Biomedical subjects

David D Ku

Publications and source records attributed to David D Ku.

7 recordsLinked to original sources

PubMed2006

Allicin in garlic protects against coronary endothelial dysfunction and right heart hypertrophy in pulmonary hypertensive rats.

We recently reported that coronary endothelial cell (CEC) dysfunction may contribute to the development of right ventricular (RV) hypertrophy (RVH) in monocrotaline (MCT)-induced pulmonary hypertensive rats. This present study investigated whether preservation of CEC function with garlic and its active metabolite allicin could abrogate RVH. Rats were fed with 1% raw garlic (RG)-supplemented diet 1 day or 3 wk before and 1 day after MCT injection, and changes in RV pressure (RVP), RVH, and CEC function were assessed 3 wk after MCT administration. In all cases, RG feeding significantly inhibited the development of RVP and RVH in these MCT rats. However, similar treatments with either boiled garlic (BG) or aged garlic (AG), which do not contain the active allicin metabolite, were ineffective. CEC function, assessed with acetylcholine-induced dilation as well as N(omega)-nitro-l-arginine methyl ester-induced constriction, revealed marked attenuation in right, but not left, coronary arteries of the MCT rats. This is consistent with our earlier report. Feeding of RG, but not BG or AG, preserved the CEC function and prevented the exaggerated vasoconstrictory responses of the MCT coronary arteries. There was no change in the coronary dilatory responses to a nitric oxide donor sodium nitroprusside. Further testings of vasoactivity to garlic extracts showed that only RG, but not BG or AG, elicited a potent, dose-dependent dilation on the isolated coronaries. Taken together, these findings show that the protective effect of garlic against the development of RVP and RVH in MCT-treated rats is probably mediated via its active metabolite allicin action on coronary endothelial function and vasoreactivity.

Animals↗

PubMed2006

Augmented endothelium-derived hyperpolarizing factor-mediated relaxations attenuate endothelial dysfunction in femoral and mesenteric, but not in carotid arteries from type I diabetic rats.

Individual vascular beds exhibit differences in vascular reactivity. The present study investigates the effects of streptozotocin-induced type I diabetes on endothelium-dependent responses of rat carotid, femoral, and mesenteric arteries. Rings with and without endothelium, suspended in organ chambers for isometric tension recording, were contracted with phenylephrine and exposed to increasing concentrations of acetylcholine. In carotid and femoral arteries, acetylcholine produced concentration- and endothelium-dependent relaxations that were abolished by Nomega-nitro-L-arginine methyl ester (L-NAME; specific nitric-oxide synthase inhibitor) and were impaired slightly in preparations from streptozotocin-treated rats (STZ-rats). This impairment could be prevented by L-arginine. In femoral arteries incubated with L-NAME, acetylcholine caused endothelium-dependent contractions that were abolished by 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid (S18886) (antagonist of thromboxane A2/prostaglandins H2-receptors) and reversed to relaxation by indomethacin (inhibitor of cyclooxygenase). The latter relaxation was inhibited by charybdotoxin plus apamin, suggesting a role of endothelium-dependent hyperpolarizing factor (EDHF). This EDHF-mediated component was augmented slightly in arteries from STZ-rats. In mesenteric arteries, relaxations to acetylcholine were only partially inhibited by L-NAME, and the L-NAME-resistant component was abolished by charybdotoxin plus apamin. In the mesenteric arteries from STZ-rats, L-NAME-sensitive relaxations to acetylcholine were reduced and the EDHF-component was augmented. These findings demonstrate a marked heterogeneity in endothelium-dependent responses in rat arteries and their differential adaptation in the course of type I diabetes. In particular, the EDHF-mediated component not only compensates for the reduced bioavailability of nitric oxide in the femoral and mesenteric artery but also counteracts the augmented endothelium-dependent contractions in the former.

Acetylcholine↗

PubMed2005

Selective right, but not left, coronary endothelial dysfunction precedes development of pulmonary hypertension and right heart hypertrophy in rats.

We investigated a causal role for coronary endothelial dysfunction in development of monocrotaline (MCT)-induced pulmonary hypertension and right heart hypertrophy in rats. Significant increases in pulmonary pressure and right ventricular weight did not occur until 3 wk after 60 mg/kg MCT injection (34 +/- 4 vs. 19 +/- 2 mmHg and 37 +/- 2 vs. 25 +/- 1% septum + left ventricular weight in controls, respectively). Isolated right coronary arteries (RCA) showed significant decreases in acetylcholine-induced NO dilation in both 1-wk (33 +/- 3% with 0.3 microM; n = 5) and 3-wk (18 +/- 3%; n = 11) MCT rats compared with control rats (71 +/- 8%, n = 10). Septal coronary arteries (SCA) showed a smaller decrease in acetylcholine dilation (55 +/- 8% and 33 +/- 7%, respectively, vs. 73 +/- 8% in controls). No significant change was found in the left coronary arteries (LCA; 88 +/- 6% and 81 +/- 6%, respectively, vs. 87 +/- 3% in controls). Nitro-L-arginine methyl ester-induced vasoconstriction, an estimate of spontaneous endothelial NO-mediated dilation, was not significantly altered in MCT-treated SCA or LCA but was increased in RCA after 1 wk of MCT (-41 +/- 6%) and decreased after 3 wk (-18 +/- 3% vs. -27 +/- 3% in controls). A marked enhancement to 30 nM U-46619-induced constriction was also noted in RCA of 3-wk (-28 +/- 6% vs. -9 +/- 2% in controls) but not 1-wk (-12 +/- 7%) MCT rats. Sodium nitroprusside-induced vasodilation was not different between control and MCT rats. Together, our findings show that a selective impairment of right, but not left, coronary endothelial function is associated with and precedes development of MCT-induced pulmonary hypertension and right heart hypertrophy in rats.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2005

Endothelium-dependent contractions occur in the aorta of wild-type and COX2-/- knockout but not COX1-/- knockout mice.

The present experiments were designed to determine whether or not endothelium-dependent contractions can be evoked in the aorta of the mouse, and if so, whether or not deleting the COX1 gene affects the response. Sex differences in the response were also examined. Rings of murine aorta were suspended in a Halpern-Mulvany myograph for recording of isometric force. In the aorta of the male wild type C57BL/b6 mice (36-40 weeks old), both acetylcholine and the calcium ionophore caused endothelium-dependent increases in force in the presence of L-NAME, and these were inhibited by valeryl salicylate (a selective COX1 inhibitor) and S18886 (a selective antagonist of TP receptors). Such endothelium-dependent contraction was absent in the aorta of COX1 knockout mice and present in that of COX2 knockout mice. Similar results were obtained in aortas of female wild-type, COX2 and COX1 knockout mice. These experiments reveal the existence of EDCF-mediated contractions in arteries of the mouse. These contractions, as in the aorta of the spontaneously hypertensive rat, are caused by endogenous agonists(s) of TP receptors produced by cyclooxygenase 1, because they are observed in the aortas of COX2 knockout mice but not in aortas of COX1 knockout mice. The present study provides direct evidence that COX1 is indeed the isoform of cyclooxygenase responsible for the production of EDCF.

Animals↗

PubMed2004

The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat.

Endothelin-1 (ET-1) stimulation of endothelial nitric oxide synthase (eNOS) via pulmonary endothelial endothelin B (ET(B)) receptors and pulmonary intravascular macrophage accumulation with expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) are implicated in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Our aim was to evaluate the role of ET-1 in the development of experimental HPS. The time course of molecular and physiological changes of HPS and the effects of selective endothelin receptor antagonists in vivo were assessed after CBDL. Effects of ET-1 on intralobar pulmonary vascular segment reactivity and on eNOS expression and activity in rat pulmonary microvascular endothelial cells (RPMVECs) were also evaluated. Hepatic and plasma ET-1 levels increased 1 week after CBDL in association with a subsequent increase in pulmonary microvascular eNOS and ET(B) receptor levels and the onset of HPS. Selective ET(B) receptor inhibition in vivo significantly decreased pulmonary eNOS and ET(B) receptor levels and ameliorated HPS. CBDL pulmonary artery segments had markedly increased ET(B) receptor mediated, nitric oxide dependent vasodilatory responses to ET-1 compared with controls and ET-1 triggered an ET(B) receptor dependent stimulation of eNOS in RPMVECs. Pulmonary intravascular macrophages also accumulated after CBDL and expressed HO-1 and iNOS at 3 weeks. Selective ET(B) receptor blockade also decreased macrophage accumulation and iNOS production. In conclusion, ET-1 plays a central role in modulating pulmonary micovascular tone in experimental HPS.

Animals↗

PubMed2002

Occupation of the prostaglandin E2-type 1 receptor increases rat atrial contractility via a Y-27632-sensitive pathway.

This study investigated whether rat left atria (LA) contain the prostaglandin E2 type 1 receptor (EP1) and whether EP1 occupation induces positive inotropic responses in superfused LA. Western analysis demonstrated that LA contain EP1 and the EP1 splice variant. Exposing isolated, superfused LA to 17-phenyl trinor PGE2, an EP1 agonist, increased isometric contractile force and its corresponding dF/dTs to approximately 70% of the isoproterenol maximum with an EC50 of approximately 80 nM. In contrast, agonists for EP2, EP3, and EP4 caused little change in LA function. While the EP1 antagonists SC-51089 and SC-19220 blocked 17-phenyl trinor PGE2-induced inotropy, neither prazosin, nadolol, atropine nor EI-283, a pan-specific protein kinase C inhibitor, affected 17-phenyl trinor PGE2-induced inotropy. However, Y-27632 and HA-1077, inhibitors of rho A-activated protein kinases, prevented and reversed the increase in LA contractility that occurred in the presence of 17-phenyl trinor PGE2. Thus, atria contain EP1 and EP1 occupation increases LA contractility via a pathway sensitive to inhibitors of rho A-activated protein kinases.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMedDate not supplied

Garlic and its active metabolite allicin produce endothelium- and nitric oxide-dependent relaxation in rat pulmonary arteries.

1. The aims of the present study were to investigate the effects of fresh garlic and one of its active metabolites, allicin, on rat isolated pulmonary arteries (RPA). 2. In endothelium-intact and phenylephrine-precontracted RPA, the addition of a water or a 5% ethanol extract of fresh garlic (1-500 microg/mL) resulted in a dose-dependent relaxation reaching a maximum (mean +/- SEM) of -91 +/- 3 and -93 +/- 2%, respectively, with an ED(50) of 113 +/- 12 and 106 +/- 10 microg/mL, respectively. The vasorelaxation was readily reversible upon washing and no tachyphylaxis was noted. 3. An extract of the external garlic storage leaf produced a significantly greater relaxation than the inner stem. Microfiltration of extracts with a 10,000 molecular sieve did not attenuate relaxation. Inactivation of alliinase and allicin formation, with either boiling of the garlic clove for 30 min or 100% ethanol treatment, completely abolished relaxation. In contrast, similar treatment of crushed garlic with formed allicin retained the relaxation response. 4. Pure allicin produced a similar relaxation as garlic extract, with an EC(50) of approximately 0.8 microg/mL. Disruption of endothelium or N(G)-nitro-L-arginine methyl ester pretreatment attenuated the relaxation, whereas indomethacin had no effect. 5. Prior garlic (500 microg/mL) treatment enhanced acetylcholine relaxation by shifting the response curve to the left, but had no effect on nitric oxide (NO) donor-induced responses. 6. These results demonstrate that garlic and the active metabolite allicin are capable of eliciting a NO-dependent relaxation in RPA and that this response is likely to be mediated via garlic activation of NO formation rather than its stabilization.

Animals↗