Portal osmopressor mechanism linked to transient receptor potential vanilloid 4 and blood pressure control

Abstract

Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induced a robust increase in BP and vascular resistance. Here, using a mouse model of baroreflex impairment, we show that the increase in blood pressure after water ingestion is mediated through sympathetic nervous system activation and that the osmosensitive transient receptor potential vanilloid 4 channel (Trpv4) is an essential component of the response. Although portal osmolality decreases after water ingestion in both wild-type and Trpv4(-/-) mice, only the wild-type animals show a pressor response. The same volume of physiological saline does not elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and Trpv4 thus represent new factors now implicated in the physiology of BP regulation.

Figure 1. Location of water’s action

Change in BP after intragastric or intraduodenal infusion of water or saline (25 µL/g). Infusions occurred between 10–16 minutes. Both gastric (orange, n=7) and duodenal (blue, n=11) infusion of water resulted in a robust increase in BP.

Figure 2. Osmopressor response is mediated by sympathetic nervous system activation

Change in BP after duodenal infusion of water (25 µL/g). A, The pressor response to water was greatly attenuated with prazosin (0.5 mg/kg IP) prior to water infusion (green, n=5). B, Dbh^−/− mice display no response to intraduodenal water (red, n=5).

Figure 3. Vagal afferents are not essential for water’s pressor effect

Change in BP after duodenal infusion of water (25 µL/g) in vagotomized (green, n=6) and inact (blue, n=11) mice.

Figure 4. Effect of osmolality on BP

Change in BP after intraduodenal infusion of water (blue, n=11) or saline (pink, n=6) (25 µL/g). Infusions occurred between 10–16 minutes A, Attenuation of the pressor response during saline infusion implicates hypo-osmolality as the stimulus. B, Systemic (●, ■) and portal (○, □) osmolality 10 minutes after intraduodenal infusion of water (●, ○, n=9) or saline(■, □, n=9). The decrease in portal osmolality after water, but not after saline infusion is consistent with portal/hepatic osmosensor involvement in the pressor response to water.

Figure 5. Trpv4 is an essential mediator in the osmopressor response

Change in BP after duodenal infusion of water (25 µL/g) in Trpv4^−/− mice (red, n=11) compared to wild-type (blue, n=11).

Figure 6. Portal and systemic osmolality in Trpv4^−/− after water infusion

Systemic (●) and portal (○) osmolality 10 minutes after duodenal infusion of water (25 µL/g) in Trpv4^−/− mice (n=10).