process. It is possible, however, that immersion to the neck had a small additional sympathoinhibitory effect, which could not be detected. During immersion to the xiphoid process, plasma epinephrine levels were not significantly suppressed compared with baseline, whereas suppression occurred in response to immersion to the neck. Because a statistical significant difference between epinephrine levels during the two immersion procedures could not be detected, it is not clear from the results of this study whether epinephrine release was more inhibited during immersion to the neck than during immersion to the xiphoid process.

Limitations. We performed accurate measurements of brachial artery pressures to quantitate arterial baroreceptor stimulation during immersion. Amplification of 15-20% of the pressure pulse from the aorta to the brachial artery has been demonstrated (19), whereas mean arterial pressure is not changed (13). Therefore, it is possible that the absolute brachial artery pulse pressure overestimates that of the central aorta (this might also be the case in the carotid sinus). Amplification of the pulse wave is mainly determined by cardiac ventricular ejection time; i.e., heart rate (19). Heart rate was very similar before, during, and after the immersion procedures, comparing water immersion to the xiphoid process with immersion to the neck. It is therefore unlikely that significant differences in pulse wave amplification confounded the measurements.

Perspectives

Many patients with congestive heart failure exhibit elevated plasma concentrations of AVP despite reduced plasma sodium concentrations and low plasma osmolalities (25). A further understanding of the interaction between low- and high-pressure baroreceptors might be important for the understanding of the abnormal nonosmotic AVP release (3) associated with this syndrome. In this investigation, cardiopulmonary baroreceptor stimulation selectively inhibited AVP release, when arterial pulse pressure was increased. Because cardiopulmonary baroreflexes are blunted in congestive heart failure, this raises the question whether of the combined stimulation of cardiopulmonary and arterial baroreceptors during central volume expansion can suppress the release of AVP in heart failure patients.