Effects of lidocaine, codeine and vadocaine hydrochloride on platelet aggregation in human platelet-rich plasma.

Lidocaine and vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine), which is structurally related to lidocaine, inhibited the second phases of human platelet aggregation induced by adenosine diphosphate (ADP, 10 mumol/l) or epinephrine (10 mumol/l) and partly aggregation induced by collagen (2.5 micrograms) at concentration relevant to local anesthetic action (0.1-1.0 mmol/l). Codeine was effective at slightly higher concentrations. The concomitant formation of thromboxane B2 (TXB2) was inhibited at similar concentrations. The aggregation induced by arachidonic acid (200 mumol/l) and the first phases of ADP (10 mumol/l)- or epinephrine (10 mumol/l)-induced aggregations were inhibited by all the compounds at the concentrations 1-10 mmol/l, codeine being the most potent inhibitor. The only exception was vadocaine, which inhibited the first phase of epinephrine-induced aggregation at concentrations greater than or equal to 0.25 mmol/l. Vadocaine may possess a2-adrenergic blocking activity. At low concentrations (less than or equal to 0.1 mmol/l), all the compounds stimulated/tended to stimulate the second phase of ADP-induced aggregation and concomitant formation of TXB2. They strongly stimulated TXB2 formation induced by exogenous arachidonic acid even at concentrations causing inhibition of aggregation. Codeine was the most and vadocaine the least potent in this respect. Lidocaine as well as vadocaine (0.1 mmol/l) and codeine (1.0 mmol/l) potentiated the antiaggregatory effect of dibutyryl-cyclic AMP (dB-cAMP) on the ADP-induced aggregation. Lidocaine (0.1 mmol/l) and codeine (1.0 mmol/l) similarly potentiated the effect of the adenylate cyclase stimulator prostaglandin E1 (PGE1).

Effects of vitamin E therapy on ethanol-induced changes in platelet aggregation, thromboxane formation, factor VIII levels and serum lipids.

A transient increase in platelet thromboxane formation has been observed in non-alcoholics during acute ethanol intoxication and in alcoholics shortly after ethanol withdrawal. Whether these effects are related to the generation of free radicals and lipid peroxidation was investigated by using vitamin E as a free radical scavenger and inhibitor of lipid peroxide formation. The results demonstrate that a high dose of vitamin E (1800 IU) taken daily by non-alcoholic men slightly (P less than 0.05) decreases aggregation-associated platelet thromboxane formation during ethanol oxidation. Likewise, vitamin E prevents the ethanol-induced increase (P less than 0.01) in factor VIII coagulant activity. These observations suggest that the enhancement of platelet thromboxane formation and factor VIII coagulant activity by acute ethanol ingestion may be related to stimulated lipid peroxidation. By contrast, similar effects of vitamin E were not found in alcoholics shortly after ethanol withdrawal suggesting other mechanisms for their platelet hyperreactivity.

Platelet thromboxane formation and bleeding time is influenced by ethanol withdrawal but not by cigarette smoking.

Platelet count, mean volume, aggregation and associated thromboxane (TXB2) formation, circulating platelet aggregates and bleeding time were examined in 19 noncirrhotic male alcoholic cigarette smokers for four weeks following cessation of prolonged heavy drinking, and in 24 nonalcoholic healthy male volunteers (10 smokers and 14 nonsmokers). The alcoholics showed a 9-fold increase (p less than 0.001) in ADP-stimulated platelet thromboxane formation one to two weeks after ethanol withdrawal. The effect was transient and coincided with a significant (p less than 0.01) shortening of skin bleeding time and a slight increase in circulating platelet aggregates suggesting proneness to thrombosis. No differences were seen between the smoking and nonsmoking healthy volunteers. We conclude that the recovery phase after prolonged heavy drinking is characterized by a transient increase in platelet reactivity which may lead to increased spontaneous formation of circulating platelet aggregates and shortening of bleeding time.

Effects of ethanol on platelet function.

To obtain evidence for an ethanol mediated disruption of hemostasis we compared the effects of acute and chronic ethanol ingestion on platelet reactivity. Since ADP may be important for hemostasis in vivo it was used to induce platelet aggregation in platelet-rich plasma. Thromboxane B2 (TXB2) formed during the aggregation was measured by radioimmunoassay. Ethanol (1.5 g/kg) given to 8 healthy non-alcoholic male volunteers increased platelet reactivity to ADP and the associated TXB2 formation rose from 289 +/- 60 (mean +/- SE) to 984 +/- 263 fmol/10(7) platelets (p less than 0.025). The effects lasted for as long as ethanol was present in blood. In 13 non-cirrhotic male alcoholics the withdrawal of ethanol caused a 4-fold increase in TXB2 formation within one week but the basal levels before ethanol withdrawal were the same as in controls. These findings are discussed in relation to the higher risk of brain infarction seen in alcoholics and even associated with binge drinking. Further studies are needed to establish the effects of ethanol on prostacyclin formation.

Acute ethanol ingestion increases platelet reactivity: is there a relationship to stroke?

The effects of ethanol ingestion on ADP-induced platelet aggregation and associated thromboxane formation were studied in the platelet-rich plasma of 10 healthy male volunteers, each serving as his own control. Ethanol caused a transient decrease in threshold concentration of ADP to produce irreversible aggregation. Over a wide range of ADP total platelet aggregation was increased. In the presence of irreversible aggregation, formation of thromboxane B2 rose from 303 +/- 56 to 950 +/- 212 fmol per 10(7) platelets (p less than 0.01). The effects lasted as long as ethanol was present in blood, did not significantly correlate to blood ethanol levels and exhibited great individual variation. It remains to be proved, whether these observations could contribute to the increased risk of ischemic brain infarction associated with acute ethanol ingestion.

Platelet aggregation and thromboxane B2 formation after ethanol abuse: is there a relationship to stroke?

Formation of thromboxane B2 (TXB2), a metabolite of the potent platelet-aggregating and vasoconstrictor agent thromboxane A2 (TXA2), during ADP-induced platelet aggregation was studied in 10 healthy men and in 10 male alcoholics during the 2-week period of detoxification. None of the alcoholics had anemia or thrombo-embolic disease. The platelets of the alcoholics were more sensitive for ADP and synthesized as much as triple the amount of TXB2 compared to those of the nonalcoholic donors. The effect was most striking during the rebound thrombocytosis and suggests that it could possible contribute to the increased incidence of various thrombotic diseases in the alcoholic.

TXA2-antagonistic properties of agents affecting prostaglandin synthesis or the cyclic nucleotide system in human platelets.

Prostaglandins (PG) E1 and E2 as well as 3-isobutyl-1-methylxanthine, nitroprusside, dibutyryl cyclic AMP and N-0164 inhibited platelet aggregation induced by the thromboxane (TX) A2-mimetic prostaglandin endoperoxide analogue U46619. Non-steroidal anti-inflammatory agents - acetylsalicylic acid, indomethacin, tolfenamic acid, flumizole, nictindole and proquazone - did not demonstrate any antagonistic actions on U46619-induced aggregation at concentrations causing inhibition of prostaglandin/thromboxane synthesis-dependent forms of platelet aggregation. Comparing with the effects of the different test substances on ADP-or arachidonic acid-induced platelet aggregation, it can be suggested that PGE2 as well as 3-isobutyl-1-methylxanthine, nitroprusside, and dibutyryl cyclic AMP are functional antagonists and N-0164 is a receptor level antagonist of TXA2 in platelets.

Effects of nonsteroidal anti-inflammatory drugs on rat gastric mucosal phosphodiesterase activity.

In the present study, the effects of acetylsalicylic acid, diclofenac, ibuprofen, indomethacin, naproxen, phenylbutazone, proquazone, fluproquazone (RF 46-790 N), sulindac (sulfoxide and sulfide forms) and tolfenamic acid were compared on rat gastric mucosal cyclic nucleotide phosphodiesterases (PDEs). Some of the drugs inhibited PDEs effectively, the Ki values being clearly lower than those of theophylline. Mostly the type of inhibition was apparently competitive. Acetylsalicylic acid and ibuprofen were ineffective. No unambiguous correlation between the inhibition of mucosal PDEs and clinically observed gastric irritation was found. However, the inhibition of PDEs may modulate gastric side-effects of NSAIDs.

Effects of ethanol intoxication and hangover on plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha and on thromboxane B2 formation by platelets in man.

We detected a significant decrease in plasma thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels together with a significant increase in plasma 6-keto-PGF1 alpha/TXB2 ratio in young healthy non-alcoholic male volunteers after acute ingestion of ethanol (1.5 g/kg). Paradoxically, during ethanol intoxication and the following hangover a significant increase in ADP-induced formation of TXB2 by the platelet rich plasma could be observed, which suggests that ethanol intoxication via some unknown mechanism sensitized platelets to produce TXB2. Whether these observations contribute to the increased risks of subarachnoid haemorrhage or ischaemic brain infarction among occasional heavy drinkers recently described by us remains to be proved.

Effects of prostaglandins on rat cardiac adenylate cyclase.

A significant stimulatory action of PGE1 on adenylate cyclase of the particulate membrane preparation of rat heart was observed at 1 X 10(-4) M. PGE1 caused a positive inotropic effect on isolated spontaneously beating rat atria 1 X (10(-5) M, and an increase in atrial cyclic AMP level at 1 X 10(-6) M. PGE2 stimulated the atrial but not the whole heart particulate adenylate cyclase. PGF 2alpha had no effect on these enzyme preparations. Our results suggest that: (i) The inotropic response of isolated spontaneously beating rat atria to PGE1 may be connected with an increase in cyclic AMP level; (ii) the effect of prostaglandins on heart in vivo must be indirect, because the concentrations needed to stimulate isolated atria and particulate adenylate cyclase were high, compared with the doses effective in vivo.

Effect of carbenoxolone on phosphodiesterase and prostaglandin synthetase activities.

Carbenoxolone inhibited in vitro cAMP and cGMP phosphodiesterases in a concentration-dependent and noncompetitive manner. Prostaglandin synthetase activity of rabbit kidney medulla was slightly stimulated by carbenoxolone 0.1--0.5 mM, but inhibited by higher concentrations.

The role of cyclic nucleotides and prostaglandins in heart function.

A short review of the role of cyclic nucleotides and prostaglandins (PGs) in normal and pathological functions of the heart is given. Possible interrelationships of these two regulatory systems have been studied by using spontaneously beating rat atria preparations. Addition of noradrenaline (NA) to the incubate (1 . 10(-6) M) caused an increase in amplitude and frequency which was preceded and parallelled by an elevation of the tissue cAMP level. A transient increase in cGMP and PGE values was also seen. Propranolol (5 . 10(-6) M) abolished the increase in amplitude and frequency as well as in cAMP and PGE concentrations. Indomethacin (1 . 10(-5) M) inhibited the formation of PGE. The increase in cGMP was blocked by phenoxybenzamine. Interchange between beta- and alpha-receptors according as the temperature is lowered has been described earlier. Hypothermia (20 degrees C) had a positive inotropic effect on the atria and increased the tissue cAMP concentration. Loading of the atria caused an increase in cAMP without any effects on cGMP or PGs. Slight hypoxia did not change the cAMP or PG levels, but elevated the cGMP values. Arrhythmias induced by hypo- or hyperpotassemia did not modify the biochemical parameters measured. PGF2alpha (1. 10(-5) M) normalized the atrial rhythm and increased the amplitude without changing cyclic nucleotide or PG levels. PGE1 (1 . 10(-4) M) increased the amplitude of normorhythmic atria and the tissue concentration of cAMP. PGE2 was the only PG tested which stimulated the heart adenylate cyclase in vitro. There seems to be close but complicated relationships between cyclic nucleotides and PGs in the heart.