Shohei Nakamura

Endothelium-dependent contraction in intrapulmonary arteries: mediation by endothelial NK1 receptors and TXA2.

1 We have examined whether three natural tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) induce an endothelium‐dependent contraction (EDC) in the rabbit isolated intrapulmonary artery. 2 Removal of the endothelium almost abolished the contraction induced by SP (10−8 m) while it did not attenuate the contraction induced by SP (10−7 m), NKA (10−9‐10−7 m) or NKB (10−9‐10−7 m). 3 The EDC induced by SP (10−8 m) was abolished by NK1 antagonists (FK‐888, CP‐96345, CP‐99994 and SR‐140333) but not by an NK2 antagonist (SR‐48968). 4 The EDC induced by SP was attenuated by cyclo‐oxygenase inhibitors (aspirin and indomethacin), thromboxane A2 (TXA2) synthetase inhibitors (OKY‐046, KY‐234 and KY‐063) and a TXA2 antagonist (S‐1452). 5 The rank order of potency causing endothelium‐independent contraction (EIC) was NKA>NKB>SP. The EIC induced by SP (10−7 m) was attenuated by an NK2 antagonist but not by NK1 antagonists, cyclo‐oxygenase inhibitors, TXA2 synthetase inhibitors or a TXA2 antagonist. 6 In conclusion, SP at 10−8 m induces EDC via endothelial NK1 receptors and TXA2 production, and SP at 10−7 m induces EIC via NK2 receptors in the rabbit intrapulmonary artery.

Heterogenous activity of BRL 35135, a beta 3-adrenoceptor agonist, in thermogenesis and increased blood flow in brown adipose tissue in anaesthetized rats.

1. The effects of BRL 35135, a β3‐adrenergic agonist, on body temperature and regional blood flow in brown adipose tissue (BAT) were simultaneously recorded in anaesthetized rats and compared to isoproterenol.

Endothelium-dependent relaxation followed by contraction mediated by NK1 receptors in precontracted rabbit intrapulmonary arteries

In the present study, we examined whether substance P (SP) and SP methyl ester (SPME), a selective NK1 agonist, cause biphasic responses consisting of endothelium‐dependent relaxation (EDR) and contraction (EDC) in precontracted rabbit intrapulmonary arteries. In arteries contracted with PGF2α (2×10−6u2003M), SP as well as SPME caused only EDR at low concentration (10−9u2003M) and EDR followed by EDC at higher concentrations, indicating the involvement of NK1 receptors. The SP (10−8u2003M)‐induced EDR was abolished in arteries moderately contracted by PGF2α (5×10−7u2003M) and the EDC in arteries maximally contracted by PGF2α (10−5u2003M), indicating that EDR and EDC are inversely dependent on preexisting tone. Indomethacin (10−8–10−6u2003M), a cyclo‐oxygenase inhibitor, and ozagrel (10−8–10−6u2003M), a TXA2 synthetase inhibitor attenuated the EDC in the SPME (10−7u2003M)‐induced biphasic response and markedly potentiated the EDR. AA‐861 (10−8–10−6u2003M), a 5‐lipoxygenase inhibitor, did not affect the EDR or EDC. L‐NG‐nitro‐arginine methyl ester (10−5–10−4u2003M), a nitric oxide synthase inhibitor, attenuated the EDR and slightly potentiated the EDC. CP‐99994 (10−10–10−8u2003M), an NK1 antagonist, attenuated the EDC and potentiated the EDR in the SPME (10−7u2003M)‐induced biphasic response, while the NK2 antagonist SR‐48968 (10−9–10−7u2003M) had no effect. CP‐99994 attenuated the SPME (10−7u2003M)‐induced EDC under EDR‐blockade to a greater extent than the EDR under EDC‐blockade, indicating that CP‐99994 enhanced the EDR component by preferential inhibition of the EDC component. In conclusion, NK1 agonists caused a biphasic endothelium‐dependent response (EDR and EDC) in submaximally precontracted intrapulmonary arteries. The EDC and EDR mediated by NK1 receptors may play physiological and/or pathophysiological roles in modulation of vascular tone.

Endothelium-dependent contraction induced by substance P in canine cerebral arteries: involvement of NK1 receptors and thromboxane A2.

We characterized the endothelial responses to substance P (SP) in the isolated canine cerebral artery. SP caused concentration-dependent contraction at 10(-10) - 10(-7) M and relaxation at 10(-10) and 10(-9) M, which were abolished by removal of the endothelium. The SP-induced endothelium-dependent relaxation (EDR) was suppressed, while the endothelium-dependent contraction (EDC) was increased by repeated application. The EDC induced by SP (10(-7) M) was attenuated by SR-140333 (10(-9) - 10(-7) M) and CP-99994 (10(-7) M), both NK1 antagonists, but not by SR-48968 (10(-7) M), an NK2 antagonist, or four antagonistic SP analogues (10(-6) M). The EDC induced by SP (10(-7) M) was attenuated by aspirin (10(-5) M), a cyclooxygenase inhibitor, OKY-046 (10(-5) M), a TXA2 synthetase inhibitor and ONO-3708 (10(-8) M), a TXA2 antagonist. Neurokinin A (10(-7) M) but not neurokinin B (10(-7) M) caused EDC similar to that induced by SP. In conclusion, SP induces EDC via endothelial NK1 receptors and TXA2 production in canine cerebral arteries.

Protective effect of the calcium antagonist NKY-722 against renal and arterial injuries in Dahl salt-sensitive rats.

OBJECTIVEnTo study the effect of long-term administration of NKY-722 and nicardipine on renal dysfunction and morphological changes in the kidneys and arteries in Dahl salt-sensitive (Dahl-S) rats.nnnDESIGNnVehicle, NKY-722 and nicardipine were administered orally to Dahl-S rats fed a high-salt diet for 6 weeks.nnnMETHODSnSystolic blood pressure was measured once a week. At the last week blood and urine were collected and an autopsy was carried out.nnnRESULTSnNKY-722 (1 mg/kg per day) lowered blood pressure reproducibly for 6 weeks, whereas nicardipine (3 mg/kg per day) showed a similar effect at week 1 only. NKY-722 tended to decrease blood urea-nitrogen, and reduced plasma creatinine and renin activity significantly. NKY-722 increased urine volume, urinary sodium, creatinine and protein excretions, but did not affect urinary N-acetyl-beta-D-glucosaminidase activity significantly. NKY-722 increased the glomerular filtration rate and reduced glomerulosclerosis and renal arterial injury morphologically. Nicardipine did not affect blood or urinary parameters, but reduced glomerular injury significantly. NKY-722 but not nicardipine reduced cerebral arterial injury. A lower dose of NKY-722 (0.3 mg/kg per day) did not affect blood pressure, blood or urinary parameters, but reduced glomerulosclerosis and renal arterial injury significantly. NKY-722 (1 mg/kg per day) and nicardipine (3 mg/kg per day) increased urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2. NKY-722 but not nicardipine increased the 6-keto-PGF1 alpha:thromboxane B2 ratio in the thoracic aorta.nnnCONCLUSIONSnNKY-722 improved the renal dysfunction, and reduced glomerular, renal and cerebral arterial injuries in Dahl-S rats. The effect of NKY-722 on glomerulosclerosis and arterial injuries is, at least partly, independent of blood pressure, and is probably related to the effect on eicosanoid metabolism.

Role of intracellular Ca2+ in endothelium-dependent contraction and relaxation of rabbit intrapulmonary arteries

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR). In the noncontracted preparations, ionomycin-induced EDC was significantly attenuated by quinacrine (10(-5) M), manoalide (10(-6) M), both phospholipase A(2) inhibitors, indomethacin (10(-5) M) and aspirin (10(-4) M), both COX inhibitors, and ozagrel (10(-5) M), a TXA(2) synthetase inhibitor. In the precontracted arteries, EDR was markedly reduced by L-NAME (10(-4) M), a NOS inhibitor, and methylene blue (10(-6) M), a guanylate cyclase inhibitor, and was enhanced by indomethacin, aspirin and ozagrel, probably due to inhibition of EDC. ZM230487, a 5-lipoxygenase inhibitor, had no effect on EDR. EIR was not affected by L-NAME, indomethacin or ZM230487. Arachidonic acid (10(-6) M) evoked EDC sensitive to indomethacin and ozagrel. L-Arginine (10(-3) M) caused EDR sensitive to L-NAME in the ionomycin-stimulated preparations. In conclusion, Ca(2+) mobilizers cause EDC and EDR via production of TXA(2) and NO, respectively.