Biomedical subjects

Kazuhide Nishimaru

Publications and source records attributed to Kazuhide Nishimaru.

6 recordsLinked to original sources

PubMed2003

Possible involvement of prostaglandins F(2alpha) and D(2) in acetylcholine-induced positive inotropy in isolated mouse left atria.

The inotropic action of prostaglandins PGF(2alpha), PGD(2) and PGE(2) on isolated mouse left atria was characterized and compared with the positive inotropic action of acetylcholine, which has previously been shown to be mediated by prostaglandins released from the endocardial endothelium. PGF(2alpha), PGD(2) and PGE(2) produced positive inotropic responses; the time course of the change in contractile force induced by PGF(2alpha) and PGD(2) was about the same as that by acetylcholine, while that by PGE(2) was slower. Fluprostenol and sulprostone, FP and EP receptor agonists, respectively, had positive inotropic effects while BW-245C, a DP receptor agonist, had no effect. AH-6809, a DP receptor antagonist, had no inhibitory effect on the positive inotropic response to PGD(2). Dimethylamiloride, an inhibitor of Na(+)/H(+) exchange, inhibited the positive inotropic response to PGF(2alpha), PGD(2) and acetylcholine, but not PGE(2). Fluorometric pH measurement with carboxy-SNARF-1-loaded atrial myocytes revealed no change in intracellular pH on application of PGF(2alpha). PGF(2alpha) and PGD(2) significantly prolonged the duration of the atrial action potential while PGE(2) had no significant effect. These findings suggest that prostaglandins induce positive inotropic response in mouse atria through FP and EP receptor stimulation and that the former mechanism mediates in part the positive inotropic response to acetylcholine.

Action Potentials↗

PubMed2003

Pharmacological evidence for involvement of phospholipase D, protein kinase C, and sodium-calcium exchanger in alpha-adrenoceptor-mediated negative inotropy in adult mouse ventricle.

The intracellular signalling pathway for alpha-adrenoceptor-mediated negative inotropy was studied pharmacologically in isolated adult mouse ventricle. The negative inotropy was inhibited by GF-109203X, a nonselective protein kinase C inhibitor. Phorbol 12-myristate 13-acetate also produced sustained negative inotropy, which was inhibited by KB-R7943, a Na(+)/Ca(2+) exchanger inhibitor. The alpha-adrenoceptor-mediated negative inotropy was augmented by RHC-80267, a diacylglycerol lipase inhibitor, but was inhibited either by C(2)-ceramide, a phospholipase D inhibitor, and high concentration of propranolol (50 micro M), which inhibits phosphatidate phosphohydrolase. The inotropy was not affected by U-73122, a phospholipase C inhibitor. Lavendustin-A, a tyrosine kinase inhibitor, also inhibited the negative inotropy. These findings suggest that alpha-adrenoceptor-mediated negative inotropy in adult mouse ventricle is mediated by activation of tyrosine kinase, the phospholipase D-phosphatidate phosphohydrolase pathway, and protein kinase C.

Animals↗

PubMed2003

Inhibition of agonist-induced positive inotropy by a selective Rho-associated kinase inhibitor, Y-27632.

We examined the effect of Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclo-hexanecarboxamide), a selective Rho-associated kinase (ROCK) inhibitor, on agonist-induced inotropy in isolated mouse left atria. Endothelin-1, angiotensin-II, and prostaglandin F(2)(alpha) (PGF(2)(alpha)) produced positive inotropy, which was significantly attenuated by Y-27632 (100 microM). On the other hand, isoproterenol-induced positive inotropy was not attenuated by the drug. These results provide the first evidence that the Rho/ROCK pathway is involved in endothelin-1-, angiotensin-II-, and PGF(2)(alpha)-induced positive inotropy, but not in beta-adrenoceptor-mediated positive inotropy.

Adrenergic beta-Agonists↗

PubMed2002

Coupling of c-Src to large conductance voltage- and Ca2+-activated K+ channels as a new mechanism of agonist-induced vasoconstriction.

The voltage-dependent and Ca(2+)-activated K(+) channel (MaxiK, BK) and the cellular proto-oncogene pp60(c-Src) (c-Src) are abundant proteins in vascular smooth muscle. The role of MaxiK channels as a vasorelaxing force is well established, but their role in vasoconstriction is unclear. Because Src participates in regulating vasoconstriction, we investigated whether c-Src inhibits MaxiK as a mechanism for agonist-induced vasoconstriction. Functional experiments in human and rat show that inhibitors of Src (Lavendustin A, PP2) but not inactive compounds (Lavendustin B, PP3) induce a pronounced relaxation of coronary or aortic smooth muscle precontracted with 5-hydroxytriptamine, phenylephrine, or Angiotensin II. Iberiotoxin, a MaxiK blocker, antagonizes the relaxation induced by Lavendustin A or PP2, indicating that c-Src inhibits the Iberiotoxin-sensitive component, likely MaxiK channels. In agreement, coronary muscle MaxiK currents were enhanced by Lavendustin A. To investigate the molecular mechanism of c-Src action on MaxiK channels, we transiently expressed its alpha subunit, hSlo, with or without c-Src in HEK293T cells. The voltage sensitivity of hSlo was right-shifted by approximately 16 mV. hSlo inhibition by c-Src is due to channel direct phosphorylation because: (i) excised patches exposed to protein tyrosine phosphatase (CD45) resulted in a partial reversal of the inhibitory effect by approximately 10 mV, and (ii) immunoprecipitated hSlo channels were recognized by an anti-phosphotyrosine Ab. Furthermore, coexpression of hSlo and c-Src demonstrate a striking colocalization in HEK293T cells. We propose that MaxiK channels via direct c-Src-dependent phosphorylation play a significant role supporting vasoconstriction after activation of G protein-coupled receptors by vasoactive substances and neurotransmitters.

Angiotensin II↗

PubMed2002

Aging, ion channel expression, and vascular function.

Cardiovascular disease remains the leading cause of death in the United States, and aging is one of the main risk factors for its development. Coronary arteries nurture the heart, but as age progresses, they suffer changes that make them stiffer, thicker, and with higher spontaneous contractile activity. Even in the absence of pathological atherosclerotic lesions, these changes make the coronary arteries at risk for vasospasm and the individual at risk for myocardial ischemia and heart failure. Thus, knowledge of the molecular mechanisms involved in the vascular physiology, disease, and aging of the coronary circulation is required to develop strategies to preserve the quality of life of an increasingly aging population. One of the key factors that regulate coronary arterial tone is the activity of K+ channels in the vascular smooth muscle cells (SMCs). In particular, voltage-dependent and Ca(2+)-activated K+ (BKCa) channels, which are abundant in the coronary SMCs, are targets of vasoconstrictors and vasorelaxants, and play a key role in determining arterial tone and diameter. Aging induces a reduction in the density of the alpha-subunit of BKCa channels in coronary smooth muscle, lowers baseline endothelial release of the relaxant nitric oxide (NO), and increases the response to endothelial constrictor factors and K+. Thus, aging induces the remodeling of important proteins involved in the excitability and contractility of the coronary circulation. Altogether, these changes increase the risk of coronary artery vasospasm, myocardial ischemia, and infarct in the elderly.

Aging↗

PubMed2002

Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents.

The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.

Aniline Compounds↗