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Biomedical subjects

A Ko

Publications and source records attributed to A Ko.

31 records · Page 2Linked to original sources
PubMed1998

Substantially attenuated hemodynamic responses to Escherichia coli-derived vascular endothelial growth factor given by intravenous infusion compared with bolus injection.

Vascular endothelial growth factor (VEGF) produces beneficial angiogenesis in animal models of coronary and peripheral ischemia. However, intravenous bolus injection of Chinese hamster ovary cell (CHO)-derived VEGF produces adverse effects on hemodynamics. The present study examined pharmacokinetic and hemodynamic responses to Escherichia coli-derived VEGF, which will be used in clinical patients, compared with responses to CHO-derived VEGF, and tested whether intravenous infusion of E. coli-derived VEGF attenuates the hemodynamic responses compared with the responses observed with intravenous bolus injection. Hemodynamic parameters were measured before and after administration of VEGF in conscious, instrumented rats. Intravenous injection of both CHO- and E. coli-derived VEGF produced a similar maximal reduction in arterial pressure, although E. coli-derived VEGF exhibited less of a depressor effect in the initial phase after injection. Either infusion or injection of E. coli-derived VEGF caused hypotension, tachycardia and reduced cardiac output and stroke volume, which were significantly attenuated when given by infusion compared with injection. The maximal hypotensive and tachycardiac responses to infusion were decreased by 50 to 60% compared with those responses observed after injection. Cardiac output was maximally reduced by 34% after injection, but only 18% after infusion. A sustained elevation in systemic vascular resistance observed after injection was avoided after infusion. Thus, the hemodynamic side effects of VEGF administration can be substantially attenuated by controlling the rate of VEGF infusion. The data indicate that infusion, instead of bolus injection, is a more appropriate regimen for VEGF administration.

Animals↗
PubMed1997

Hemodynamic effects of scatter factor in conscious rats.

Scatter factor (SF), also known as hepatocyte growth factor, is a potent mitogen that has been suggested to exhibit greater efficacy than vascular endothelial growth factor (VEGF) in rabbits with hindlimb ischemia. Our study examined the effects of SF on cardiovascular hemodynamics and compared the responses to VEGF. Hemodynamic parameters were monitored before and after administration of SF or VEGF in conscious, instrumented rats. Intravenous injection of SF produced a dose-related reduction in mean arterial pressure (MAP) and increase in heart rate (HR). These responses were significantly attenuated by pretreatment with N omega-nitro-L-arginine methyl ester a nitric oxide (NO) synthase inhibitor, suggesting the depressor effect of SF may be mediated by NO. SF (250 micrograms/kg) reduced stroke volume and cardiac output, but did not affect the maximal first derivation of left ventricular pressure (dP/dt), suggesting that the reduction in cardiac output is caused by decreased stroke volume that probably results from a reduction in venous return. Compared with SF, VEGF produced greater hypotensive and tachycardic responses and greater reductions in stroke volume and cardiac output, indicating that SF has fewer side effects on hemodynamics. Although both growth factors might reduce venous return, SF decreased hematocrit presumably through venodilation, whereas VEGF increased hematocrit as a result of vascular hyperpermeability.

Animals↗
PubMed1996

Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED50 = 1.8 nM) and was reduced in NPR-C binding by approximately 200-fold. When infused into conscious rats at 0.325 microg/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 microg/min of rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure.

Amino Acid Sequence↗
PubMed1996

In vivo effects of cardiotrophin-1.

Cardiotrophin-1 (CT-1) is a recently discovered cytokine that was isolated based on its ability to induce cardiac myocyte hypertrophy in vitro. In this study, the effects of chronic administration of CT-1 to mice (0.5 or 2 microg by intraperitoneal injection, twice a day for 14 days) were determined. A dose-dependent increase in both the heart weight and ventricular weight to body ratios was observed in the treated groups. The body weights of the animals were unaffected. These results indicate that CT-1 can induce cardiac hypertrophy in vivo. CT-1 was not specific for the heart, however. It stimulated the growth of the liver, kidney, and spleen, and caused atrophy of the thymus. CT-1 administration also increased the platelet counts by 70%, with no change in mean platelet volume. Red blood cell counts were increased in the treated animals, and there was a concomitant increase in haemoglobin concentration. Thus, CT-1 has a broad spectrum of biological activities in vivo. This observation is consistent with previous in-vitro findings showing that the mRNA for CT-1 is expressed in several tissues, and that CT-1 can function through binding to the leukaemia inhibitory factor (LIF) receptor and signalling through the gp130 pathway.

Animals↗
PubMed1996

Effects of vascular endothelial growth factor on hemodynamics and cardiac performance.

Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, has therapeutic benefit in animal models of coronary or limb ischemia. However, the hemodynamic effects of VEGF have not been investigated. We examined the effects of VEGF on hemodynamics and cardiac performance. Mean arterial pressure (MAP), heart rate (HR), cardiac output, stroke volume, left ventricular (LV) dP/dt, and hematocrit were measured before and after intravenous injection of VEGF in conscious, instrumented rats. VEGF caused a dose-dependent reduction in MAP and an associated increase in HR. VEGF (250 micrograms/kg) significantly decreased cardiac output and stroke volume without affecting the inotropic state of the left ventricle, as determined by dP/dt. VEGF significantly increased hematocrit. Furthermore, VEGF did not affect contractility or HR in the isolated rat heart in vitro. The data suggest that the VEGF-induced decrease in cardiac output is due to reduced stroke volume, which may be caused by a decrease in venous return rather than a direct effect on myocardial contractility. In addition, pretreatment with N omega-nitro-L-arginine methyl-ester (L-NAME), a nitric oxide (NO) synthase inhibitor, significantly attenuated the depressor and tachycardic responses to VEGF, suggesting that VEGF-induced hypotension may be mediated by NO.

Animals↗
PubMed1996

Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo.

Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.

Aging↗
PubMed1995

Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition.

The effects of growth hormone (GH) plus insulin-like growth factor-1 (IGF-1) were tested in an experimental model of cardiac failure treated with chronic angiotensin-converting enzyme (ACE) inhibition. Myocardial infarction was induced in rats by left coronary artery ligation. Two weeks after ligation, the animals received either captopril (2 g/L in drinking water) or water for 3 months. The rats were then given either GH (2 mg/kg/day) plus IGF-1 (2 mg/kg/day) or vehicle for 14 days. Captopril treatment decreased mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) (p < 0.05), and increased cardiac index (CI) and stroke volume index (SVI) (p < 0.05). GH/IGF-1 or captopril+GH/IGF-1 treatment decreased MAP, LVEDP, and SVR (p < 0.05), and increased left ventricular maximum dP/dt, CI, and SVI (p < 0.05). The increases in CI and SVI were significantly greater in the captopril+GH/IGF-1-treated animals than in those treated with captopril alone (p < 0.05). The beneficial effect of captopril in reducing cardiac hypertrophy was preserved in the captopril+GH/IGF-1 group. The results indicate that GH/IGF-1 and captopril can improve cardiac performance in congestive heart failure by independent and complementary mechanisms.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Regioselectivity and stereoselectivity of androgen hydroxylations catalyzed by cytochrome P-450 isozymes purified from phenobarbital-induced rat liver.

The regioselectivity and stereoselectivity of androgen hydroxylations catalyzed by five isozymes of cytochrome P-450 purified from phenobarbital-induced rat liver were studied in a reconstituted monooxygenase system using testosterone (T) and androst-4-ene-3,17-dione (delta 4-A) as substrates. P-450 PB-3, an isozyme exhibiting low catalytic activity with many xenobiotic substrates, catalyzed efficient (turnover = 15.7 to 18.5 min-1 P-450-1 at 25 microM substrate) and highly stereoselective B-ring hydroxylations of both steroid substrates, with the corresponding 7 alpha- and 6 alpha-hydroxy alcohols formed in ratios of approximately 20 to 30:1, respectively. P-450 PB-2c metabolized testosterone to a mixture of 16 alpha OH-T, 2 alpha OH-T, and delta 4-A (product ratio = 1.0/0.78/0.33; turnover = 10.2 min-1 P-450-1). PB-2c is present in significantly larger amounts in mature male rats as compared to immature males, and probably catalyzes the male-specific testosterone 16 alpha-hydroxylase activity known to be induced at puberty and subject to endocrine control. P-450 PB-4, the major phenobarbital-induced isozyme in rat liver, catalyzed efficient D-ring hydroxylations, yielding 16 beta OH- delta 4-A as the predominant product with delta 4-A as substrate (turnover = 12.0 min-1 P-450-1) and a mixture of 16 beta OH-T, 16 alpha OH-T, and delta 4-A (the latter compound presumably formed via 17 alpha hydroxylation) with testosterone as substrate (turnover = 5.2 min-1 P-450-1). P-450 isozymes PB-1 and PB-5 hydroxylated both steroids with essentially the same regioselectivity as PB-4 but at only 5 to 10% the catalytic rate. Cytochrome b5 stimulated most of these steroid hydroxylations up to 2-fold with no change in regio- or stereoselectivity. The identification of specific steroid metabolites as diagnostic of particular P-450 isozymes should be useful for the assessment of isozymic contributions to microsomal activities and, in addition, facilitate comparisons of P-450 isozymes isolated in different laboratories.

Androgens↗
PubMedDate not supplied

Anti-beta2 glycoprotein I and anticardiolipin antibodies in leptospirosis, syphilis and Kala-azar.

OBJECTIVE: Reports have shown that anticardiolipin (aCL) antibodies present in patients with autoimmune diseases are dependent on the cofactor,beta2 glycoprotein I (beta2 GPI), as opposed to aCL antibodies seen in infectious diseases such as syphilis, HIV hepatitis C, etc. The assay for anti-beta2GPI antibodies has been reported to be more specific for antiphospholipid syndrome (APS). However, the prevalence of these antibodies in diseases such as leishmaniasis and leptospirosis remains unknown. The aim of the present study was determine the prevalence of antibodies to cardiolipin and to beta2GPI in patients with different infectious diseases, including leptospirosis, syphilis and leishmaniasis. METHODS: Samples from patients with Kala-azar (visceral leishmaniasis), syphilis or leptospirosis were tested for IgG and IgM anticardiolipin and IgG anti-beta2GPI antibodies by ELISA. RESULTS: In patients with Kala-azar the prevalence of IgG aCL, IgM aCL and anti-beta2GPI was 6% (2/30), 3% (1/30) and 53% (16/30), respectively. In syphilis the prevalence was 18% (14/74), 13% (10/74) and 10% (8/70), respectively. In leptospirosis the frequency of these antibodies was 23% (9/39), 10% (4/39) and 17% (6/34), respectively. There was no statistical correlation between aCL and anti-beta2GPI antibodies in these diseases. DISCUSSION: This study clearly shows a significant prevalence of anti-beta2GPI antibodies in leptospirosis and leishmaniasis and syphilis. This indicates that the assay for antibeta2GPI antibodies should be thoroughly validated before it is introduced as a definitive tool for the diagnosis of APS, testing a larger number of sera from patients with a wider range of clinical conditions.

Adolescent↗