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1. The present study investigated the in vitro effect of dopamine on platelet responses in healthy subjects. 2. Dopamine concentrations over 5 mumol/L induced a primary aggregating response and a slight release of alpha-granule proteins, beta-thromboglobulin and platelet factor-4 in all subjects. In 25% of investigated subjects a delayed secondary aggregation was observed with dopamine concentrations over 100 mumol/L. 3. Low dopamine concentrations (5-7.5 nmol/L) increased the platelet sensitivity to other aggregating agents (adenosine diphosphate, collagen and sodium arachidonate). The effect of subaggregating concentrations of serotonin was potentiated by dopamine. 4. The effect of dopamine on platelet responses was prevented by low concentrations of alpha-adrenoceptor antagonists (phentolamine and yohimbine); antagonists of dopamine receptors (haloperidol and domperidone) were able to decrease the extent of the dopamine-induced secondary aggregating wave in the responders, but they failed to prevent the primary aggregation and the effects on platelet response to other aggregating agents. 5. The present data demonstrated that the effects of dopamine on human platelets are mainly mediated by interactions with alpha-adrenoceptors.

We investigated the influence of insulin on human polymorphonuclear leukocyte (PMN) chemotaxis induced by mediators in a microchamber assay. Insulin increased, with a dose-response relationship, chemotaxis induced by formyl-methionyl-leucyl-phenylalanine, calcium ionophore and phorbol-miristyl acetate (p = 0.0057, p = 0.0001 and p = 0.0215, respectively). The hormone effect was present also at the physiological concentration of 40 microU/ml. Our data show that insulin affects PMN activity in normal subjects and therefore support the hypothesis that insulin deficiency may be responsible for the impaired PMN function observed in diabetic patients in poor metabolic control.

The European NIDDM Policy Group classifies both fasting and post-prandial blood glucose concentrations into 'good', 'acceptable', and 'poor' categories. The aim of the present study was to evaluate whether a 'good' fasting blood glucose concentration in Type 2 diabetic patients on diet or diet + oral hypoglycaemic agents is able to predict 'good' blood glucose values throughout the day, and therefore to discover whether or not it is necessary to perform blood glucose profiles in Type 2 diabetic patients when their fasting value is 'good'. Capillary blood glucose profiles (n = 417) were measured in 287 Type 2 diabetic patients, on diet alone (279 profiles), or on diet + tablets (138 profiles). We observed that 66% of profiles on diet and 44% of profiles on diet + tablets had only 'good' blood glucose concentrations (p less than 0.001). Eleven percent of profiles on diet and 30% of profiles on diet + tablets included 'poor' blood glucose concentrations (p less than 0.001). Despite matched fasting blood glucose concentrations (diet 5.69 +/- 0.04 (+/- SE) vs tablets 5.75 +/- 0.05 mmol l-1), levels were higher in the diet + tablet treated patients at all later time-points (p less than 0.01-0.001). HbA1c was significantly higher in tablet-treated patients than in patients on diet alone (6.6 +/- 0.1 vs 5.9 +/- 0.1%, p less than 0.001), and correlated with the mean blood glucose concentration (r = 0.43, p less than 0.001) but not with the fasting glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

1. This study investigated the influences of calcium-channel blocking agents verapamil and diltiazem on platelet responses induced by arginine vasopressin (AVP) and lysine vasopressin (LVP). 2. The substances inhibited platelet aggregation induced by both low and high AVP concentrations, LVP and adrenaline plus AVP. IC50 values of each drug are lower than those determined for ADP- and collagen-elicited aggregation. Verapamil and diltiazem also decreased AVP-induced thromboxane B2 synthesis. 3. Other series of experiments showed that the addition of ethyleneglycol-bis-(beta-amino-ethyl ether) N, N'-tetra-acetic acid to platelet-rich plasma samples also prevented the platelet response to vasopressin polypeptides. 4. Our data provide evidence that the effects of verapamil and diltiazem on vasopressin-induced platelet responses may be directly related to inhibition of extracellular calcium entry.

The present study evaluated the effects of the calcium-channel blocking agent diltiazem on platelet aggregation and on synthesis of thromboxane B2 (the stable metabolite of thromboxane A2) from platelet-rich plasma (PRP) and whole blood samples. Our results showed that diltiazem inhibits collagen- and thrombin-induced platelet aggregation and TXB2 production from PRP. Since no significant interference with conversion of arachidonate to thromboxane A2 was demonstrated, inhibition of phospholipase A2 activity may be the prevailing mechanism of the diltiazem effect. The drug demonstrated a dose-related inhibitory activity on TXB2 synthesis from whole blood samples during spontaneous clotting or following stimulation with collagen or thrombin. The present results give further evidences for an antiplatelet activity of diltiazem and support the hypothesis that inhibition of platelet function contributes to the therapeutic efficacy of this drug in the treatment of cardiovascular diseases.

The European NIDDM Policy Group states that the lowest target for good control of Type 2 (non-insulin-dependent) diabetic patients is a blood glucose level 4.4 mmol/l, both fasting and postprandially. The aim of this study is to evaluate the occurrence and temporal distribution of values under this target in the clinical records of 463 Type 2 diabetic patients, treated by diet or diet and oral hypoglycaemic agents, monitored for at least 2 years. The protocol includes blood glucose measurements after overnight fasting (08.00 hours), 120-150 min after breakfast (11.00 hours) and 120 and 240 min after lunch (14.00 and 16.00 hours). At least one blood glucose concentration of less than 4.4 mmol/l was presented by 42% of the patients. The only difference between patients showing and not showing glycaemic levels under this target was the higher percentage on oral hypoglycaemic agents in the first group (68.4% vs 56.9%, p = 0.016). We considered 299 blood glucose profiles containing at least one value of less than 4.4 mmol/l, observing that a) 46.9% of profiles from patients treated by diet alone and 68.7% of profiles from patients treated both by diet and oral hypoglycaemic agents presented the lowest blood glucose concentration at 16.00 hours (p = 0.002). b) No correlation existed between fasting blood glucose and values at 16.00 hours in profiles from diet-treated patients, whereas a negative correlation was present in patients on diet and oral hypoglycaemic agents, indicating that an excess of oral agents, administered to correct fasting hyperglycaemia, was the cause of the low glycaemic values in the afternoon.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a platelet defect characterised by absence of aggregation to adrenaline and lack of secondary aggregation to ADP and platelet-activating factor (PAF) in a male subject without a significant bleeding tendency. The platelets also exhibited a decreased response to the phorbol ester PMA and to vasopressin polypeptides. We obtained evidence that the defect did not involve the cyclooxygenase pathway and that it was not dependent on altered intraplatelet levels of cyclic AMP (cAMP). Furthermore, adrenaline-stimulated cAMP production was normal. Irreversible aggregation was obtained in response to a combination of two stimuli at subaggregating concentrations. This observation indicates that the lack of a bleeding tendency in this subject may be ascribed to subthreshold concentrations of agonists in vivo overcoming the defect to a single agonist.

1. The aim of the present study was to investigate the effects of phenothiazine compounds chlorpromazine and trifluoperazine on human platelet response to collagen and sodium arachidonate. 2. The results demonstrated that phenothiazines inhibit collagen-induced platelet aggregation and thromboxane B2 synthesis in a dose-dependent way and increase the antiaggregating properties of forskolin. 3. Phenothiazines at high concentrations decreased the platelet aggregation in response to arachidonate, without a significant reduction of thromboxane B2 production. 4. The data provides evidence that phenothiazine effects could involve calmodulin-dependent enzymatic activities.

In the present study we investigated the influence of phentolamine and the phenothiazine compounds chlorpromazine and trifluoperazine on human platelet aggregation as well as the effect of the association of phentolamine and the phenothiazines on responses to adenosine diphosphate, collagen, thrombin, ionophore A23187 and phorbol-myristate acetate, release reaction, thromboxane B2 synthesis and intraplatelet cyclic adenosine monophosphate levels. Phentolamine and phenothiazines exerted a dose-dependent inhibitory effect on aggregation induced by different concentrations of adenosine diphosphate and decreased the response to other agonists; furthermore, the phenothiazines enhanced the inhibitory effects of phentolamine on aggregation and thromboxane B2 synthesis, without influencing intraplatelet cyclic adenosine monophosphate levels. Phorbol ester-induced platelet activation was also inhibited in a dose-dependent way by each compound and by an association of phentolamine and phenothiazines, suggesting that the antiplatelet properties of these compounds might also be ascribed to intracellular events.

The aim of the present study was to investigate the influence of insulin-induced hypoglycaemia on platelet sensitivity to adrenaline and non-adrenergic agonists in man. Twenty-five healthy male subjects volunteered for the study. To evaluate the effects on platelets of different insulin-adrenaline interrelationships, two experimental models were used. In the first, hypoglycaemia was induced by a 60-min IV infusion of human insulin at the rate of 64 mU m-2 min-1, whereas in the other the same insulin dose was administered as an IV bolus (3.84 U m-2). Throughout the studies, plasma glucose, insulin, and adrenaline were measured together with platelet sensitivity to adrenaline, ADP, platelet activating factor, collagen, and sodium arachidonate. In both studies, hypoglycaemia induced a reduction of platelet sensitivity to adrenaline (p = 0.006 in infusion and p = 0.045 in injection study). In particular, maximal aggregation to adrenaline fell from 47.9 +/- 9.9 (+/- SE) to 31.1 +/- 11.3% at the hypoglycaemic nadir in the infusion study, and from 64.6 +/- 8.2 to 34.6 +/- 10.3% at the hypoglycaemic nadir in the injection study. In the injection study an increase of platelet sensitivity to ADP (p = 0.05), platelet activating factor (p = 0.018), sodium arachidonate (p = 0.035), and collagen (p = 0.027) was also found, in agreement with observations already published using the infusion protocol. Thus, insulin-induced hypoglycaemia increases platelet sensitivity to non-adrenergic agonists and decreases platelet response to adrenaline.

1. Aim of the present investigation was to investigate the effects of calcium blocking agent diltiazem on human platelet response to aggregating agents. 2. Results showed that diltiazem inhibits platelet aggregation induced by ADP, arginine vasopressin, adrenaline, collagen, Na arachidonate, thrombin and phorbol ester PMA in a dose-dependent way. 3. Diltiazem decreased also beta-thromboglobulin release and Thromboxane B2 production from stimulated platelets. 4. Intraplatelet cyclic AMP levels were not modified by the substance. 5. Data provide evidence that the modulation of human platelet function by diltiazem could be also related to inhibition of protein kinase C.

1. The release of arginine vasopressin from human platelets was investigated in platelet-rich plasma after irreversible aggregation induced by adenosine 5'-pyrophosphate, collagen, sodium arachidonate, thrombin and adrenaline in vitro. 2. Arginine vasopressin levels were significantly higher in the supernatant from stimulated platelet-rich plasma than from unstimulated samples, reaching 3.5 X 10(-12) (range 1.6-12.5 X 10(-12) mol/l in the absence of an aggregating agent, 8.8 X 10(-12) (range 4.2-17.5 X 10(-12) mol/l after adenosine 5'-pyrophosphate, 13.7 X 10(-12) (2.2-63.2 X 10(-12) mol/l after collagen, 7.8 X 10(-12) (2.2-14.6 X 10(-12) mol/l after sodium arachidonate, 7.8 X 10(-12) (2.2-16.3 X 10(-12) mol/l after thrombin and 12.2 X 10(-12) (4.8-32.1 X 10(-12) mol/l after adrenaline. 3. An arginine vasopressin level of 18 X 10(12) mol/l, which can be achieved physiologically, increased the sensitivity of platelets to adenosine 5'-pyrophosphate and collagen in vitro; the same concentration of arginine vasopressin caused a potentiation of the effect of catecholamines on the response of platelets to sodium arachidonate. 4. These results indicate that intraplatelet arginine vasopressin is released during aggregation and suggest that a local release of arginine vasopressin could occur after complete platelet aggregation in vivo.

Insulin-induced hypoglycaemia causes profound haemodynamic changes, commonly ascribed to catecholamine increase. The aim of the present study was to investigate the influence of insulin-induced hypoglycaemia on non-adrenergic factors potentially involved in haemodynamic regulation: angiotensin II and alpha-human atrial natriuretic polypeptide. Fourteen healthy male subjects, aged 25.5 +/- 0.74 years, body mass index 23.81 +/- 0.68 kg/m2, received (after an overnight fast and at least 60 min rest in a supine position) an i.v. bolus injection of human regular insulin (Actrapid HM, Novo, Bagsvaerd, Denmark: 3.84 U/m2). Serial venous blood samples were drawn in the following 150 min, to measure plasma glucose, angiotensin II, alpha-human natriuretic polypeptide, and factors potentially involved in the regulation of the renin-angiotensin-aldosterone system. During the study, we observed a plasma glucose fall, reaching a nadir of 1.95 +/- 0.11 mmol/l between 25 and 30 min, and an increase of angiotensin II (from 7.6 +/- 0.8 to 13.5 +/- 1.1 pg/ml, p = 0.01, quadratic model evaluated by an analysis of the variance for repeated measures), whereas atrial natriuretic polypeptide remained unchanged. As far as the regulation of the renin-angiotensin-aldosterone system is concerned, the increase of angiotensin II is attributable to the increased plasma renin activity, whereas angiotensin converting enzyme was not modified. The increase of plasma renin activity, in turn, is attributable both to the increased catecholamine concentrations and to the decreased potassium levels. Both adrenocorticotropic hormone and angiotensin II are potentially involved in the hypoglycaemia-induced increase of aldosterone concentrations.

This study investigates whether insulin influences the renin-angiotensin-aldosterone system in humans. Six healthy male volunteers were placed on a 30-minute euglycemic insulin clamp at 160 microU/mL; euglycemia was maintained also in the following 60 minutes by means of appropriate dextrose infusion. Throughout the study, plasma renin activity, angiotensin II, aldosterone, and factors involved in the regulation of the renin-angiotensin-aldosterone system were measured: catecholamines, angiotensin-converting enzyme, sodium, and potassium. A significant increase of plasma renin activity and angiotensin II was observed, and a decrease of aldosterone was also detected. These changes can be ascribed to the effects of the rapid insulin-induced plasma potassium decrease on plasma renin activity and aldosterone secretion because they did not occur in a control clamp study with a potassium infusion.