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Biomedical subjects

C Patrono

Publications and source records attributed to C Patrono.

At least 109 records · Page 6Linked to original sources
PubMed1991

Proarrhythmic activity of intracoronary endothelin in dogs: relation to the site of administration and to changes in regional flow.

The endothelium-derived peptide, endothelin, has been shown to exert powerful constrictor activity in both isolated and in situ coronary arteries. Recent in vitro data on isolated cardiac myocytes suggest that the substance might also possess electrophysiologic properties. We investigated the possibility that endothelin (ET-1) may exert proarrhythmic effects when infused selectively in the coronary circulation of open-chest-anesthetized dogs. Animals were instrumented for the measurement of left anterior descending (LAD) or left circumflex (LCX) coronary artery blood flow, left systolic ventricular pressure (LSVP), dP/dtmax, mean arterial pressure (MAP), and epicardial electrocardiogram (ECG; three leads). Data were recorded during infusion (2 min) of saline (n = 5) or increasing doses of endothelin (5-80 pmol/kg) given selectively in either the LCX (n = 10) or the LAD (n = 10). When infused into the LCX, endothelin produced a dose-dependent decrease in flow (40 +/- 23% at 80 pmol/kg, mean +/- SD, p less than 0.01) with a concomitant increase in coronary resistance and a decrease in dP/dtmax and MAP. ECG changes typical of myocardial ischemia paralleled the decrease in flow and culminated in ventricular fibrillation at the highest dose (80% of dogs). Endothelin caused similar hemodynamic effects when infused in the LAD, but fatal arrhythmias occurred for lower doses and for little or no change in coronary blood flow. Thirty percent of the animals died at 10 and 60% died at 20 pmol/kg, doses that induced only a moderate decrease (8 +/- 7 and 21 +/- 12%, respectively) in LAD total blood flow. Ventricular tachycardia always preceded ventricular fibrillation and death.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Dyslipoproteinemia in an inbred rat strain with spontaneous chronic progressive nephrotic syndrome.

Rats of the Milan Normotensive Strain (MNS) develop a dyslipoproteinemia that is associated with a spontaneous, age-dependent and slowly progressive nephropathy characterized by proteinuria and hypoalbuminemia (nephrotic syndrome). We assumed that the MNS strain might be a suitable model for studying the features of nephrotic dyslipoproteinemia and its relationship with proteinuria, hypoalbuminemia, and hepatic apolipoprotein production. Plasma lipoproteins were investigated in MNS rats at various ages (4-48 weeks) and in another rat strain (Milan Hypertensive Strain, MHS), genetically related to MNS but free of nephropathy, that was used as control. In MNS rats, abnormal proteinuria was detectable at 20 weeks and increased 2-fold up to 34 weeks with no reduction of plasma albumin (compensated stage). During this stage we found increased levels of plasma cholesterol (+ 34%), high density lipoprotein-1 (HDL1) (+ 73%), and HDL2 (+ 31%) that were positively correlated with proteinuria but not with plasma albumin. The later stage (34-48 weeks) (nephrotic stage) was characterized by a further increase of proteinuria, moderate hypoalbuminemia (- 25%), a 2-fold increase of plasma cholesterol, triacylglycerols, low density lipoprotein (LDL), and HDL1, and a 1.2-fold increase of HDL2. In this stage the levels of LDL, HDL1, and HDL2 were positively correlated with proteinuria, and negatively correlated with plasma albumin. The most striking change in apolipoproteins was a progressive increase of the relative content of apoA-I in HDL (in 48-week-old MNS rats the A-I/E ratio was 3-fold that found in MHS rats) that was associated with a similar increase of plasma apoA-I. None of these lipoprotein changes were observed in age-matched MHS rats. At the end of the compensated stage, the hepatic levels of A-I, B, A-II, and albumin mRNA were 5.3-, 3.5-, 1.3-, and 2.0-fold, respectively, those found in age-matched MHS rats. During the nephrotic stage, albumin mRNA continued to increase, whereas A-I, B, and A-II mRNAs decreased toward the levels found in age-matched MHS rats. Thus, nephrotic dyslipoproteinemia in MNS rats starts to develop in the compensated stage before the onset of hypoalbuminemia, is characterized by an early elevation of HDL1 + HDL2, and is associated with an increased content of hepatic mRNAs of some apolipoproteins, especially apoA-I. The slow progression of nephrotic syndrome with the long-standing proteinuria and no reduction in plasma albumin renders the MNS strain the most suitable animal model for the study of the effect of proteinuria on plasma lipoprotein metabolism.

Albumins↗
PubMed1990

Effects of racemic, S- and R-indobufen on cyclooxygenase and lipoxygenase activities in human whole blood.

Racemic indobufen inhibits human platelet aggregation by reducing thromboxane (TX) A2 biosynthesis. In order to ascertain which of the two optical isomers is responsible for its pharmacological activity, we compared the effects of racemic (SR +/-), S(+) enantiomer and R(-) enantiomer indobufen on cyclooxygenase and 5-lipoxygenase activities by assessing the biosynthesis of TXB2, prostaglandin (PG) E2 and leukotriene (LT) B4 in human whole blood stimulated with the Ca2+ ionophore A23187. Racemic indobufen caused a dose-dependent inhibition of TXB2 and PGE2 production (IC50: 0.53 +/- 0.06 and 0.34 +/- 0.02 micrograms/ml, respectively; mean +/- S.D., n = 4). S-Indobufen was approximately 2-fold more potent than the racemate in inhibiting the synthesis of cyclooxygenase products. R-Indobufen affected the same enzyme but only at considerably higher concentrations (IC50: 53 +/- 8 micrograms/ml, n = 3). Serum LTB4 concentrations were significantly reduced only at indobufen concentrations greater than 50 micrograms/ml. In conclusion, indobufen is a selective inhibitor of the cyclooxygenase activity of platelet PGG/H synthase in a concentration range corresponding to the therapeutic plasma levels in man. This inhibitory effect is largely due to the S isomer of the drug.

Adult↗
PubMed1990

Thromboxane biosynthesis and platelet function in type II diabetes mellitus.

It has been suggested that platelet hyperreactivity in patients with diabetes mellitus is associated with increased platelet production of thromboxane. We therefore compared the excretion of a thromboxane metabolite and platelet function in 50 patients with Type II diabetes mellitus who had normal renal function and clinical evidence of macrovascular disease and in 32 healthy controls. The mean (+/- SD) excretion rate of urinary 11-dehydro-thromboxane B2 was significantly higher in the patients than in the controls (5.94 +/- 3.68 vs. 1.50 +/- 0.79 nmol per day; P less than 0.001), irrespective of the type of macrovascular complication. Tight metabolic control achieved with insulin therapy reduced the levels of 11-dehydro-thromboxane B2 by approximately 50 percent. The fractional conversion of exogenous thromboxane B2 (infused at a rate of 4.5, 45.3, or 226.4 fmol per kilogram of body weight per second) to urinary 11-dehydro-thromboxane B2 was assessed in four patients, in whom it averaged 5.4 +/- 0.1 percent; this value did not differ from that measured in healthy subjects. Aspirin in low doses (50 mg per day for seven days) reduced urinary excretion of the metabolite by approximately 80 percent in four patients. The fact that thromboxane biosynthesis recovered over the following 10 days was consistent with a platelet origin of the urinary metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina.

A dynamic thrombotic process, coronary spasm or both can be responsible for recurrent episodes of transient reduction of coronary blood flow in unstable angina. We have investigated the temporal relationship between episodic platelet activation, as detected by increased urinary excretion of 11-dehydro-TXB2, and spontaneous myocardial ischemia, assessed by continuous electrocardiographic monitoring and recording in 21 patients with unstable angina pectoris. In order to validate measurements of metabolite excretion as a reflection of intracoronary platelet activation, we have also performed repeated urine sampling from 8 patients undergoing PTCA and from 6 patients with peripheral vascular disease. The latter showed a 16% coefficient of variation in 3 consecutive 8-h urine samples. 11-dehydro-TXB2 increased significantly, by up to 15-fold, in the 2.5- to 5.0-h urine collection encompassing PTCA and decreased by greater than 50% during the following 2-h period. Patients with unstable angina were characterized by episodic increases (greater than 2 SD of controls) in metabolite excretion, in successive 6-8 h specimens. Paired measurements of 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 15 urine samples did not reveal evidence of altered metabolic disposition of endogenously released TXB2. A total of 125 ECG ischemic episodes were recorded, of which 64% asymptomatic. We have compared these biochemical and ECG changes in patients randomized to i.v. low-dose aspirin or i.v. isosorbide dinitrate and oral diltiazem. Twenty-five of 56 (i.e. 45%) urine samples obtained in aspirin-free periods showed increased metabolite excretion as compared to 15 of 88 (i.e. 17%) samples collected during aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Thromboxane synthesis inhibitors and receptor antagonists.

The biochemical, functional and clinical consequences of thromboxane (TX) A2 synthesis inhibition and receptor antagonism are reviewed, with emphasis on human studies in health and disease. Both platelet and glomerular TXA2 synthesis and action are discussed as potential targets for cyclooxygenase inhibitors, TX-synthase inhibitors and TXA2-receptor antagonists. While Aspirin remains the reference standard for new agents aimed at suppressing TXA2-dependent platelet activation, both synthase inhibitors and receptor antagonists might have a unique therapeutic potential in affecting TXA2-dependent loss of renal function.

Cyclooxygenase Inhibitors↗
PubMed1990

The use of antiplatelet agents in glomerulonephritis: a pharmacological approach.

The use of antiplatelet agents in chronic glomerular disease is reviewed, with emphasis on drugs affecting thromboxane A2 synthesis or action. The results of short-term and long-term studies in human as well as animal models suggest a role for enhanced intrarenal synthesis of thromboxane A2, though not clearly defining the potential platelet vs glomerular targets of drug action. The availability of novel inhibitors and antagonists may provide new therapeutic strategies against thromboxane-A2-dependent loss of renal function.

Animals↗
PubMed1990

Biosynthesis and pharmacological modulation of thromboxane in humans.

Thromboxane (TXA2), a potent proaggregatory and vasoconstricting eicosanoid, is produced at a very low rate and is cleared rapidly from the human circulation. Its chemically stable hydration product, TXB2, is extensively metabolized through dehydrogenation of the hemiacetal alcohol group at C-11 and beta-oxidation, resulting in the formation of two main enzymatic derivatives (i.e., 11-dehydro-TXB2 and 2,3-dinor-TXB2). A large discrepancy exists between the platelet biosynthetic capacity and actual TXA2 production in vivo. This has both methodological and pathophysiological relevance. Platelet synthesis of TXA2 can be reduced by cyclooxygenase and thromboxane-synthase inhibitors. Furthermore, the platelet and vascular actions of TXA2 can be antagonized by prostaglandin H2/TXA2-receptor antagonists. The combined administration of a thromboxane-synthase inhibitor and a TXA2-receptor antagonist gives stronger inhibition of platelet aggregation and prolongs bleeding time more than either drug alone or acetylsalicylic acid. Finally, TXA2-dependent glomerular damage, as seen in lupus nephritis, might represent a unique therapeutic target for receptor antagonists and/or tissue-selective synthase inhibitors.

Aspirin↗
PubMed1990

Thromboxane biosynthesis in cardiovascular diseases.

Sudden fissuring of an atherosclerotic plaque has been suggested as the primary trigger of transient spontaneous ischemia in both the coronary and cerebral circulation. Measurements of urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2, as well as results of Aspirin trials, have suggested that episodic platelet activation at the site of this acute vascular lesion is mediated, at least partly, by enhanced thromboxane (TX) A2 biosynthesis. Thus, episodic increases in metabolite excretion have been detected in unstable angina. Aspirin (75-325 mg/day) prevents about one third of all fatal and nonfatal thrombotic events in this setting. That a similar "dynamic" thrombotic process occurs during the early phase of acute myocardial infarction is suggested by thromboxane metabolite measurements and by the results of the ISIS-2 trial showing a similar impact of short-term Aspirin therapy to that seen in unstable angina. Percutaneous transluminal coronary angioplasty is associated with transiently enhanced TXA2 biosynthesis and Aspirin-suppressable periprocedural thrombotic complications. On the other hand, both non-insulin-dependent diabetes mellitus and type IIa hypercholesterolemia are associated with a relatively reproducible and persisting abnormality of TXA2-dependent platelet function. This association is likely to reflect a systemic rather than localized stimulus to platelet activation and a continuous rather than episodic alteration. Low-dose (50 mg/day) Aspirin can largely suppress thromboxane metabolite excretion in both diseases. Thus, low-dose Aspirin and/or selective prostaglandin H2/TXA2-receptor antagonists may be important tools to test the hypothesis that TXA2-dependent platelet activation represents an important transducer of the enhanced thrombotic risk associated with these metabolic abnormalities.

Aspirin↗
PubMed1990

Comparison of low-dose aspirin and coronary vasodilators in acute unstable angina.

Episodic platelet activation has been shown to occur in unstable angina, and aspirin should have an important therapeutic role in the management of these patients. The response to aspirin alone or to aspirin in combination with vasodilators such as heparin and beta-blockers has been assessed in 41 patients with unstable angina. Therapy was added sequentially in the event of recurrence of transient myocardial ischemia. Patients were randomly assigned to two groups. Group 1 (21 patients) received an intravenous infusion of isosorbide dinitrate and oral diltiazem, and group 2 (20 patients) received intravenous aspirin (60 mg the first day and 20 mg on successive days). This dose of aspirin reduced serum thromboxane B2 from 160 +/- 88 ng/ml (mean +/- SD) to undetectable values (less than 6 ng/ml, p less than 0.01). If episodes of ischemic ST segment shift continued, the therapy of group 1 was added to that of group 2 or vice versa; if further ST segment changes were documented, intravenous heparin and oral beta-blockers were added; if episodes of myocardial ischemia persisted, urgent coronary arteriography and myocardial revascularization were performed. Nine patients in group 1 and six in group 2 (p = 0.8) had no further episodes of myocardial ischemia on their initial therapy; 12 additional patients had no further episodes when taking combined therapy of aspirin and vasodilators. Thus, the administration of aspirin alone was not superior to coronary dilators; 30% of all patients continued to have episodes of myocardial ischemia or had a myocardial infarction develop when heparin and beta-blockers were added. Myocardial infarction occurred in one patient on vasodilator therapy alone, in two on combined therapy, and in two on full therapy. These results suggest that in some patients, the stimulus to coronary thrombosis and vasoconstriction occasionally becomes so strong that it cannot be inhibited by certain antagonist drugs. The unstable tendency to continuation of ischemia or evolution to myocardial infarction is not related to the severity of the persisting stenosis. Those patients not promptly responding to combined therapy immediately from admission should have early coronary angiography and aggressive treatment.

Angina Pectoris↗
PubMed1989

Hemodynamic and tubular effects of endothelin and thromboxane in the isolated perfused rat kidney.

We have investigated the effects of the endothelium-derived peptide, endothelin, and of a chemically stable analog of thromboxane (TX) A2, U46619, on the glomerular hemodynamics and tubular function of isolated, perfused rat kidneys. Endothelin (10(-11)-10(-9) M) dose dependently decreased the renal plasma flow to a significantly greater extent than it did the glomerular filtration rate. In contrast, U46619 (10(-9)-10(-7) M) had more pronounced effects on the glomerular filtration rate than on the renal plasma flow. As a consequence, the filtration fraction was increased by endothelin and decreased by U46619. Endothelin, unlike U46619, enhanced urinary Na+ excretion and reduced oxygen consumption at concentrations that greatly decreased the tubular load, thus suggesting that it has a direct effect on tubular Na+ reabsorption. Addition of the TXA2/PGH2-receptor antagonist, BM13177 (4.10(-4) M), or the cyclooxygenase inhibitor, acetylsalicylic acid (10(-3) M), to the perfusion medium failed to modify the endothelin-induced increase in Na+ excretion or the reduction in renal plasma flow, whereas acetylsalicylic acid, but not BM13177, partially prevented the decrease in the glomerular filtration rate. These results demonstrate that two contractile agonists produced by the kidney have specific and differential effects on cortical and tubular functions. Moreover, the intrarenal production of eicosanoids does not appear to play a major role in the renal effects of endothelin.

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

Fractional conversion of thromboxane B2 to urinary 11-dehydrothromboxane B2 in man.

Thromboxane (TX) B2, the chemically stable hydration product of pro-aggregatory TXA2, undergoes two major pathways of metabolism in man, resulting in the formation of 2.3-dinor-TXB2 and 11-dehydro-TXB2, respectively. We have measured the excretion of the latter during the infusion of exogenous TXB2 over a 50-fold dose range in order to examine the fractional conversion of TXB2 to urinary 11-dehydro-TXB2 and to re-assess the rate of entry of endogenous TXB2 into the circulation. Four healthy male volunteers received 6-h intravenous infusions of the vehicle alone and TXB2 at 0.1, 1.0 and 5.0 ng.kg-1.min-1 in random order. They were pretreated with aspirin 325 mg/d in order to suppress endogenous TXB2 production. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured before, during and up to 24 h after the infusions and in aspirin-free periods, by means of NICI-GC/MS-validated radioimmunoassays. Aspirin treatment suppressed urinary 11-dehydro-TXB2 by 91%. The fractional elimination of 11-dehydro-TXB2 was independent of the rate of TXB2 infusion and averaged 6.8 +/- 0.7%, as compared to 6.4 +/- 0.9% for 2,3-dinor-TXB2. Interpolation of 11-dehydro-TXB2 values obtained in aspirin-free periods onto the linear relationship between the quantities of infused TXB2 and the amount of metabolite excreted in excess of control values (y = 0.0058x, r = 0.94, P less than 0.001) permitted calculation of the mean rate of entry of endogenous TXB2 into the circulation as 0.12 ng.kg-1.min-1. We conclude that: (a) urinary 11-dehydro-TXB2 is at least as abundant a conversion product of exogenously infused TXB2 as 2,3-dinor-TXB2; (b) its excretion increases linearly as a function of the rate of entry of TXB2 into the circulation up to approx. 40-fold the calculated rate of secretion of endogenous TXB2; (c) the latter is consistent with previous estimates based on monitoring of the beta-oxidation pathway of TXB2 metabolism.

Adult↗