Chinese Journal of Physiology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 63  |  Issue : 2  |  Page : 53--59

Portal vein innervation underlying the pressor effect of water ingestion with and without cold stress


Shi-Hung Tsai1, Jou-Yu Lin2, Yu-Chieh Lin3, Yia-Ping Liu4, Che-Se Tung3,  
1 Department of Emergency Medicine, National Defense Medical Center, Tri-service General Hospital, Taipei, Taiwan
2 Department of Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan
3 Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan
4 Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan

Correspondence Address:
Dr. Che-Se Tung
Division of Medical Research and Education, Cheng Hsin General Hospital, No. 45, Cheng Hsin Street, Beitou, Taipei 11280
Taiwan

Abstract

Water-induced pressor response appears mediated through the activation of transient receptor potential channel TRPV4 on hepatic portal circulation in animals. We sought to elucidate the mechanism of portal vein signaling in this response. Forty-five rats were divided into four groups: control rats without water ingestion (WI), control rats with WI, portal vein denervation rats with WI (PVDWI), and TRPV4 antagonist-treated rats with WI (anti-TRPV4WI). Cardiovascular responses were monitored throughout the experiments. Data analysis was performed using descriptive methods and spectral and cross-spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV). Key results showed that at baseline (PreCS) before cold stress trial (CS), WI elicited robust pressor and tachycardia responses accompanied by spectral power changes, in particular, increases of low-frequency BPV (LFBPV) and very-LFBPV (VLFBPV), but decrease of very-low-frequency HRV. PVDWI, likewise, elicited pressor and tachycardia responses accompanied by increases of high-frequency BPV, high-frequency HRV, LFBPV, low-frequency HRV, and VLFBPV. When compared with WI at PreCS, WI at CS elicited pressor and tachycardia responses accompanied by increases of high-frequency BPV, LFBPV, and VLFBPV, whereas in WI, the CS-evoked pressor response and the accompanied LFBPV and VLFBPV increases were all tended augmented by PVDWI. When compared with WI and PVDWI at both PreCS and CS, however, anti-TRPV4WI attenuated their pressor responses and attenuated their increased LFBPV, VLFBPV, and very-low-frequency HRV. The results indicate that the portal vein innervation is critical for a buffering mechanism in splanchnic sympathetic activation and water-induced pressor response.



How to cite this article:
Tsai SH, Lin JY, Lin YC, Liu YP, Tung CS. Portal vein innervation underlying the pressor effect of water ingestion with and without cold stress.Chin J Physiol 2020;63:53-59


How to cite this URL:
Tsai SH, Lin JY, Lin YC, Liu YP, Tung CS. Portal vein innervation underlying the pressor effect of water ingestion with and without cold stress. Chin J Physiol [serial online] 2020 [cited 2020 Jun 1 ];63:53-59
Available from: http://www.cjphysiology.org/text.asp?2020/63/2/53/283351


Full Text

 Introduction



An intriguing phenomenon of water ingestion (WI), i.e., water-induced pressor response or osmopressor response, has been demonstrated to be associated with the efferent sympathetic activation and thermogenesis.[1],[2],[3],[4],[5] However, this pressor response is overlooked in the beginning because of the buffering baroreflex mechanism in cardiovascular homeostasis.

The underlying mechanisms of the hepatic portal osmosensory system contribute to the water-induced pressor response, which is well investigated and reviewed previously. Besides, it is well known that the hepatic portal sensory (afferent) system containing an osmotically activated ion channel, TRPV4, plays the role of detection of mechanosensation and blood osmolality shift.[6],[7],[8],[9],[10] While under the osmolality reduction, the activated TRPV4 signaling in the portal vein region has demonstrated to be prominent in the pressor effect of water infusion.[3]

On the other hand, in a healthy individual for many years, the cold pressor test was used in the evaluation of the sympathetic neural influence on peripheral circulation.[11] Similar to the acute WI, the rapid immersion of the extremities into 4°C water will evoke hemodynamic perturbations (cold stress-elicited hemodynamic perturbations [CEHP]), namely cold-induced pressor (CIP) and tachycardia (CIT), which has revealed the central mechanisms of cardiovascular regulation. Previously, we performed serial studies to investigate the causes of CEHP and found that the sympathetic activation and pressor responses were associated with marked increases in powers for low-frequency blood pressure variability (LFBPV) and very-LFBPV (VLFBPV). We have rationalized that the VLFBPV power might reflect the myogenic vascular responsiveness induced by shear stress to the stressful cooling challenge.[12],[13],[14] However, the mechanisms underlying the afferent structure signaling for the instigation of water-induced pressor response or CEHP are still poorly understood.

Furthermore, based on the current understanding of the pressor effect of acute WI, it is unclear whether the underlying mechanisms in the effect of acute WI on the efferent sympathetic activation is related to the efferent sympathetic activation of the early pressor effect of CEHP. A better understanding of how different afferent signals interacted to produce the water-induced pressor response under CEHP would contribute to our understanding of fundamental mechanisms in cardiovascular regulation and perhaps suggest options for novel treatments. The purpose of the present study was to determine whether the innervation of the portal vein or signaling by TRPV4 channels is crucial for autonomic cardiovascular regulations in water-induced pressor response before and under CEHP.

 Materials and Methods



Animals

Adult male Sprague-Dawley rats weighing between 300 and 350 g were received from the Laboratory Animal Center of the National Defense Medical Center (NDMC, Taiwan, ROC) 1 week before the experiments. The studies were performed according to a protocol approved by the Institutional Animal Care and Use Committee of NDMC (IACUC-17-097). All efforts were made to reduce the number of experimental animals and their suffering in experiments. Rats from the same experimental groups were housed together in an ambient thermoneutral environment (23°C) and humidity-controlled holding facility with a 12-h light/dark cycle (lights-on from 07:00 to 19:00) maintained by manual light control switches, and they received food and water ad libitum.

Experimental design

Rats were randomly distributed into the following four groups: the control group rats (n = 12) received the gavage needle insertion but no WI on the testing day; the WI group rats (n = 12) received a volume of 5 ml/kg of body weight plain water over 1 min period through the similar inserted gavage needle on the testing day; the portal vein denervation rats with WI (PVDWI) group rats (n = 12) of WI received portal vein denervation (PVD) at 7 days before the testing day; and the anti-TRPV4WI group rats (n = 9) received a dose of TRPV4 antagonist 2 h before given WI on the testing day. To sum up, the gavage needle has very gently inserted and slid down the esophagus to the proper distance of each rat of all experimental groups 20 min before the cold stress trial (CS) at ambient temperature (23°C) on the testing day. PVD was performed in the PVDWI rats to assess the need for intact portal vein innervation for the mechanisms in water-induced pressor response. Phenol (90% wt/vol) was applied to a 1.5-cm region of the portal vein proximal to the liver,[15] and portal vein extravascular tissue necrosis, denoted by vessel discoloration, was observed in all phenol-treated animals. Finally, a chemical selective TRPV4 antagonist (HC-067047) was injected intraperitoneally (20 mg/kg) of the anti-TRPV4WI group rats to examine the TRPV4 function in water-induced pressor response.

Cooling procedure

All rats were brought to an adjacent room and given the same acute cooling procedure after they had adjusted to the experimental environment. A maximum of five rats were tested at the same time every day. All experiments were performed between 08:30 and 11:30.

Following a complete stabilization of systolic blood pressure (SBP) and heart rate (HR) at room temperature, every rat was quickly placed in a Plexiglas test cage (35 cm × 18 cm × 25 cm) to immerse its glabrous palms and soles for 10 min in the 4°C water (CS). After this cooling procedure, the rat was removed from the cage, dried with a cloth, and placed in a similar cage for 20 min to facilitate recovery. Beat-to-beat SBP signals were recorded continuously via telemetric monitoring equipment (TL11M2-M2-C50-PXT, Data Sciences International, St. Paul, Minnesota, USA) including 10 min for baseline before the CS trial (PreCS), 10 min during the CS trial, and 40–50 min after the CS trial (PostCS). Afterward, successive signals from a 5-min period (3–8 min) at each trial were submitted to spectral analyses because the mean and variance of VLFBPV signals were stable and the oscillations of SBP during this period were observed to be steady.

Surgical intervention

The telemetry transmitter was implanted intra-abdominally into each rat under anesthesia (sodium pentobarbital, 50 mg/kg) 14 days before the testing day. A laparotomy was performed under aseptic conditions to insert a catheter containing the transmitter into the abdominal aorta, distal to the kidneys, and fixed. One week after this implantation, the PVDWI group rats have received another surgery for PVD under similar anesthesia.

Spectrum signal acquisition and processing

The SBP signal-processing and spectral and cross-spectral analyses used the methods reported in our previous study.[13],[14] Briefly, signals of the SBP and HR oscillations were computed independently to obtain the total power (0.00–3.0 Hz) and spectral power of the three major frequency regions, namely very low frequency (VLF; 0.02-0.2 Hz), low frequency (LF; 0.20–0.60 Hz), and high frequency (HF; 0.60–3.0 Hz). The ratio of low-frequency power to high-frequency power (LF/HF ratio) of HR variability (HRV), which is commonly used as a measure of sympathovagal balance, was also calculated. The modulus of the spectral density for each frequency had units of BPV (mm Hg2) and HRV (ms2). On the other hand, the squared coherence function was computed as the square of the cross-spectrum normalized by the product of the spectra of the BPV and HRV signals. When the peak coherence value (K2HR/SBP) exceeded 0.58 within a frequency range, the two signals were considered to covary significantly at that frequency.

Statistics

Statistical analyses were performed using SPSS 18.0 for Windows (Chicago, Illinois, USA). Data were tested for normality using Kolmogorov and Smirnov distributions. Comparisons between groups were performed by the within-group design to fit the multifactor analysis of variance (ANOVA) with a within-subject factor, TRIAL (3 conditions along the experimental procedures, i.e., PreCS, CS, and PostCS, according to a repeated-measurement design), and a between-subject factor, GROUP (4 treatments: control, WI, PVDWI, and anti-TRPV4WI). If necessary, post hoc comparisons were carried out with Tukey or Student's t-tests, where appropriate. Data were presented as the mean value per group ± standard error of the mean. Results were considered statistically significant at P < 0.05.

 Results



Averaged data are shown in [Figure 1], [Figure 2], and [Table 1] and [Supplementary Table 1].{Figure 1}{Figure 2}{Table 1}[INLINE:1]

Response of systolic blood pressure and heart rate

For SBP and HR [[Figure 1]a and [Figure 1]b, respectively] throughout the experiment course, ANOVA revealed a significant main effect of TRIAL (SBP and HR: F (3, 41) = 26.97~33.62, all P < 0.05) and GROUP (SBP and HR: F (2, 41) = 26.97~33.62, all P < 0.05) and significant interaction TRIAL X GROUP (SBP and HR: F (6, 83) = 17.23~21.12, all P < 0.05).

When compared with the healthy rats not experienced WI (Control) at both PreCS and CS conditions, the WI-experienced healthy rats (WI) statistically significantly showed increased SBP (all P < 0.05), whereas the WI-experienced PVD rats (PVDWI) showed a tendency toward augmented the increased SBP effects of the WI rats [Figure 1]a. Furthermore, when compared CS with the respective PreCS and PostCS conditions, CS of the WI group rats as to CS of the control group rats similarly showed somewhat the CIP response (PreCS and PostCS versus CS: F (2, 10) = 35.72, P < 0.05), whereas CS of the PVDWI group rats showed a tendency toward augmented the CIP response of the WI group rats (PreCS and PostCS versus CS: F (2, 10) = 18.69, P < 0.05). However, when compared with the PVDWI group rats, the anti-TRPV4WI group rats showed a significantly lower SBP level at both PreCS and CS conditions (all P < 0.05).

On the other hand, at PreCS condition, when the WI, PVDWI, and anti-TRPV4WI group rats compared with the control group rats, all have respectively caused a significant increase in HR (all P < 0.01); however, at PreCS condition, both PVDWI and anti-TRPV4WI group rats showed similarly a tendency toward augmented the HR effects of the WI rats [Figure 1]b. Furthermore, when compared CS with the respective PreCS and PostCS conditions, CS of the WI group rats as to CS of the Control group rats similarly showed somewhat the CIT response (PreCS and PostCS versus CS: F (2, 10) = 19.33, P < 0.05). However, when compared with the respective HR magnitude at PreCS and CS conditions, there was a greater HR level of the anti-TRPV4WI group rats compared with the PVDWI group rats.

Response of frequency powers and coherence functions

For frequency powers [[Figure 2]a, [Figure 2]b, [Figure 2]c: VLF, LF, and HF, respectively] throughout the experiment course, ANOVA revealed a significant main effect of TRIAL (VLFBPV; VLFHRV; LFBPV; LFHRV; HFBPV; TPBPV and TPHRV: F (3, 41) = 11.36–44.12, all P < 0.05) and GROUP (VLFBPV; VLFHRV; LFBPV; LFHRV; and HFBPV: F (2, 41) = 18.69~63.60, all P < 0.05) and significant interaction TRIAL X GROUP (VLFBPV, VLFHRV, LFBPV, LFHRV, and HFBPV: F (2, 41) = 17.23~47.66, all P < 0.05).

When compared with control group rats at PreCS condition, the WI group rats increased LFBPV and VLFBPV (all P < 0.01) but decreased VLFHRV (P < 0.05), whereas the PVDWI group rats increased the following frequency powers of the Control group rats, HFBPV (P < 0.01), HFHRV (P < 0.05), LFBPV (P < 0.01), LFHRV (P < 0.05), VLFBPV (P < 0.05) and a tendency toward increased VLFHRV. On the other hand, when compared with the PVDWI group rats at the PreCS condition, except for LFHRV which is higher, the anti-TRPV4WI group rats generally showed a lesser frequency power of HFBPV, HFHRV, LFBPV, VLFBPV, and VLFHRV.

Furthermore, when compared CS with the respective PreCS and PostCS conditions, CS of the WI group rats as to CS of the Control group rats similarly showed increased the frequency powers, HFBPV (PreCS and PostCS versus CS, all P < 0.05), LFBPV (PreCS and PostCS versus CS, all P < 0.05), and VLFBPV (PreCS and PostCS versus CS, all P < 0.05), but decreased LFHRV (PreCS and PostCS versus CS, all P < 0.05) and tended toward decreased HFHRV and VLFHRV. When compared with the respective PreCS or PostCS conditions of both Control and WI group rats, the PVDWI group rats at CS condition showed a tendency toward augmented LHBPV and VLFBPV, increased but inverted LHHRV and VLFHRV, except for HFBPV although decreased but still showed enhancing response in CS. On the other hand, when compared with the PVDWI group rats at the CS condition, except for HFHRV and LFHRV which is no difference, the anti-TRPV4WI group rats generally showed a lesser frequency power of HFBPV, LFBPV, VLFBPV, and VLFHRV.

[Table 1] shows the strength of a relationship between BPV and HRV signals as assessed by the peak coherence value (K2HR/SBP) at a specific frequency region. When compared with the Control group rats throughout the experiment course, the WI group rats generally showed a small coherence value (<0.58) at all frequency regions. When compared with the Control group rats throughout the experiment course, both PVDWI and anti-TRPV4WI group rats also showed small coherence values at all frequency regions, whereas these values of both PVDWI and anti-TRPV4WI group rats were larger when compared with the WI rats particularly at the LF and HF regions.

 Discussion



Our present study attempts to assess the need for intact portal vein afferent innervation for autonomic cardiovascular regulation in water-induced pressor response before and under CEHP. We find that (1) a robust pressor and tachycardia accompanied by increases of high-frequency BPV, LFBPV, and VLFBPV in the WI group rats at both baseline (PreCS) and stressful cooling (CS) conditions; (2) the PVDWI group rats present a tendency toward augmented the CIP and CIT responses accompanied by augmented LFBPV, VLFBPV, low-frequency HRV, and very-low-frequency HRV of the WI group rats particularly at the CS condition; and (3) when compared with PVDWI group rats at both PreCS and CS conditions, the anti-TRPV4WI group rats present a significantly lower SBP and a tendency toward decrease most frequency powers, high-frequency BPV, high-frequency HRV, LFBPV, VLFBPV, and very-low-frequency HRV (except for increased low-frequency HRV at the PreCS condition). Overall, these results support the concept that activation of the sympathetic nervous system plays a crucial role in generating the water-induced pressor response.[2],[4]

Responses of plain water ingestion in baseline condition

Studies in humans provide indirect evidence that increased sympathetic output activity underlie the pressor effect of water. In the present study, we observed the WI group rats at PreCS, sympathetic activation concurrent with myogenic vascular oscillations due to the increases of LFBPV and VLFBPV, evidenced again to elicit the pressor response of WI the efferent sympathetic nervous system is required. However, in the aspect of the HR changes, it is noteworthy that HR changes obtained from our study, the increase of HR during WI in conscious rats, noted an inconsistency with Rai's claim.[4] We demonstrated WI caused a combination increase in HR and SBP could be interpreted as a result of the gastric distension. The results are concordant well with the past report on gastric distension and the emerging importance of vagal and splanchnic systems in cardiovascular responses due to acute WI.[16]

Although the water-induced pressor response has reported dependent on hypo-osmolarity action in the proximal gastrointestinal tract and or the portal circulation, the effects triggering sympathetic activation could be due to the mechanosensitivity of osmolarity shift and or gastric distension of volume expansion too.[7],[8],[10],[16] To date, the efferent sympathoexcitatory effects of water-induced pressor response have well-identified; however, the afferent signal for this response is still poorly understood.

The neural pathways that compose the loop of this pressor response to water might consist brain stem centers, where receive splanchnic afferent input via the vagus nerve or could be limited to spinal afferent nerves from the hepatic/portal region,[16],[17] which can directly influence sympathetic output at the level of the spinal cord via TRPV4 channel. TRPV4 is indeed a specific transducer located on the upper gastrointestinal tract, portal venous system, and or spinal afferents and thoracolumbar dorsal root ganglion.[6],[7]

Therefore, we further investigated the effect of PVD and inhibition of TRPV4 channel on the pressor response of WI in this study. At first, we thought this pressor response is likely because of the expansion of blood volume in the portal circulation by WI, while the TRPV4 channel in the hepatic/portal venous afferents senses the water loading evokes sympathetic activation then might increase SBP. However, the acquired data failed to account for the augmented hemodynamic perturbations observed in the PVDWI group rats when compared with the WI group rats, in spite of the reduced responses observed in the anti-TRPV4WI group rats.

One possible explanation for such results is discussed in follow. Researches describing the water-induced pressor reflex circuitry are ongoing, whereas the crucial role in mechanisms of this circuitry through the hepatic and or portal tract have been identified. WI likely results in osmolality shifts predominantly in the portal tract and the liver.[3],[18] The innervation of splanchnic nerves is known to be necessary for both the afferent and efferent arms of such pressor response. Literature reports indicate the importance of splanchnic nerves for the maintenance of water-induced pressor response,[19] probably through the arterial and venous constriction in the splanchnic circulation to aggregate SBP, total peripheral resistance, and cardiac output owing to an increased splanchnic sympathetic activity.

In our experimental setting, the afferent portal nerves seemed to exert an inhibitory influence on sympathetic activation, because after PVD, we observed WI augments hemodynamic perturbations in the denervation group as well as in the Control group rats [Figure 1] and [Figure 2]: PVDWI versus WI versus Control]. These results could be related to an unmasked inhibitory action of the portal afferents on splanchnic sympathetic activity in splanchnic circulation to maintain a static water-induced pressor response.

In contrast, we observed the augmented hemodynamic perturbations by PVDWI were attenuated by anti-TRPV4WI, as the appearance of the diminished SBP, reduced LFBPV, and reduced both HFBPV and HFHRV, indicate a weakening sympathetic activity and cardiopulmonary function by anti-TRPV4 in WI. These results also indicate a defect in the osmolality sensing circuit because of TRPV4 channels inhibition, rather than an abnormality in portal vein innervation, which is responsible for the lack of response to WI stimulus in the anti-TRPV4WI group rats.[3],[9]

As per the above explanations, one attractive candidate mediator for control of homeostatic circulation in the splanchnic/portal system is calcitonin gene-related peptide (CGRP). CGRP is a novel vasodilator neurotransmitter, which is dependent on the status of intrinsic sympathetic activity to exert its effects on cardiovascular regulation in the rat,[20],[21] whereas TRPV4 has been reported express in sensory afferent nerves and co-localize with CGRP.[6],[22] Based on the results of the anti-TRPV4WI group rats, we speculate that WI causes splanchnic sympathetic activation but remained CGRP releasing from hepatic/portal afferent nerves at sympathetic nerve terminals thus causes splanchnic vasodilatation after inhibition of TRPV4 in this group rats. The subsequent decrease of SBP and reduced LFBPV could be a compensatory response to counteract the sudden volume expansion of splanchnic circulation, especially in the afferents innervated portal region.

Responses of plain water ingestion in stressful cooling condition

We observed that compared with WI in PreCS, WI in CS-evoked pressor and tachycardia responses accompanied by increases of high-frequency BPV, LFBPV, and VLFBPV. When compared CS with PreCS, we also observed a similar pattern in changes of SBP of those four group rats in both two conditions. Furthermore, CS of the WI group rats similarly CS of the control group rats both exerted the CIP and CIT responses. When compared with the control group rats at the CS condition, we observed a similar pressor, augmented CIP and SBP, but without changes of LFBPV and VLFBPV of the WI group rats. Our prior studies suggest the underlying mechanism of CEHP is highly relevant to the sympathetic activation.[12],[13],[14] However, from the data of this study, we speculate that in the stressful cooling condition, some other vasoconstriction factors may also engage the pressor response besides the splanchnic sympathetic activation of WI. We discuss the possible mechanisms of this observation below.

One possible mechanism for WI to augment CIP and SBP at the CS condition is because of catecholamine from adrenal medulla that might increase both regional and systemic vascular responses to the splanchnic sympathetic activation.[15] We thus speculate if the splanchnic sympathetic activation is a reason for the water-induced pressor effect, the water-induced pressor response will be higher than the CS alone-induced pressor response (CIP) because of the addition of epinephrine in CS. Another possible mechanism is that there might be other vasoactive mediators yielded to augment splanchnic vasoconstriction, such as angiotensin II, vasopressin, and endothelin-1, such vasoconstrictors may serve to respond to the stressful cooling challenge (CS) for overall circulatory homeostasis.[15],[23]

Next, we turn to examine the underlying mechanisms of portal vein innervation and TRPV4 channels in signaling water-induced pressor response at the CS condition. When compared with WI group rats, we observed both PVDWI and anti-TRPV4WI group rats their augmentation or reduction phenomena of respective hemodynamic perturbations in CS similar to the baseline PreCS. Because CS compared with PreCS the tendency to change SBP between PVDWI and anti-TRPV4WI group rats is very similar, we consider that the splanchnic circulation and portal mechanisms of water-induced pressor response in those two group rats are the same, thus for CS, we adopt the same explanation that has been aforementioned in PreCS.

Finally, in the aspect of coherence strength, we observed throughout the experiment course, WI caused a low K2IBI/SBP value in both LF and HF regions of all the other three groups except the control group rats. As per the concept of the cross-spectrum analysis, we speculate the observed weakening of the LF region coherence is because of those rats' afferent portal nerves, when given WI exerted an inhibitory influence on sympathetic activation thus detached the sympathetic baroreflex modulation. On the other hand, weakening of the HF region coherence by WI suggests that the oscillations in HRV and BPV are unrelated to their respiratory movement, i.e., a detached cardiorespiratory coupling effect.

 Conclusion



Overall results indicate that in the splanchnic circulation at PreCS and CS conditions, an integral portal system and their afferent nerves containing osmoreceptors, TRPV4, play a critical buffering role in splanchnic sympathetic activation and water-induced pressor response. These results further our understanding of the cardiovascular control mechanisms. Additional research is required to determine the afferents signaling in WI by gastric distension and the role of interaction between hepatic nerves and spinal pathways.

Financial support and sponsorship

This work was supported by grants from the Ministry of Science and Technology (MOST 103-2320-B-350-001) and the Cheng Hsin General Hospital-National Defense Medical Center cooperative research project (CH-NDMC-108-30 and 109-16), Taipei, Taiwan, ROC.

Conflicts of interest

There are no conflicts of interest.

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