Implication of nigral tachykinin NK₃ receptors in the maintenance of hypertension in spontaneously hypertensive rats: a pharmacologic and autoradiographic study

Abstract

1 The role of nigral tachykinin NK 1 , NK 2 and NK 3 receptors in central cardiovascular regulation was studied by measuring the eects of selective agonists and antagonists on mean arterial pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra of spontaneously hypertensive rats (SHR ]NKA(4-10)) agonists at 25 and 100 pmol while the NK 3 agonist (senktide, 50 and 100 pmol) had no signi®cant eect. The three agonists had no eect on behaviour, and increases in MAP were elicited by the NK 1 agonist only.3 Whereas antagonists at NK 1 (RP 67580, 500 pmol) and NK 2 (SR 48968, 500 pmol) receptors had no signi®cant eect on MAP and HR, the NK 3 antagonist (R-820, 500 pmol) reduced MAP for over 3 h in SHR. That anti-hypertensive eect did not occur after intracerebroventricular or intravenous injection of R-820. Also, R-820 had no cardiovascular eect in WKY. 4 The anity (K D : 0.7 nM) and densities of speci®c NK 3 receptor binding sites measured in the substantia nigra, ventral tegmental area, hippocampus and amygdala were not signi®cantly dierent in SHR and WKY. 5 It is concluded that endogenous tachykinins exert a tonic activity on NK 3 receptors in the substantia nigra of SHR to maintain high blood pressure. Hence, nigral tachykinin NK 3 receptors may represent a promising therapeutic target in the treatment of arterial hypertension.

Characterization of nuclear neurokinin 3 receptor expression in rat brain

“…NK3-R antagonists blocked cocaine induced locomotor activity and anxiety behaviors in marmosets (De Souza Silva et al, 2006) while an NK3 agonist injected into SNc and VTA increased locomotor activity and rearing behavior in rats (Stoessl et al, 1991). Altered NK3-R expression occurs in a strain of hamsters with dystonia (Friedman et al, 2002), and a NK3-R antagonist reduces blood pressure in spontaneously hypertensive rats (Lessard et al, 2003). Nuclear NK3-R-IR has recently been shown ultrastructurally in globus pallidus and VTA neurons (Levesque et al, 2006; Lessard et al, 2009).…”

The ventral tegmental area as a putative target for tachykinins in cardiovascular regulation

“…The exact site and mechanism of action of tachykinins in the central autonomic control of blood pressure remain unclear. Thus far, the anterior hypothalamus represents the primary putative target for tachykinins (Itoi et al ., 1991, 1994), although a role for the nigrostriatal dopaminergic system was highlighted in recent pharmacological studies in normotensive and spontaneously hypertensive rats (Lessard & Couture 2001; Lessard et al ., 2003).…”

Blockade of tachykinin NK3 receptor reverses hypertension through a dopaminergic mechanism in the ventral tegmental area of spontaneously hypertensive rats

“…Interaction between tachykinins and dopamine specific NK3R binding sites measured in the VTA and other midbrain nuclei are, however, not significantly different between SHR and WKY (Lessard et al, 2003). As i.c.v.…”

“…Reciprocally, tonic activation of NK 3 R may contribute to the hyperactivity of the VTA dopaminergic neuronal pathway and thereby in the maintenance of hypertension in SHR. The affinity and densities of specific NK 3 R binding sites measured in the VTA and other midbrain nuclei are, however, not significantly different between SHR and WKY (Lessard et al ., 2003).…”