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Biomedical subjects

J Y Jeremy

Publications and source records attributed to J Y Jeremy.

At least 91 records · Page 5Linked to original sources
PubMed1993

Effect of milrinone in human platelet shape change, aggregation and thromboxane A2 synthesis: an in vitro study.

Milrinone (MIL; a cAMP-specific phosphodiesterase type-III inhibitor), added in vitro to achieve concentrations below the therapeutic levels, inhibited agonist-induced platelet shape change (PSC). Arachidonic acid (AA)-induced PSC was significantly more inhibited by a combination of MIL and indomethacin (INDO; a cyclooxygenase inhibitor) than by either alone. PSC induced by 5-hydroxytryptamine was inhibited by MIL but not by INDO; and this effect of MIL was not augmented by INDO. Whole blood-platelet aggregation (WB-PA) and platelet-rich plasma aggregation induced by potent stimulators of thromboxane A2 (TXA2) synthesis such as AA and calcium ionophore and by less potent agonists (e.g. ADP and U46619) were inhibited by MIL at or near therapeutic concentrations. WB-PA induced by collagen was significantly more inhibited by the MIL and INDO combination than by either of these agents alone whereas with ADP-induced WB-PA no additional effect could be shown when both MIL and INDO were co-incubated. MIL and similar types of drugs may be of benefit in conditions associated with platelet hyperactivity and some of these effects may be enhanced by cyclooxygenase inhibitors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Effect of milrinone on thromboxane A2 synthesis, cAMP phosphodiesterase and 45Ca2+ uptake by human platelets.

The phosphodiesterase inhibitors milrinone and isobutylmethylxanthine (IBMX) inhibited the conversion of [3H]cAMP to [3H]AMP by washed human platelets in concentration-dependent manners (IC50: milrinone, 2.6 x 10(-6) M; IBMX, 4.6 x 10(-6) M). Milrinone and IBMX increased cAMP levels when stimulated by a single concentration (0.3 microM) of iloprost. EC50:milrinone, 5.6 x 10(-5) M; IBMX, 3 x 10(-5) M. Milrinone was a potent inhibitor of platelet thromboxane A2 (TXA2) synthesis when stimulated by median stimulatory doses of collagen (IC50: 3 x 10(-7) M), sodium fluoride (NaF) (a non-specific G protein activator; IC50: 3 x 10(-7) M) and phorbol ester myristate acetate (PMA) (a protein kinase C activator; IC50: 2.2 x 10(-7) M). In contrast, at median stimulatory doses of A23187 and arachidonate there was a marked decrease in the potency of milrinone in inhibiting TXA2 synthesis. Milrinone had a weak inhibitory effect on TXA2 synthesis when elicited by freeze fracturing. In all experiments IBMX was a weaker inhibitor of TXA2 synthesis, although the general pattern of effects was similar to milrinone. Milrinone inhibited both collagen- and adrenaline-stimulated 45Ca2+ uptake by human platelets in dose-dependent manners. Since platelet TXA2 synthesis is dependent on Ca2+, and milrinone inhibited 45Ca2+ uptake, it is concluded that milrinone exerts its inhibitory effect on platelet activity, principally through an action on Ca2+ mobilisation/binding to effector proteins (protein kinase C and/or phospholipase A2).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Effect of hypothermic storage in liver allograft preservation solutions on vasoactivity and prostacyclin synthesis by the rabbit aorta, in vitro.

Primary graft dysfunction following orthoptic liver transplantation has been ascribed to thrombotic and ischemic complications in a high proportion of cases. It has been suggested that hypothermic storage of livers in preservation solutions elicits damage to the vascular endothelium. Since the endothelium controls vasoactivity and hemostasis via release of endothelium derived relaxing factor (EDRF) and prostacyclin (PGI2), storage injury to the endothelium may predispose the allograft to thrombosis, ischemia and impaired perfusion. In order to test this, the effect of long-term hypothermic storage in modified University of Wisconsin solution (UW), kidney perfusion solution (KPS) and minimum essential medium (MEM) on phenylephrine (PE)-stimulated contraction and acetylcholine (ACh)-stimulated relaxation, as well as PGI2 release by rabbit aortic rings was investigated. Following cold storage for 24, 48 and 72 h, PE and ACh dose response curves were unaffected by storage in MEM, UW or KPS. Following hypothermic storage for 24 h and 48 h, PGI2 release (stimulated with PE, ACh, arachidonate, fluoride, calcium ionophore and phorbol ester) was not significantly altered from zero time responses. These results demonstrate that hypothermic storage of rabbit aortic rings in both UW and KPS do not influence two key endothelial functions (the release of EDRF or PGI2) which in turn indicates that endothelial damage associated with reperfusion following hypothermic storage is not causally related to alterations in EDRF and PGI2 release.

Animals↗
PubMed1993

Differential changes of adrenoceptor- and muscarinic receptor-linked prostacyclin synthesis by the aorta and urinary bladder of the diabetic rat.

1. The effect of experimental diabetes mellitus (DM; hyperglycaemic, non-ketototic; 2 months duration) in the rat on receptor-linked prostacyclin (PGI2) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) was studied in the aorta and urinary bladder using adrenaline, angiotensin II (AII) and acetylcholine (ACh). Signal transduction systems were studied via stimulation of PGI2 synthesis with phorbol ester dibutyrate (PDBU; a protein kinase C activator [PKC]), Ca2+ ionophore A23187 (A23187) and thapsigargin (both elevate intracellular Ca2+, activating phospholipase A2 [PLA2]) and arachidonate (AA; substrate for PGI2 synthesis). 2. In response to adrenaline, AII and phorbol ester, aortic PGI2 release was markedly reduced (all > 75%) in diabetic rats compared to controls. EC50s of the dose-response curves for adrenaline, AII and PDBU were also markedly increased in aortae from DM rats compared to controls. Although there was decreased output of PGI2 in response to A23187 by aortae from diabetic rats compared to controls, there was no difference in the EC50s (mean +/- s.e. mean: diabetic, 2.7 +/- 0.2 x 10(-6) M; controls 2 +/- 0.18 x 10(-6) M). There were no differences in PGI2 release (or in the EC50s) in response to thapsigargin or AA between aortae from diabetic and control rats. 3. In the urinary bladder, there was a marked increase in PGI2 output in response to ACh and a marked decrease in EC50s for the ACh-PGI2 dose-response curves in diabetic rats (EC50 = 5.8 +/- 0.32 x 10(-7) M) compared to controls (EC50 = 2.2 +/- 0.15 x 10(-6) M). Although there was an increase in PGI2 output in the urinary bladders from diabetic rats in response to A23187, there were no differences in the EC50s (control, 1.8 +/- 0.2 x 10-6 M; diabetic, 1.1 +/- 0.15 X 10-6 M). In the urinary bladders, there were no differences in PGI2 output (or the EC50s) in response to PDBU, thapsigargin or AA between diabetic or control rats.4. These data indicate that: (i) reduced PGI2 synthesis coupled to adrenoceptors and AII receptors in the aortae of diabetic rats may be due to diminished PKC activity and not to changes in receptor density and/or affinity, Ca2+ stores, PLA2, cyclo-oxygenase or PGI2 synthase; (ii) the diametrically opposite effect of DM on ACh-stimulated PGI2 synthesis is not due to an increase in PKC activity, but possibly to an increase in muscarine receptor number and/or affinity; (iii) changes in receptor-linked PGI2 synthesis are not ubiquitous in experimental DM and may be organ-specific.

Angiotensin II↗
PubMed1993

Effect of buflomedil on in vitro prostacyclin and endothelin synthesis by vascular (rat and human) and penile (rat) tissue and calcium uptake by isolated human platelets.

The effect of buflomedil, a vasodilator, on: (a) in vitro prostacyclin (PGI2) synthesis by the rat aorta and penis, human cultured endothelial cells (HUVECs) and human iliac artery, (b) endothelin synthesis by HUVECs and (c) 45Ca2+ uptake by isolated human platelets was investigated. Buflomedil had no effect on PGI2 synthesis by rat aorta, iliac artery or HUVECs (short or long-term incubations). However, buflomedil inhibited noradrenaline- (but not arachidonate- or ionophore A23187-) stimulated PGI2 synthesis. Buflomedil had a weak stimulatory effect on PGI2 synthesis by the isolated rat penis, but this was not inhibited by cholinergic antagonists. Buflomedil (except at supra-therapeutic concentrations) exerted no effect on endothelin release by HUVECS. Buflomedil inhibited 45Ca2+ uptake by human platelets when stimulated with collagen and adrenaline, but not when stimulated with calcium ionophore A23187. These data demonstrate that buflomedil has no deleterious effect on the enzymes that control vascular PGI2 synthesis. The data also adds to the evidence that buflomedil is an alpha-adrenoceptor blocker and has stimulatory effects on penile PGI2 synthesis. Both of these properties may prove useful in the treatment of impotence. The specific inhibition of 45Ca2+ uptake consolidates that buflomedil has some calcium-channel-blocking properties which may explain, at least in part, its vasodilator and antiplatelet properties. Buflomedil may prove beneficial in the treatment of impotence via three mechanisms: (a) stimulation of penile PGI2 synthesis (b) alpha-adrenoceptor blockade and (c) calcium-mobilization-blocking properties.

Animals↗
PubMed1992

5-Hydroxytryptamine stimulates 45Ca2+ uptake by human umbilical vein endothelial cells in culture: mediation by 5-HT2 receptor subtypes.

In cultured human umbilical vein endothelial cells, 5-HT and alpha-methyl 5-HT stimulated [45Ca2+] uptake in concentration-dependent manner, whereas the 5-HT1 agonists, m-CPP (1-(3-chlorophenyl)piperazine and 2-MPP (1-(2-methoxyphenyl)piperazine), were without effect. In turn, 5-HT-stimulated [45Ca2+] uptake was inhibited in concentration-dependent manners by the 5-HT receptor antagonists ketanserin (5-HT2), LY 53,857 (5-HT2) and methiothepine (5-HT1/2) and to a lesser degeree by MDL 72222 (5-HT3) and BRL 43694 (5-HT3) whereas (+/-)-propranolol (5-HT1) was without effect. These data indicate that 5-HT stimulates Ca2+ uptake by endothelial cells via activation of a 5-HT2 receptor subtype. 5-HT was without effect on de novo prostacyclin (PGI2) synthesis over the concentration of 5-HT that elicited [45Ca2+] uptake. Since 5-HT did not stimulate PGI2, an event associated with an increase in levels of intracellular Ca2+, it is postulated that the uptake of 45Ca2+ reflects changes of Ca2+ at the level of the plasma membrane rather than on intracellular changes. 5-HT-stimulated Ca2+ uptake may be of relevance to endothelium-dependent relaxation, vascular permeability and endothelial repair and proliferation.

Biological Transport, Active↗
PubMed1992

The effect of cold storage of rat thoracic aortic rings in organ preservation solutions--a study of receptor-linked vascular prostacyclin synthesis.

An important aspect of organ preservation is the maintenance of intrinsic dilator and antithrombotic mechanisms of blood vessels. Blood vessels synthesize prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet adhesion and aggregation. PGI2 synthesis is controlled by complex mechanisms including adrenoceptor-linked calcium influx and protein kinase C. Since organ preservation solutions may influence these mechanisms, we investigated the effect on in vitro PGI2 synthesis of cold storage of rat aortic rings in lactobionate-raffinose solution (LRS) and hypertonic citrate kidney preservation solution (KPS) on in vitro PGI2 synthesis. Acute incubation of aortic tissue in both preservation solutions at 37 degrees C (compared with minimal essential medium) completely inhibited PGI2 synthesis when stimulated with noradrenaline (NA), phorbol ester (a protein kinase C activator), NaF (a G protein activator), or A23187. Following storage of aortic rings at 4 degrees C (for up to 72 hr) in LRS and KPS, subsequent washing and incubation in MEM, PGI2 synthesis was initially markedly enhanced in response to NA when compared with tissues stored in MEM. These enhanced responses disappeared, and PGI2 synthesis returned to normal following 1 hr incubation of tissues in MEM at 37 degrees C. These data demonstrate that cold storage in preservation fluids exerts minimal deleterious effects, not only on PGI2 synthesis, but possibly on other key processes (calcium homeostasis, protein kinase C activity) in blood vessels.

Adenosine↗
PubMed1992

Lisinopril and nifedipine administration inhibits the ex vivo uptake of [45Ca2+] by platelets from hypertensive diabetic patients.

1. The effect of administration of the angiotensin converting enzyme inhibitor (ACEI), lisinopril (Carace; 10-40 mg twice daily) and the calcium channel blocker, nifedipine (Adalat Retard; 20-40 mg twice daily) on ex vivo [45Ca2+] uptake by platelets from hypertensive diabetic (type 1 and 2) patients was investigated. 2. At the end of at least 3 months treatment, blood was collected prior to the patient taking the morning dose of medication and washed platelets prepared. [45Ca2+] uptake was monitored following the addition of adrenaline, isoprenaline and dibutyryl cAMP (dbcAMP), as well as in unstimulated (zero) platelets. 3. Both nifedipine and lisinopril significantly inhibited the ex vivo uptake of [45Ca2+] by platelets when this process was stimulated by adrenaline, isoprenaline and dibutyryl cAMP. Basal uptake was also inhibited in both groups. 4. These data consolidate the hypothesis that ACE inhibitors may possess calcium channel/calcium mobilisation blocking properties. Apart from its hypertensive action, lisinopril may also reduce platelet activity via modulation of calcium dynamics, thereby reducing the incidence of vascular complications associated with diabetes mellitus.

Adult↗
PubMed1992

Differential changes in alpha- and beta-adrenoceptor linked [45Ca2+] uptake in platelets from patients with anorexia nervosa.

[45Ca2+] Uptake was studied in response to adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP in platelets from patients with anorexia nervosa. In both controls and anorectics, adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP stimulated [45Ca2+] uptake. In receptor subtype characterisation studies on control platelets, adrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine (an alpha 2-adrenoceptor antagonist) and the specific beta 2-adrenoceptor antagonist ICI 118,551, but not by atenolol (a beta 1-antagonist). Isoprenaline action was blocked by ICI 118,551, but not by yohimbine. Noradrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine but not by ICI 118,551. In platelets from anorectic patients, there was a significant increase in noradrenaline-stimulated [45Ca2+] uptake, a significant diminution in adrenaline and isoprenaline-stimulated [45Ca2+] uptake, but no significant difference in (Bu)2cAMP-stimulated [45Ca2+] uptake, when compared with controls. Basal uptake was also significantly enhanced in anorectics and was found to be inhibited with verapamil but not adrenoceptor antagonist. These data firstly indicate that both alpha 2- and beta 2-adrenoceptor activation elicits [45Ca2+] uptake by platelets. It is proposed that this stimulated [45Ca2+] uptake does not reflect changes in cytosolic Ca2+ but to localized changes of Ca2+ at the plasma membrane, possibly associated with receptor activation, per se. The respective increase and decrease of alpha- and beta-adrenoceptor activity in platelets from anorectic patients is in accord with other reports of changes of adrenoceptor number and type in platelets and other cells from anorectic patients. There may also be an increase in calcium channel activity in platelets from anorectics.

Adolescent↗
PubMed1991

Effects of dietary fatty acids in an animal model of focal glomerulosclerosis.

The obese Zucker rat develops hyperlipidemia, proteinuria and focal glomerulosclerosis without prior changes in renal hemodynamics. To study the effects of oral fatty acid intake on the development of renal injury in this model, rats were fed standard chow or chow supplemented with either 14% fish oil or 14% beef tallow after unilateral nephrectomy at the age of 10 weeks. At 32 weeks post-nephrectomy animals were sacrificed and renal tissue saved to assess histology and glomerular eicosanoid production. Fish-oil treated rats had lower mean plasma cholesterol levels and developed less proteinuria than control or tallow-fed animals although there was no difference in plasma creatinine or blood pressure. Histological analysis showed significantly fewer sclerosed glomeruli in the fish oil group (4.0 +/- 0.8% vs. control 19.4 +/- 4.1%, P less than 0.0005 and vs. beef tallow 10.8 +/- 1.9%, P less than 0.005). Glomeruli derived from rats on fish oil supplements produced smaller amounts of prostaglandin (PG)E2 and of the stable metabolites of PGI2 (6-oxo-PGF1 alpha), PGF2 (PGF2 alpha) and thromboxane (TX)A2 (TXB2) than those from tallow-fed animals. This study demonstrates that oral fatty acid intake may influence the development of glomerulosclerosis. The apparent beneficial effects of fish oil have not been fully defined, but may relate to favorable changes in plasma lipid concentration and renal eicosanoid production.

Animals↗
PubMed1991

Intraplatelet serotonin, beta-thromboglobulin, and histamine concentrations and thromboxane A2 synthesis in renal disease.

Intraplatelet serotonin (5-HT), beta-thromboglobulin (beta-TG), and histamine content as well as platelet total thromboxane A2 (TXA2) synthesizing capacity were measured in 53 patients with chronic renal disease: nephrotic syndrome (n = 18); end-stage renal failure (ESRF; n = 13); continuous ambulatory peritoneal dialysis (CAPD; n = 9); hemodialysis (HD; n = 13). These indices of platelet function were correlated with plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations. When compared with controls, intraplatelet 5-HT was significantly reduced in all patient groups studied and beta-TG was diminished in all patient groups except CAPD. Total platelet TXA2 synthesizing capacity was increased in ESRF and HD groups. Intraplatelet histamine content was not altered in any of the patient groups studied. There was a significant inverse correlation between intraplatelet 5-HT content on the one hand and plasma TC, LDL-C, and TG on the other. The depletion of intraplatelet 5-HT and beta-TG and the increase in total TXA2 synthesizing capacity are consistent with platelet activation in chronic renal disease. The correlation between these indices of platelet activation and TC, LDL-C, HDL-C, and TG suggests that changes in the concentrations of these lipids may contribute to the activation of platelets in these conditions.

Adolescent↗