Faculty Profiles - ZAMAMI Yoshito

A ketolide antibiotic, telithromycin, inhibits vascular adrenergic neurotransmission in the rat mesenteric vascular bed Reviewed

Y. Hatanaka, Y. Zamami, T. Koyama, N. Hobara, X. Jin, Y. Kitamura, H. Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 155 ( 6 ) 826 - 836 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background and purpose: A ketolide antibiotic, telithromycin, has side effects including temporary loss of consciousness in clinical use, but the underlying mechanisms remain unclear. This study investigated the effects of telithromycin on perivascular nerve function in rat mesenteric arteries, in comparison with those of macrolide (erythromycin and clarithromycin) and new quinolone antibiotics (levofloxacin and gatifloxacin).
Experimental approach: In vitro, vascular responses and release of noradrenaline induced by periarterial nerve stimulation (PNS) of rat perfused mesenteric vascular beds were measured in the presence of each antibiotic. In vivo blood pressure measurement was performed in Wistar rats.
Key results: In mesenteric preparations with resting tone, telithromycin (10 nM-10 mu M) markedly inhibited PNS (4 -12 Hz)-induced adrenergic nerve- and exogenous noradrenaline-mediated vasoconstriction, whereas the other antibiotics slightly inhibited PNS-induced responses without affecting noradrenaline-induced responses. Telithromycin significantly reduced PNS (12Hz)-evoked noradrenaline release in the perfusate. In pre-constricted preparations with or without endothelium, telithromycin (0.1 nM-10 mu M) caused a concentration-dependent vasodilation. Telithromycin (10 nM) inhibited calcium-induced vasoconstriction in high KCl and calcium-free medium. None of the antibiotics used affected PNS (0.5-2 Hz)-induced calcitonin gene-related peptide (CGRP) nerve- and exogenous CGRP-mediated vasodilation. Intravenous injection of telithromycin significantly lowered blood pressure in anaesthetized rats.
Conclusions and implications: These results suggest that telithromycin causes not only strong inhibition of perivascular adrenergic neurotransmission but also a vasodilator action in mesenteric vascular beds and hypotension. It is thus possible that telithromycin increases visceral blood flow, consequently reducing cerebral blood flow and resulting in a temporary loss of consciousness.

DOI： 10.1038/bjp.2008.313

Characterization of the inhibitory effect of vascular endothelium on agonist-induced vasoconstriction in rat mesenteric resistance arteries Reviewed

Xin Jin, Yukiko Satoh-Otonashi, Yoshito Zamami, Toshihiro Koyama, Pengyuan Sun, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 108 ( 1 ) 95 - 103 2008.9

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE PHARMACOLOGICAL SOC

Vascular endothelium regulates vascular tone by releasing endothelium-derived vasoactive substances. We performed this study to characterize the Inhibitory effect of the endothelium on vasoconstrictor stimuli in rat mesenteric vascular beds. Changes in perfusion pressure induced by continuous perfusion of Krebs solution containing methoxamine (alpha(1)-adrenoceptor agonist) or high KCl were measured over 180 min. In preparations with intact endothelium, methoxamine-Induced vasoconstriction was time-dependently decreased to cause 60%-80% reduction of the initial vasoconstriction level, while no reduction was observed in high-KCl-induced vasoconstriction. Endothelium removal significantly blunted the time-dependent reduction of methoxamine-induced vasoconstriction without affecting high-KCl-induced vasoconstriction. Neither a nitric oxide synthase inhibitor (L-NAME) nor indomethacin (cyclooxygenase inhibitor) altered the time-dependent reduction of vasoconstriction. High KCl, K+-channel inhibitors tetraethylammonium and apamin plus charybdotoxin, and 18 alpha-glycyrrhetinic acid (18 alpha-GA, a gap-junction inhibitor) significantly inhibited the time-dependent reduction of methoxamine-induced vasoconstriction. In preconstricted preparations, bolus injection of acetylcholine and Ca2+-ionophore A23187 (A23187) evoked a sharp vasodilation, which was inhibited by endothelium removal, high KCl and tetraethylammonium, but not indomethacin, L-NAME, or 18 alpha-GA. However, 18 alpha-GA plus L-NAME inhibited vasodilation induced by A23187, but not acetylcholine. These findings suggest that endothelium-derived hyperpolarizing factor (EDHF) via gap junctions mainly counteracts vasoconstriction induced by methoxamine in mesenteric resistance arteries.

DOI： 10.1254/jphs.08115FP

Acute hyperglycemia and hyperinsulinemia enhance adrenergic vasoconstriction and decrease calcitonin gene-related peptide-containing nerve-mediated vasodilation in pithed rats Reviewed

Yoshito Zamami, Shingo Takatori, Kousuke Yamawaki, Satoko Miyashita, Mitsunobu Mio, Yoshihisa Kitamura, Hiromu Kawasaki

HYPERTENSION RESEARCH 31 ( 5 ) 1033 - 1044 2008.5

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Recent clinical studies have demonstrated that transient postprandial hyperglycemia and hyperinsulinemia may contribute to the development of hypertension. Therefore, we investigated the influence of acute hyperglycemia and/or hyperinsulinemia induced by glucose or insulin infusion on neuronal and humoral control of vascular tone in rats. Euglycemic male Wistar rats were pithed under anesthesia and arterial blood pressure was measured. Changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin 11, calcitonin gene-related peptide (CGRP), acetylcholine and sodium nitroprusside (SNP) were studied by infusing various concentrations of glucose or insulin. Continuous glucose infusion, which increased both blood glucose and serum insulin levels, significantly augmented adrenergic nerve-mediated pressor responses to SCS without affecting pressor responses to injection of noradrenaline or angiotensin II. In pithed rats with artificially increased blood pressure and blockade of autonomic outflow, glucose infusion attenuated CGRPergic nerve-depressor responses to SCS without affecting depressor responses to injection of CGRP, acetylcholine or SNP. In pithed rats treated with octreotide, which increased blood glucose without increasing serum insulin levels, glucose infusion caused only significant augmentation of adrenergic nerve-mediated pressor responses. Combined infusion of insulin and glucose, which resulted in increased serum insulin levels with euglycemia, significantly augmented adrenergic nerve-mediated pressor responses and attenuated CGRPergic nerve-mediated depressor responses. The present results suggest that acute hyperglycemia and hyperinsulinemia increase adrenergic nerve-mediated vasoconstriction, which in turn blunts CGRPergic nerve function, and that the increase in plasma insulin concentration associated with hyperglycemia may be responsible for the alteration of neuronal vascular regulation.

DOI： 10.1291/hypres.31.1033

Pioglitazone opposes neurogenic vascular dysfunction associated with chronic hyperinsulinaemia Reviewed

S. Takatori, Y. Zamami, N. Yabumae, N. Hanafusa, M. Mio, T. Egawa, H. Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 153 ( 7 ) 1388 - 1398 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Background and purpose: We previously demonstrated that chronic hyperinsulinaemia induced by drinking high levels of fructose augments adrenergic nerve-mediated vasoconstriction and suppresses vasodilatation mediated by calcitonin gene-related peptide ( CGRP)-containing (CGRPergic) vasodilator nerves. In this study, the effects of pioglitazone on vascular responses induced by stimulation of adrenergic nerves, CGRPergic nerves and vasoactive agents were investigated in pithed rats given 15% fructose solution to drink ( FDR).
Experimental approach: To assess the effect of pioglitazone on the altered vascular responsiveness in the hyperinsulinaemic state in vivo, changes in vascular responses to spinal cord stimulation ( SCS) and intravenous bolus injections of noradrenaline, angiotensin II and CGRP were evaluated in pithed control rats and FDR either untreated or treated with pioglitazone.
Key results: In the pithed FDR, vasoconstrictor responses to SCS and to injections of noradrenaline and angiotensin II were significantly greater than those of pithed control rats. In pithed FDR with artificially increased blood pressure and blockade of the autonomic ganglia, the vasodilator responses to SCS and CGRP injection were significantly smaller than those of pithed control rats. Oral administration of pioglitazone to FDR for two weeks markedly decreased plasma levels of insulin, triglycerides and blood glucose. In FDR pioglitazone diminished the augmented vasoconstrictor responses to SCS, noradrenaline and angiotensin II, and ameliorated the decrease in vasodilator responses to SCS.
Conclusions and implications: The present results suggest that pioglitazone improves not only insulin resistance, but also the dysfunctions in vascular control regulated by adrenergic and CGRPergic nerves in the hyperinsulinaemic state.

DOI： 10.1038/bjp.2008.8

Effect of postprandial hyperglycemia and hyperinsulinemia on vascular responsiveness Reviewed

Yoshito Zamami, Shingo Takatori, Yukiko Iwatani, Kousuke Yamawaki, Satoko Miyashita, Nana Yabumae, Fusako Takayama, Mitsunobu Mio, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 ( 3 ) 419 - 424 2008.3

Language：Japanese Publisher：PHARMACEUTICAL SOC JAPAN

Recent clinical studies demonstrated that transient postprandial hyperglycemia and hyperinsulinemia may contribute to the development of hypertension. Therefore, we investigated influence of acute hyperglycemia and/or hyperinsulinemia induced by glucose or insulin infusion on neuronal and humoral control of vascular tone in rats. Euglycemic male Wistar rats were pithed under anesthesia and arterial blood pressure was measured. Changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin 11, calcitonin generelated peptide (CGRP), acetylcholine and sodium nitroprusside (SNP) were studied by infusing various concentration of glucose or insulin. Continuous glucose infusion, which increased both blood glucose and serum insulin levels, significantly augmented adrenergic nerve-mediated pressor responses to SCS without affecting injection of pressor responses to noradrenaline or angiotensin II. In pithed rats with artificially increased blood pressure and blockade of autonomic outflow, glucose infusion attenuated CGRPergic nerve-depressor responses to SCS without affecting depressor responses to injection of CGRP, acetylcholine or SNP. In pithed rats treated with octreotide, which increased blood glucose without increasing serum insulin levels, glucose infusion caused only significant augmentation of adrenergic nerve-mediated pressor responses. Combined infusion of insulin and glucose, which resulted in increased serum insulin levels with euglycemic, significantly augmented adrenergic nerve-mediated pressor responses and attenuated CGRPergic nerve-mediated depressor responses. The present results suggest that acute hyperglycemia and hyperinsulinemia increases adrenergic nerve-mediated vasoconstriction, which is partly associated with the blunted CGRPergic nerve function, and that plasma insulin concentration associated with hyperglycemia may be responsible for alteration of neuronal vascular regulation.

DOI： 10.1248/yakushi.128.419

Drug development using novel pharmacological evaluation Reviewed

Norifumi Shioda, Yoshito Zamami

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 ( 3 ) 393 - 393 2008.3

脊髄穿刺ラットの神経性血管反応に及ぼす一酸化窒素合成酵素阻害薬の影響

山脇康佑, 奥畑智, 座間味義人, 高山房子, 川崎博己

血管 30 ( 1 ) 28 - 28 2007.1

Chronic hyperinsulinemia enhances adrenergic vasoconstriction and decreases calcitonin gene-related peptide-containing nerve-mediated vasodilation in pithed rats Reviewed

Shingo Takatori, Yoshito Zamami, Mitsunobu Mio, Yuji Kurosaki, Hiromu Kawasaki

HYPERTENSION RESEARCH 29 ( 5 ) 361 - 368 2006.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

The present study investigated the influence of chronic hyperinsulinemia on vascular responsiveness induced by adrenergic nerves and calcitonin gene-related peptide-containing (CGRPergic) nerves in pithed rats with insulin resistance. Male Wistar rats (6 weeks old) received 15% fructose solution in drinking fluid for 10 weeks (fructose-drinking rats: FDR), which resulted in significant increases in plasma levels of insulin, total cholesterol and triglyceride, and systolic blood pressure, as compared with control rats. Pithed FDR showed greater adrenergic nerve-mediated pressor response to spinal cord stimulation (SCS) at the lower thoracic vertebra (Th 9-12) and pressor response to exogenous noradrenaline than control rats. In pithed FDR with blood pressure artificially increased by continuous infusion of methoxamine and blockade of autonomic ganglia by hexamethonium, CGRPergic nerve-mediated depressor responses to SCS were significantly smaller than those in control rats, but depressor responses to other vasodilators such as acetylcholine, CGRP and sodium nitroprusside were similar to those in control rats. These results suggest that chronic hyperinsulinemia in FDR facilitates adrenergic nerve-mediated vasoconstriction, which is associated with attenuated CGRPergic nerve-mediated vasodilation.

DOI： 10.1291/hypres.29.361

簡易懸濁法を用いた経管栄養チューブによる薬剤投与方法の改善

座間味義人, 高山房子, 川崎博己, 石井雅人, 柴田和彦, 五味田裕

TDM研究 23 ( 2 ) 101 - 102 2006.4

Effects of insulin on vascular responses to spinal cord stimulation and vasoactive agents in pithed rats Reviewed

S Takatori, M Mizote, Y Zamami, Y Kurosaki, H Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 140 ( 6 ) 1137 - 1145 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

1 Effects of insulin (2-600 pmol kg(-1) min(-1), i.v.) on vascular responses to spinal cord (lower thoracic vertebra, Th 9-12) stimulation (SCS) and to i.v. injection of noradrenaline (NA, 125-500 ng kg(-1)), angiotensin II (Ang II, 40-200 pmol kg(-1)), acetylcholine (ACh, 1 nmol kg(-1)), calcitonin gene-related peptide (CGRP, 0.1 nmol kg(-1)) and sodium nitroprusside (SNP, 5 mug kg(-1)) were examined in pithed rats.
2 In euglycemic pithed rats, low and medium doses of insulin dose-dependently potentiated vasopressor responses to SCS (2-8 Hz), NA, while higher doses of insulin had little effect on SCS- and NA-induced pressor responses. All doses of insulin significantly augmented pressor responses to Ang II.
3 In pithed rats with artificially increased blood pressure, SCS (2 and 4 Hz) induced a frequency-dependent depressor response, which was blocked by infusion of CGRP(8-37) (CGRP receptor antagonist, 60 nmol kg(-1) min(-1)).
4 In euglycemic pithed rats, low-doses of insulin significantly attenuated depressor responses to SCS and CGRP, but medium and high doses of insulin remained unaffected.
5 All doses of insulin significantly inhibited depressor response to ACh, while SNP-induced depressor response was not significantly affected by any doses of insulin.
6 These results suggest that insulin at low and medium concentrations increases adrenergic vasoconstriction, which is partly associated with inhibition of CGRPergic nerve function and endothelium function. It is also suggested that lack of insulin effect at higher concentrations may result from acute desensitization of insulin action, possibly via insulin receptors.

DOI： 10.1038/sj.bjp.0705539