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Biomedical subjects

H S Doktor

Publications and source records attributed to H S Doktor.

9 recordsLinked to original sources
PubMed1993

Thromboxane A2 receptor antagonism and synthase inhibition in essential hypertension.

Short-term effects of ridogrel, a combined thromboxane synthase inhibitor and receptor antagonist, were investigated in 16 patients with uncomplicated essential hypertension. After a 2-week placebo period without antihypertensive medication, patients were admitted to the hospital overnight on two occasions 3 weeks apart. On each occasion, they received two doses of either placebo or ridogrel (300 mg) 12 hours apart according to a double-blind crossover protocol. Renal and systemic thromboxane A2 and prostacyclin biosynthesis were investigated by measuring urinary excretion of thromboxane B2, 6-oxo-prostaglandin F1 alpha, and their respective 2,3-dinor metabolites using gas chromatography/mass spectrometry. Responses of platelets to a thromboxane A2 mimetic and to adenosine diphosphate were studied turbidometrically. Blood pressure was measured automatically at 20-minute intervals. Ridogrel reduced excretion of 2,3-dinor-thromboxane B2 and thromboxane B2 compared with placebo (21 +/- 6 versus 279 +/- 28 and 14 +/- 4 versus 39 +/- 9 ng/g creatinine, respectively; P < .0001 and P < .05). Excretion of 2,3-dinor-6-oxoprostaglandin F1 alpha and 6-oxoprostaglandin F1 alpha was increased by ridogrel compared with placebo (184 +/- 20 versus 146 +/- 11 and 86 +/- 9 versus 58 +/- 6 ng/g creatinine, respectively; P < .05). Ridogrel selectively antagonized platelet aggregation to the thromboxane mimetic (P < .0001). Blood pressure did not differ significantly between ridogrel and placebo treatment periods. Thus, in patients with essential hypertension, acute administration of ridogrel reduces renal and extrarenal thromboxane A2 biosynthesis, increases renal and extrarenal prostacyclin biosynthesis, inhibits thromboxane receptor-activated platelet aggregation, but has no effect on systemic arterial pressure.

Adult↗
PubMed1991

Vascular responsiveness and cation exchange in insulin-dependent diabetes.

1. We measured forearm blood flow during brachial artery infusions of vasoconstrictors (angiotensin II and noradrenaline) and vasodilators (sodium nitroprusside and carbachol) in 16 healthy control subjects and in 18 patients with uncomplicated insulin-dependent diabetes mellitus. Erythrocyte Na+/Li+ countertransport and platelet Na+/H+ antiport activities were also measured. 2. The mean basal forearm vascular resistance was 22% lower in diabetic patients than in control subjects. The effects of each infusion on forearm vascular resistance were similar in diabetic patients and control subjects. 3. Erythrocyte Na+/Li+ countertransport activities were similar in diabetic patients and control subjects. Platelet Na+/H+ exchange (Vmax) was approximately 40% greater in diabetic patients than in control subjects, whereas the Km for Na+ was similar. 4. In diabetic patients, but not in control subjects, the responses to sodium nitroprusside and carbachol correlated inversely with Na+/Li+ countertransport in erythrocytes (rs = -0.76, P less than 0.001, and rs = -0.66, P less than 0.005, respectively), but not with Na+/H+ exchange in platelets.

Adult↗
PubMed1991

Sodium dependence of sodium-proton exchange in platelets from patients with essential hypertension.

The sodium dependence of recovery of cytoplasmic pH (pHi) after an acid load was studied in platelets from 15 patients with untreated essential hypertension (mean arterial pressure 117 +/- 2.3 mmHg, mean +/- SE) and in 15 normotensive controls (mean arterial pressure 90 +/- 2.2 mmHg). Proton flux was measured in gel-filtered platelets loaded with pH sensitive fluorescent indicator. Sodium dependent proton efflux was prevented by 5 (N,N hexamethylene) amiloride, a potent inhibitor of sodium-proton exchange. The relationship between initial rate of proton efflux and extracellular sodium concentration obeyed Michaelis-Menten kinetics. The maximum initial rate of proton efflux was similar in hypertensive and normotensive subjects (1.93 +/- 0.35 mmol H+1/sec, mean +/- SE, and 1.88 +/- 0.26 mmol H+l/sec respectively). The Michaelis-Menten constant (the sodium concentration at which the initial rate of proton efflux is half maximal) was also similar in the two groups: 75.7 +/- 13.9 mmol/l and 8.15 +/- 10.6 mmol/l respectively. There was no significant correlation between either of these parameters and arterial blood pressure.

Adult↗
PubMed1991

On the mechanism of the prolonged action in man of GR32191, a thromboxane receptor antagonist.

Twenty four healthy men were treated with GR32191, a thromboxane receptor antagonist with a long duration of action, in a double blind placebo-controlled crossover study. Platelet aggregation in response to a thromboxane (TX) mimetic (U46619) was studied turbidometrically using platelet rich plasma (PRP) prepared 12 h after dosing (80 mg po) and 1.5 h after a second dose (40 mg po). To determine whether the long lasting inhibition caused by GR32191 is associated with persistent inhibitory activity in plasma (from residual drug or from an active metabolite), platelet poor plasma (PPP) from treated subjects was mixed with PRP from placebo treated controls. 12 h after dosing this caused 40-80% inhibition, consistent with the plasma concentration of GR32191. Inhibition of U46619 in PRP from GR32191 treated subjects mixed with PPP from controls was even greater (essentially 100%). We conclude that the prolonged activity of GR32191 is due in part to a reduction in available thromboxane receptors and in part to its persistence in plasma for longer than had previously been appreciated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Paradoxical effect of bicarbonate on cytoplasmic pH.

The effect of an abrupt rise in bicarbonate concentration on cytoplasmic pH was studied in human platelets suspended in a Tyrode's buffer. Addition of bicarbonate raised extracellular pH but simultaneously caused pronounced cytoplasmic acidification. This effect may be due to combination of bicarbonate with hydrogen ions in extracellular fluid to form carbonic acid, which is converted by carbonic anhydrase to water and carbon dioxide. Bicarbonate ions do not diffuse rapidly across cell membranes, whereas carbon dioxide is highly diffusible and can combine with water in the cytoplasm, forming carbonic acid and reducing the intracellular pH. In accord with this explanation cytoplasmic acidification by bicarbonate was antagonised by acetazolamide (an inhibitor of carbonic anhydrase). Cytoplasmic acidification could contribute to adverse effects of intravenous sodium bicarbonate in patients with severe acidaemia. These findings add weight to the body of opinion that such treatment is both illogical and dangerous.

Acetazolamide↗
PubMed1990

Effects of a selective thromboxane receptor antagonist (GR32191B) and of glyceryl trinitrate on bleeding time in man.

1. GR32191B is a potent and selective thromboxane receptor antagonist. Glyceryl trinitrate (GTN) also inhibits platelet function in vitro. Both have been reported to prolong bleeding time. Since they may be used together in patients with coronary artery disease, we have investigated the possibility of an interaction between them. 2. Twenty-four healthy male volunteers were treated with GR32191B using a double-blind placebo-controlled crossover design. Bleeding times were determined before and after GR32191B or placebo and during co-administration of GTN. Plasma GR32191B concentration was measured. Platelet aggregation in response to adenosine diphosphate and to a thromboxane mimetic, U46619, was measured ex vivo. Urinary excretion of thromboxane (TX)B2 and 2,3-dinor-TXB2 was determined in 24 h urine samples. 3. Twelve hours after GR32191B (80 mg; p.o.), the plasma concentration was 36.6 +/- 2.7 nM (mean +/- s.e. mean) and bleeding time was increased by 66%. Ninety minutes after a second dose (40 mg; p.o.) the plasma concentration was 431.9 +/- 23.6 nM but bleeding time was not further prolonged. 4. Responses of platelets to U46619 were selectively antagonised following GR32191B. Urinary excretion rates of TXB2 and 2,3-dinor TXB2 were similar after treatment with GR32191B or placebo. 5. GTN (1 mg sub-lingually) had no significant effect on bleeding time 90-100 min following either placebo or GR32191B. 6. We conclude that GR32191B, in a dose that causes profound yet specific blockade of thromboxane receptors, causes only a modest prolongation of bleeding time that is unaffected by a therapeutic dose of GTN. This may prove advantageous when GR32191B is used in patients with ischaemic heart disease.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.

1. Effects of a single intravenous dose of aspirin (600 mg) on bradykinin-stimulated prostaglandin (PG) and on thromboxane (TX) biosynthesis were determined in nine healthy male volunteers. Plasma concentrations of 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha were measured in samples obtained during repeated 10 min intravenous infusions of bradykinin before and up to 6 h after the dose of aspirin. TXB2 was measured in serum from blood allowed to clot at 37 degrees C. 2. Aspirin inhibited bradykinin stimulated PG and platelet TX biosynthesis 0.5 h after the dose. Serum TXB2 remained low, whereas PG synthesis recovered within 6 h. 3. Effects of intravenous sodium salicylate (600 mg) were studied identically in eight subjects. Prostanoid biosynthesis was not inhibited. 4. Biosynthesis of prostacyclin and TXA2 under basal conditions was studied in eight subjects by measuring 2,3-dinor-6-oxo-PGF1 alpha and 2,3-dinor-TXB2 in hourly urine samples obtained during and after intravenous infusion of aspirin and, on a separate occasion, of vehicle. 5. Aspirin infusion reduced urinary excretion of both metabolites greater than 90%, but excretion of 2,3-dinor-6-oxo-PGF1 alpha recovered more rapidly than did that of 2,3-dinor-TXB2. 6. We conclude that cyclo-oxygenase is rapidly synthesised in bradykinin-responsive tissues in vivo and that this reflects similarly rapid enzyme biosynthesis in tissues that produce PGI2 under basal conditions.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Actions of bradykinin and related peptides on rabbit coeliac artery rings.

1. Rabbit coeliac artery rings were mounted in tissue baths containing Krebs solution at 37 degrees C in order to determine whether their response to bradykinin is initiated by B1- or B2-receptors. Tension was recorded isometrically. 2. Phenylephrine contracted the tissue. Subsequent addition of bradykinin or des Arg10-kallidin caused relaxation which was not dependent on an intact endothelium. Des Arg10-kallidin, a B1-receptor selective agonist, was more potent than bradykinin. 3. [beta-Thienyl alanyl6,9, D-Phe8]-kallidin and [Leu9]-des Arg10-kallidin antagonized bradykinin and des Arg10-kallidin. [Leu9]-des Arg10-kallidin, a B1-receptor selective antagonist, was more potent than [Thi6,9, D-Phe8]-kallidin, a less selective drug that acts on both B1- and B2-receptors. 4. Kinin-induced relaxation was reversibly antagonized by ibuprofen (a cyclo-oxygenase inhibitor) and by 5-(N,N-hexamethylene)amiloride (an inhibitor of Na+/H+ exchange). Ibuprofen caused a parallel shift to the right of a semi-logarithmic plot of the agonist concentration-effect relationship, whereas the amiloride analogue depressed the maximum response and reduced the slope. 5. We conclude that bradykinin and des Arg10-kallidin relax rabbit coeliac artery by combining with B1-receptors. The response is mediated by a cyclo-oxygenase product and may be influenced by cellular Na+/H+ exchange.

Animals↗