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 Ϫ/Ϫ 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. (Hypertension. 2010;55:1438-1443.) Key Words: Trpv4 Ⅲ blood pressure Ⅲ osmopressor Ⅲ sympathetic nervous system Ⅲ baroreflex S tudies in patients with baroreflex impairment led us to discover that water ingestion increases blood pressure (BP) and vascular resistance. We found that ingestion of 16 oz (473 mL) of water induces a profound increase in systolic BP, averaging Ϸ40 mm Hg, with occasional increases Ͼ75 mm Hg. The effect appears within 10 minutes, is maximal at 25 to 40 minutes, and largely dissipates by 90 minutes after ingestion. Although the effect of water was greatest in individuals with impaired baroreflex buffering, it was also present in healthy persons. In healthy young subjects with intact baroreflexes, water elicits an increase in peripheral vascular resistance without an increase in BP because of a compensatory reduction in cardiac output. 1 Importantly, water ingestion raises plasma norepinephrine but not renin or vasopressin, supporting a sympathetic nervous system mechanism. 2,3 Furthermore, induction of reversible autonomic blockade with the autonomic ganglionic blocking drug trimethaphan abolishes the pressor action of water. 2 Although these studies in human subjects suggest a sympathetic nervous system mechanism for the pressor action of water, we sought to discover the physiological and molecular basis of the response. There has been increasing interest in splanchnic, neural, and vascular mechanisms in BP control in a number of animal models. 4 The transient receptor potential cation channel family, especially the vanilloid family (TRPV), constitutes potential mediators of the pressor response to water. These channels mediate the effects of many environmental factors, including osmolality and stretch, on neuronal and cardiovascular function. 5 Trpv4, in particular, is sensitive to osmotic perturbations 6,7 and is found along the gastrointestinal (GI) tract, mesenteric vessels, liver, cholangiocytes, dorsal root ganglia, and other locations throughout the body. ...

Water ingestion induces a robust increase in blood pressure in patients with baroreflex impairment. To better understand this phenomenon, we use a modified sino‐aortic denervated mouse model. Water (750μL/30g body weight), but not saline solution, infused into the duodenum of these mice stimulates an increase in blood pressure (BP) similar in magnitude and time course to that in patients. This indicates that hypo‐osmolality is the stimulus for this response. Previous studies provided evidence that increased sympathetic outflow underlies this pressor effect. However, physiological and molecular mediators of this effect remain unknown. Calcitonin Gene Related Peptide (CGRP) exerts effects centrally and peripherally in the gastrointestinal, respiratory and endocrine systems. It has been implicated in conveying afferent information that leads to sympathetic activation in response to sensory input. To determine whether CGRP plays a crucial role in the osmopressor response, water was given intraduodenally to sino‐aortic denervated α‐CGRP −/−mice. Although CGRP−/− mice had higher baseline BP before denervation (MAP = 82 ± 2 mmHg in CGRP−/− mice compared to 77 ± 2 mmHg in the WT, P value<0.001), the magnitude of BP increase after water infusion was similar in the knockout (ΔMAP= 14.4 ± 5 mmHg) and wild type mice (ΔMAP= 15.9 ± 4 mmHg) (P value = 0.49). This indicates that CGRP is not required for the pressor effect of water.

Introduction: VT inducibility is often used to assess the efficacy of VT ablation. Sinus rhythm voltage maps (VMs) are used to guide ablation of VT substrate, but catheter manipulation may mechanically traumatize critical sites, altering VT inducibility. We prospectively evaluated the effect of VM on VT inducibility. Methods: Twenty-nine patients (mean age 62, 70% ischemic cardiomyopathy) with planned VT ablation underwent initial programmed electric stimulation (PES). Fifteen patients then underwent VM followed by repeat PES and 14 patients underwent a waiting period with ICE imaging and transseptal puncture but no VM (imaging group) before repeat PES. Responses to repeat PES were categorized as type I if the same VT was induced, type II if a different VT was induced, and type III if no VT was inducible. Results: In the VM group, the same VT was inducible in 3 patients, a different VT in 9, and no VT in 3 patients (figure). In contrast, those in the imaging group had the same VT induced in 10 patients, a different VT in 3 and no VT in 1 patient. There was no difference in the number of extrastimuli needed to induce VT between the two PES in either group. VT cycle length in the VM group was shorter after mapping (295 vs 331ms), although this was not statistically significant. There was no difference between the groups in anesthesia method, time between initial and second PES, type of cardiomyopathy, or ejection fraction. Conclusions: The mechanical effects of VM can alter inducibility of VT independent of ablation. This may contribute to late recurrences of VT by preventing mapping of clinically relevant VT circuits, or falsely indicating effective ablation when PES is repeated only after ablation.