Hiro-o Kamiya

Role of central tachykinin peptides in cardiovascular regulation in rats

The mechanisms of action of tachykinin peptides thought to be involved in central cardiovascular regulation were examined. Intracerebroventricular injections (i.c.v.) of tachykinin peptides caused dose-dependent increases in blood pressure and heart rate. The pressor responses to substance P (SP) (10 micrograms, i.c.v.) and neurokinin A (NKA) (10 micrograms, i.c.v.) were blocked by peripheral administration of pentolinium or phentolamine, and partially attenuated by adrenalectomy. In contrast, the only initial pressor response to the neurokinin B (NKB) analogue senktide (10 micrograms, i.c.v.) was blocked by pentolinium or phentolamine. The pressor response to senktide was inhibited by pretreatment with a vasopressin V1 receptor antagonist (d(CH2)5OMe(Tyr)AVP) (10 micrograms/kg, i.v.), and senktide (10 micrograms, i.c.v.) caused an increase in plasma vasopressin level. However, the vasopressin antagonist did not influence the SP- and NKA-induced pressor responses. These results suggest that central SP and NKA increase the blood pressure and heart rate via sympathetic nerve activity, whereas central NKB increases the blood pressure mainly via release of vasopressin from the hypothalamus.

Antidiuretic action of tachykinin NK-3 receptor in the rat paraventricular nucleus

Studies were performed on the central antidiuretic actions via the tachykinin NK-3 receptor in the rat hypothalamic paraventricular nucleus (PVN). Microinjections of the selective tachykinin NK-3 receptor agonist senktide (2-200 pmol) into the PVN resulted in prolonged inhibition of urine output in water-loaded rats, its effect being dose-dependent. The antidiuretic action of senktide was blocked by pretreatment with the vasopressin V2 receptor antagonist OPC-31260 (1 mg/kg, i.v.), but not by microinjection of the angiotensin II AT-1 receptor antagonist losartan (1 nmol) into the PVN. NK-3 receptor mRNA was strongly detected in the magnocellular part of the PVN and the supraoptic nucleus (SON) of the hypothalamus as detected by in situ hybridization histochemistry. Moreover, [3H]senktide binding sites were also detected in the PVN and the SON by receptor autoradiography. These findings suggest that NK-3 receptors in the PVN may be involved in water regulation by stimulation of vasopressin secretion from the posterior pituitary gland, and that vasopressin caused water reabsorbtion via the kidney V2 receptor.

Nitric oxide is a mediator of tachykinin NK3 receptor‐induced relaxation in rat mesenteric artery

1 The mechanism of vasodilatation induced by tachykinin peptides was studied in isolated mesenteric arteries of rats. 2 Senktide, a selective NK3 agonist, elicited potent endothelium‐dependent relaxation of arteries precontracted with phenylephrine (10‐5m), but an NK1 agonist did not. 3 A non‐peptide NK3 antagonist, SR 142801, inhibited senktide‐induced relaxation. However, a non‐peptide NK1 antagonist, CP‐96,345, and a peptide‐based NK2 antagonist, L‐659,877, had no effect on senktide‐induced relaxation. 4 Nω‐nitro‐L‐arginine (l‐NOARG), a nitric oxide synthesis inhibitor, markedly attenuated the relaxant response to senktide. 5 These results suggest that the endothelium of rat mesenteric arteries possesses tachykinin NK3 receptors, and that NK3 agonist‐induced vasodilatation is mediated by release of nitric oxide (NO) from the endothelium.

Central pressor actions of tachykinin NK-3 receptor in the paraventricular nucleus of the rat hypothalamus

The central pressor actions of the tachykinin NK-3 receptor in the paraventricular nucleus (PVN) of the hypothalamus were examined in anesthetized rats. In forebrain-restricted animals, the selective tachykinin NK-3 receptor agonist senktide (10 micrograms, i.c.v.) increased the blood pressure, and this pressor response was more potent than in control animals. Injection of senktide into the PVN also increased the blood pressure, and this pressor response was inhibited by pretreatment with the vasopressin V1 receptor antagonist (10 micrograms/kg, i.v.). These results suggest that central injection of senktide stimulated the NK-3 receptor in the PVN of the hypothalamus, and increased blood pressure by inducing release of vasopressin from the pituitary gland.

Central administration of senktide, a tachykinin NK-3 agonist, has an antidiuretic action by stimulating AVP release in water-loaded rats

Intracerebroventricular (i.c.v.) injections of senktide (0.01-10 nmol), a tachykinin NK-3 agonist, had an antidiuretic action in water-loaded rats (4.5% body wt.). Pretreatment with OPC-31260 (1 mg/kg, i.v.), a non-peptide vasopressin V2 antagonist, inhibited the antidiuretic action induced by exogenous arginine vasopressin (AVP, 0.1 micrograms/kg, i.v.) and senktide (0.1 nmol, i.c.v.). In addition, senktide (11.8 nmol, i.c.v.) caused a marked increase of the plasma AVP level in conscious rats. These results suggest that the central NKB analogue senktide has an antidiuretic effect by stimulating AVP secretion from the pituitary gland through the NK-3 receptor in the hypothalamus.

Modulation of the arterial baroreceptor reflex by the vasopressin receptor in the area postrema of the hypertensive rats

The role of arginine8-vasopressin (AVP) in regulation of the baroreceptor reflex in the area postrema was examined in anesthetized hypertensive rats. The sensitivity of the baroreceptor reflex in a one-kidney one clip (1K1C) hypertensive rats was increased in only the initial stage (2 weeks), in association with increase in blood pressure, and then returned to the normal level. This increase in the sensitivity of the baroreceptor reflex in the initial stage was reversed by microinjection of a V1 or V2 antagonist (1 microg) into the area postrema. AVP V2 receptor mRNA was expressed temporarily in the area postrema in this period. These results suggest that vasopressin receptors in the area postrema is important in regulating the sensitivity of the baroreceptor reflex.

The central pressor actions of a novel tachykinin peptide, γ-preprotachykinin-(72–92)-peptide amide

Intracerebroventricular (i.c.v.) injections of a novel tachykinin peptide, gamma-preprotachykinin-(72-92)-peptide amide (neuropeptide gamma, NP gamma), caused dose-dependent increases in blood pressure. The NP gamma-induced pressor responses (1 microgram i.c.v.) were blocked by peripheral administration of pentolinium (10 mg/kg i.v.) and phentolamine (10 mg/kg i.v.), but were not inhibited by a vasopressin antagonist. These results suggest that central NP gamma increases the blood pressure via sympathetic nerve activity.

Role of NK-1 receptor in central cardiovascular regulation in rats: Studies on a novel non-peptide antagonist, CP-96,345, of substance P NK-1 receptor

CP-96,345[(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)- methyl]-1-azabicyclo [2.2.2] octan-3-amine] was recently discovered to be a nonpeptide substance P (SP) antagonist. We examined the effects of CP-96,345 on the central cardiovascular responses to tachykinin peptides in anesthetized rats. CP-96,345 (200 nmol, i.c.v.) inhibited the pressor responses of the NK-1 receptor-selective agonist GR 73632 (0.5 nmol, i.c.v.) and SP (7 nmol, i.c.v.). It also inhibited the increase in blood pressure elicited by neurokinin A (7 nmol, i.c.v.). However, it had no effect on the earlier pressor response induced by neuropeptide gamma (l nmol, i.c.v.) or by a selective NK-3 agonist senktide (1 nmol, i.c.v.). These findings suggest that SP (i.c.v.) induces pressor responses via the NK-1 receptor, and that the pressor response to neurokinin A may also be mediated by the NK-1 receptor in the brain.

Evidence for Cardiovascular Roles of Tachykinin Peptides in the Brain of the Rat

In addition to substance P (SP), 4 other tachykinin peptides have so far been isolated from the mammalian nervous system, namely neurokinin A (NKA), neuropeptide K (NPK), neuropeptide γ (NPγ) and neurokinin B (NKB) (Maggio, 1988; Krause et al., 1989). These tachykinin peptides have a variety of pharmacological effects, indicating smooth muscle contraction, salivation, endothelium-dependent vasodilator actions, and depolarization of central neurons (Erspamer, 1981; Pernow, 1983). These peptides are extensively distributed and play important physiological roles in the mammalian central nervous system (CNS). Several lines of evidence have proposed the existence of multiple tachykinin receptor subtypes in peripheral tissues and the CNS, called NK-1, NK-2 and NK-3 (TABLE I). SP, NKA and NKB are considered to be endogenous ligands of the NK-1, NK-2 and NK-3 subtypes, respectively (Henry, 1987).