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Biomedical subjects

A E Farah

Publications and source records attributed to A E Farah.

At least 19 recordsLinked to original sources
PubMed1989

Studies on the mechanism of action of the bipyridine milrinone on the heart.

Milrinone is a positive inotropic and vasodilator agent when tested in experimental animals and in human heart-failure patients. It is generally believed that milrinone acts by inhibiting phosphodiesterase IV, thus increasing cyclic AMP, [Ca++]i and cardiac contractile force and relaxation. Maximal force produced by milrinone is greater when single-dose response curves are compared to cumulative dose-response curves. In vitro, milrinone produces a tachyphylaxis, the extent of which is both dose- and time-dependent. Recovery of tachyphylaxis is both dose- and time-dependent and is not influenced by inhibitors of protein or RNA synthesis. There is a specific cross-tachyphylaxis between milrinone and amrinone, theophylline, papaverine, and Bay K8644. This tachyphylaxis may explain the low maximal contractile response of the cumulative dose-response observed in isolated tissues. Milrinone increased cyclic AMP in dog and guinea pig cardiac muscle. As previously shown by Endoh et al., milrinone in low doses produced a biphasic effect on cyclic AMP. The early increase (first 60-70 s) in cyclic AMP shows a good correlation with contractile force changes. If cyclic AMP is determined at maximal contractile force this correlation was poor. Here we also present instances where the increase in cyclic AMP after milrinone (determined at maximal effect) does not correlate with the contractile response. The cross-tachyphylaxis of milrinone with Bay K8644 suggests that milrinone has an action on the sarcolemmal Ca++ channels. Bay K8644 suppresses the positive inotropic effect of catecholamines by 50%, but not the cyclic AMP response. The inotropic effect of milrinone, in contrast to norepinephrine is highly sensitive to [Ca++]0, stimulation rate, and [K+]0. In this respect milrinone behaves more like Bay K8644. We postulate that the main inotropic action of milrinone is due to a sarcolemmal effect. The early cyclic AMP production described could be in the sarcolemmal compartment and this may explain some of the similarities of milrinone's actions with those of Bay K8644. The tachyphylaxis observed with the inotropic effect of milrinone does not extend to the decreases in relaxation time. This and other findings to be discussed suggest that the positive inotropic and reduction in relaxation time by milrinone depend on different mechanisms, possibly through differential compartmentalization of cyclic AMP.

Animals↗
PubMed1989

The role of cyclic AMP and the dihydropyridine-sensitive channels on the mechanism of action of milrinone (Corotrope).

Milrinone (Corotrope) increased cyclic AMP levels in dog guinea pig and rat cardiac muscle. A correlation between the increase in contractile force and cyclic AMP levels in dog ventricular trabeculae was obtained when measurements were made 60-70 s after the addition of milrinone. When cyclic AMP levels were determined at the time of maximal contractile response, only concentrations of milrinone 200-300 times the inotropic dose had any effects in elevating cyclic nucleotide levels. In dog Purkinje tissue and rat cardiac muscle, milrinone had minimal or no effects on contractile force but increased cardiac cyclic AMP levels. Sequential doses of milrinone to perfused guinea pig hearts resulted in severe tachyphylaxis to the inotropic activity of milrinone. However, under these conditions, milrinone was found to elevate cardiac cyclic AMP upon each administration. Furthermore, in this preparation, cross-tachyphylaxis between Bay K 8644 and milrinone was demonstrated. The mechanism of action of Bay K 8644, which acts on sarcolemmal Ca2+, is not mediated by increases in cyclic AMP. Following development of tachyphylaxis to Bay K 8644, in the guinea pig hearts, addition of milrinone results in no increases in contractile force but a significant increase in cyclic AMP levels. In all of the instances of tachyphylaxis, isoproterenol increased both contractile force and cyclic AMP. The data are discussed and we put forth the hypothesis that increased cardiac force due to milrinone is in part due to a direct or indirect action on sarcolemmal Ca2+ channels.

Animals↗
PubMed1989

Seroepidemiology of the human immunodeficiency virus in Lebanon. Preliminary evaluation.

In order to evaluate the prevalence of infection with the human immunodeficiency virus in Lebanon, serologic studies were performed in a group of 1406 individuals, of whom 397 belonged to high risk groups. There were 7 seropositive individuals in the high risk population. One additional patient who was known to have the acquired immunodeficiency syndrome was also positive. It appeared that among these eight persons, the virus was acquired either through sexual activity outside Lebanon or through transfusion of foreign blood products.

Blood Transfusion↗
PubMed1989

Clinical and serological study of the human immunodeficiency virus infection in a cohort of multitransfused persons.

A group of 64 multitransfused individuals with hemophilia or congenital hemolytic anemias were tested for antibodies against the human immunodeficiency virus. Thirty five of them were also evaluated clinically and their blood products supply was investigated. Only four hemophiliacs were found to be seropositive. The major risk factor that seemed associated with the acquisition of the virus was the transfusion of lyophilized factor VIII concentrate imported from the USA. A suggestion for control of transfusion associated infection and of contamination of hemophiliacs is presented.

Adolescent↗
PubMed1988

The effect of extracellular Ca2+ and related ions on the cardiac action of milrinone.

The biphasic single dose, dose-response curve of milrinone was sensitive to [Ca2+]0. At concentrations of 1.8 nM Ca2+ or less this biphasic response is observed but at [Ca2+]0 of 4.5 mM or more the dose response curve becomes monotonic. The inotropic response to milrinone in contrast to norepinephrine is highly sensitive to the extracellular [Ca2+]0. At low [Ca2+]0 of 0.15 mM milrinone could produce a negative inotropic effect. The positive inotropic effect of milrinone was proportional to [Ca2+]0 up to 2.7 mM. With [Ca2+]0 above 3.6 mM and low [Na+]0, the inotropic response to milrinone was reduced. These effects were due to increased [Ca2+]i and not due to the increase in contractile force produced by Ca2+. The positive inotropic effect of milrinone in contrast to norepinephrine is increased with an increase in [K+]0 possibly due to the depolarization produced by K+. The positive inotropic response to 10 micrograms of milrinone when [Ka+]0 = 4 mM was not significantly changed by Ca2+ channel blocking agents. In depolarized tissue (20 mM K+) the electropharmacological and contractile effects of milrinone are blocked by verapamil and ruthenium red. This suggests that under these conditions different mechanisms of Ca2+ channel activation are operative. Substitution of Sr2+ for Ca2+ increased contractile force and prolonged time to peak tension and relaxation time. Milrinone decreased time to peak tension but had no detectable effect on relaxation time. The results are discussed and it is suggested that milrinone acts on Ca2+ channels in the sarcolemma and intracellularly by increasing cyclic AMP which activates Ca2+ release and uptake from the sarcoplasmic reticulum.

Action Potentials↗
PubMed1987

Effect of milrinone (Corotrope) on the contractility of isolated dog ventricular muscle.

The bipyridine milrinone (Corotrope) is a new positive inotropic agent for treatment of congestive heart failure. The dose-response curves on electrically paced isolated dog ventricular trabeculae on contractile force were determined with single as well as cumulative dosages of milrinone. These dose-response curves differed both quantitatively and qualitatively. The "single-dose, dose-response" curve shows a flattening out in the dosage range of 1-5 micrograms/ml, which was followed by a second "single-dose, dose-response" curve between 5-50 micrograms milrinone/ml bathing fluid. The maximal response obtained at 50 micrograms/ml with the single dose-response was 1.44 +/- 0.15 g (132 +/- 9%), while with the cumulative dose-response maximum contractile change attained at 1 microgram/ml was 0.58 g (40 +/- 7%). This difference is possibly due to the tachyphylaxis produced by the first dose of milrinone which reduced the effects of the second dose. The biphasic dose-response to milrinone was converted to a monophasic one by raising [Ca2+] from 1.8-4.5 mM. A statistical analysis of the single-dose, dose-response curve was conducted by applying a third-degree polynomial fitted by least squares; the curve gave a statistically significant fit with the experimentally obtained data. This suggests that the plateau observed is not due to random variation and that the single-dose, dose-response curve consists of at least two portions. This point was further substantiated by showing that the Ca2+ channel blockers had an effect on the low dosages of milrinone (less than 2.5 micrograms/ml) but had no significant effect on the dosages above 5 micrograms/ml. Milrinone increases the rate of relaxation and decreases the time for 50 and 90% relaxation. The data suggest that milrinone may act on two different types of calcium channels.

Animals↗
PubMed1986

Historical perspectives on inotropic agents.

Although early experiments in animals and humans suggested that digitalis glycosides increased cardiac output only in the failing heart, later studies showed that these cardiotonic agents increase intraventricular systolic pressure and decrease relaxation time in the normal animal. The controversy concerning the peripheral vascular or direct cardiac effects of digitalis was finally resolved when new methods were applied to the study of the effects of this drug on intraventricular pressures and cardiac contractile force. Other positive inotropic agents, such as the adrenergic agonists, have also been tested for the treatment of heart failure. However, during long-term oral or intravenous therapy, the effectiveness of these drugs appears to diminish. Clinical studies of glucagon, a polypeptide with positive inotropic and chronotropic effects, have revealed its potential for causing side effects and its reduced activity in patients with chronic heart failure. With the discovery of several new types of inotropic agents, i.e., the bipyridines and the imidazole and benzimidazole derivatives, interest in revising our therapeutic approach to congestive heart failure has increased. This review discusses recent developments in this area.

Alkaloids↗
PubMed1983

Glucagon and the circulation.

Glucagon is a vasodilator substance that reduces blood pressure via a decreased vascular resistance in the splanchnic and hepatic vasculature. Species differences in the response of various vascular beds to glucagon have been documented. In the kidney, glucagon in relatively large doses increased renal plasma flow, glomerular filtration, and electrolyte excretion. It has been shown that intraarterial injection of glucagon into the renal artery can produce an increase in electrolyte excretion on the side that received an injection with minimal or no changes in glomerular filtration. This indicated a direct tubular effect of this polypeptide. This effect may be related to the increased glomerular filtration observed in poorly controlled diabetics where insulin concentrations are low and glucagon concentrations are high. The tubular effects of glucagon are probably mediated via cAMP and prostaglandin formation in renal tubular cells, especially the ascending limbs of Henle and collecting ducts. Glucagon increases the RNA concentration in glomerular tissue, and this effect is probably independent of cAMP. The latter effect of glucagon has been related to the glomerular enlargement and membrane thickening observed in poorly controlled insulin-dependent diabetics. Starvation natriuresis has been related to increased concentrations of glucagon in blood. The likely mechanism is that glucagon increased the renal excretion of organic acids, possibly by inhibiting the renal tubular reabsorption of these acids. Little is known concerning the effects of glucagon on the cAMP content of vascular smooth muscle. Indirect evidence suggests that such effects may be mediated via the production of cAMP. If this can be established, it would be likely that the glucagon-induced vasodilation is due to a cAMP-dependent phosphorylation of the myosin light chain kinase. This kinase shows reduced sensitivity to the Ca++ calmodulin complex when it is phosphorylated by the cAMP-dependent kinase and thus may produce relaxation of smooth muscle. In cardiac muscle, glucagon produced positive inotropic and chronotropic effects. These effects show species differences and in some species activate only the auricle with minimal effects of ventricular muscle. The effects of glucagon in general resemble those of a beta-adrenergic agent; however, glucagon seems to be nonarrhythmogenic in a variety of cardiac preparations and its effects are not blocked by propranolol. In some of these experimental conditions the chronotropic effects of glucagon play an important role in the antiarrhythmogenic effects, although direct cardiac membrane effects have been postulated. Several factors can modify the

Adenylyl Cyclases↗
PubMed1980

Potential therapeutic applications of aspirin and other cyclo-oxygenase inhibitors.

1 The ubiquitous actions of the cyclo-oxygenase inhibitors are described. 2 These include the inhibitory effect on prostaglandin synthesis and the direct effect of aspirin on lymphocytes and their ability to produce lymphokines. 3 Aspirin reduces some types of platelet aggregation possibly involving inhibition of the precursors of thromboxane A2 and prostacyclin. 4 The therapeutic implications in relation to transient ischaemic attacks, coronary artery disease and reno-allograft rejection are discussed. 5 The beneficial and adverse effects on the gastro-intestinal tract are described. 6 The effects of aspirin-like drugs on the genito-urinary tract are described with particular reference to their adverse effects on labour and their therapeutic effect on dysmenorrhoea.

Animals↗
PubMed1979

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

The cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, was investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-100 microgram/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 microgram/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na+, K+-activated ATPase.

Adenosine Triphosphatases↗
PubMedDate not supplied

Electrophysiological actions of amrinone in dogs with cardiac lesions.

We examined the actions of amrinone in five models using dogs to determine under what circumstances intravenous amrinone might exert arrhythmogenic or antiarrhythmic properties. In dogs with 24-h post-coronary artery ligation arrhythmias, amrinone, given at incrementally increasing doses of 1.5, 3.0, and 6.0 mg/kg at 30-min intervals, produced significant increases of cardiac contractility without altering the severity of the arrhythmia. In dogs with 2- to 6-day-old ischemic lesions and 90-100% sinus beats, a bolus dose of 3.0 mg/kg amrinone was followed by an increased incidence of abnormal beats (p = 0.013); neither 1.5 nor 6.0 mg/kg caused a significant incidence of arrhythmias. Acute occlusion of the left anterior descending coronary artery followed by reperfusion caused fibrillation in nine of 15 control dogs and two of 14 dogs treated with 2.3 mg/kg amrinone. This difference was significant at the level p less than 0.05. In ouabain-intoxicated dogs, amrinone at 1.0 and 3.0 mg/kg neither worsened nor improved the arrhythmias. In the atrial circus flutter arrhythmia, amrinone increased ventricular heart rate by a significantly greater amount than it increased atrial rate, suggesting that amrinone facilitates atrioventricular conduction.

Aminopyridines↗
PubMedDate not supplied

The effect of milrinone (Win 47203) on the in vitro electropharmacological properties of mammalian cardiac tissue.

The electropharmacological effects of milrinone (Win 47203), a new positive inotropic agent of the bipyridine class, were studied on dog and guinea pig cardiac muscle by means of microelectrode techniques. In dog Purkinje fibers perfused with a Krebs solution containing 4 mM K+, milrinone did not produce any changes in action potential configuration. However, rate of discharge from spontaneously active Purkinje fibers was increased by milrinone. In dog auricular and ventricular trabeculae, milrinone increased action potential amplitude, overshoot, and phase 2 of the action potential. The duration of the action potential and the effective refractory period were decreased. In guinea pig papillary muscle, the changes in the action potential produced by milrinone consisted of a slight increase in overshoot and a reduction in the duration of the action potential. Dog Purkinje fibers depolarized with 20 mM K+ did not respond to milrinone. When such depolarized Purkinje tissue was treated with norepinephrine, slow action potentials appeared, and these could be increased by milrinone. Depolarized dog trabeculae were quiescent and addition of milrinone produced a slow action potential; the amplitude, rate of depolarization, and duration of the slow action potentials were dependent on the milrinone concentration. In depolarized guinea pig papillary muscles, milrinone induced dose-dependent slow action potentials and contractions which could be reversed on washing. Preexisting slow action potentials induced by tetraethylammonium plus high [Ca]o were potentiated by milrinone in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗