Raised arterial blood pressure in neurokinin-1 receptor deficient mice (NK1R-/-): Evidence for a neural rather than a vascular mechanism

Abstract

Mice with functional ablation of the neurokinin-1 receptor gene (NK1R-/-) express behavioural abnormalities equivalent to those seen in Attention Deficit Hyperactivity Disorder (ADHD). An established model of ADHD is the spontaneously hypertensive rat (SHR), which exhibits high blood pressure due to increased central sympathetic drive. In light of the evidence that NK1R also influence cardiovascular haemodynamics, we have investigated whether NK1R-/- similarly 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. NK1R-/- mice exhibited a higher blood pressure than wildtype animals throughout the 24 h period. Heart rate and locomotor activity in NK1R-/- mice were higher than wildtypes 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 & phenylephrine) and the endothelium-dependent vasodilator, acetylcholine, were not altered in these animals, suggesting that NK1R do not regulate vascular tone. Analysis of heart rate variability revealed a higher low frequency: high frequency (LF:HF) ratio in NK1R-/- indicative of increased cardiac sympathetic activity. We propose that the raised blood pressure in NK1R-/- mice could be due 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 similarly affected.

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