Raised arterial blood pressure in neurokinin‐1 receptor‐deficient mice (NK1R^−/−): evidence for a neural rather than a vascular mechanism

Abstract

New Findings r What is the central question of this study?Does genetic ablation of neurokinin-1 receptors alter arterial blood pressure? r What is the main finding and its importance? NK1R−/− mice have increased mean arterial blood pressure, but without a concomitant change in vascular reactivity. This finding suggests that neurokinin-1 receptors play a role in the neural regulation of blood pressure.Mice with functional ablation of the neurokinin-1 receptor gene, Tacr1, (NK1R −/− ) express behavioural abnormalities equivalent to those seen in attention deficit hyperactivity disorder (ADHD). An established model of ADHD is the spontaneously hypertensive rat, which exhibits high blood pressure owing to increased central sympathetic drive. In light of the evidence that the neurokinin-1 receptor (NK1R) also influences cardiovascular haemodynamics, we have investigated whether NK1R −/− mice exhibit raised blood pressure. Cardiovascular parameters were recorded for 24 h in conscious mice using radiotelemetry. Vascular function was assessed in mesenteric resistance arteries by wire myography. The NK1R −/− mice exhibited a higher blood pressure than wild-type animals throughout the 24 h period. Heart rate and locomotor activity in NK1R −/− mice were higher than in wild-type mice during the night period (active phase), consistent with an ADHD-like phenotype, but not during the day. Mesenteric and renal arteries from NK1R −/− mice exhibited normal vascular function; the responses to vasoconstrictors (U46619 and phenylephrine) and the endothelium-dependent vasodilator, acetylcholine, were not altered in these animals, suggesting that the NK1R does not regulate vascular tone. Analysis of heart rate variability revealed a higher low-frequency to high-frequency ratio in NK1R −/− mice, indicative of increased cardiac sympathetic activity. We propose that the raised blood pressure in NK1R −/− mice could be due to a neural mechanism rather than a change in vascular reactivity. Further studies are required to understand this mechanism and to establish whether a subgroup of ADHD patients with polymorphism of the equivalent (TACR1) gene are affected in a similar way.

The Regulation of Pulmonary Vascular Tone by Neuropeptides and the Implications for Pulmonary Hypertension

“…Yet, endothelial NK1R activation can also result in thromboxane-mediated vasoconstriction ( Figure 4 ). Interestingly, global knockout of the NK1R gene ( Tacr1 ) resulted in no alteration to vascular function in isolated systemic arteries ( Moyes et al, 2016 ). Given that both smooth muscle and endothelial cells were lacking NK1R in these mice, it may explain the phenotype.…”

Neurogenic substance P—influences on action potential production in afferent neurons of the kidney?

“…We could show a substance P-dependent sympatho-inhibitory control circuit via afferent nerves even under healthy conditions [14]. Mice lacking NK1 receptors have an increased blood pressure [40]. The authors, who examined these mice, assumed a neurogenic mechanism rather than a change in vascular reactivity of these mice.…”

The NK1R-/- mouse phenotype suggests that small body size, with a sex- and diet-dependent excess in body mass and fat, are physical biomarkers for a human endophenotype with vulnerability to attention deficit hyperactivity disorder

“…First, comparisons of the locomotor behaviour of NK1R-/- mice and their wildtypes have revealed that the former genotype typically displays locomotor hyperactivity in a range of different experimental settings (Fisher et al, 2007; Herpfer et al, 2005; Moyes et al, 2016; Porter et al, 2015a, 2015b). …”