Differential actions of naftopidil, doxazosin and nifedipine on platelet thromboxane generation and platelet-derived growth factor efflux in vitro.

We examined the effects of the alpha(1)-adrenoreceptor blockers naftopidil and doxazosin and the Ca(2+) antagonist nifedipine on platelet function with reference to stimulus-induced thromboxane (TxB(2)) generation and platelet-derived growth factor (PDGF) efflux. Collagen (5 micro g/ml) caused a 12.5-fold increase in TxB(2) generation, from a basal level of 7.69 +/- 1.28 ng/10(8) platelets to 96.34 +/- 13.37 ng/10(8) platelets (P<0.001). Adrenaline (16 micro M) increased TxB(2) production 3-fold from 2.44 +/- 0.61 to 8.02 +/- 1.08 ng/10(8) platelets (P<0.01). Adrenaline-induced TxB(2) generation was inhibited 42.5 +/- 10.3% (P<0.05) and 81.8 +/- 7.5% (P<0.05) by 10 and 40micro M naftopidil, respectively. Collagen-stimulated TxB(2) generation was inhibited 59.5 +/- 9.2% (P<0.01) by 40 micro M naftopidil and 53.7 +/- 11.3% (P<0.01) by 28 micro M nifedipine. Doxazosin (7.5 and 30 micro M) did not influence adrenaline- or collagen-induced TxB(2) synthesis. Collagen increased PDGF efflux from 1.17 +/- 0.39 to 4.25 +/- 0.51 ng/10(8) platelets (P<0.01), whilst adrenaline raised concentrations from 1.08 +/- 0.19 to 5.37 + 1.02 ng/10(8) platelets (P<0.01). Naftopidil had no effect on collagen-induced PDGF release. Adrenaline-stimulated PDGF efflux was, however, inhibited 82.9 +/- 13.7% (P<0.001) and 125.7 +/- 16.3% (P<0.001) by 10 and 40 micro M naftopidil, respectively. Doxazosin (30 micro M) inhibited adrenaline-induced PDGF release by 70.3 +/- 31.5% (P<0.05), whilst nifedipine (28 micro M) had no effect on collagen-stimulated release. We conclude that naftopidil, like nifedipine, may block stimulated TxB(2) generation via inhibition of phospholipase A(2), the Ca(2+)-dependent, rate-limiting enzyme in thromboxane synthesis. Although adrenaline-induced PDGF release was inhibited by naftopidil and doxazosin, collagen-induced release was unaffected by either alpha(1)-adrenoreceptor blocker or nifedipine, indicating that platelet alpha-granular release is not dependent on Ca(2+) mobilisation or thromboxane generation. Thus, the effects of these drugs on PDGF release may be mediated through alternative cellular signalling mechanisms.

Beta-adrenergic blocking drugs in the treatment of hypertension.

The reduction in blood pressure seen with the use of beta-blocking drugs was an unexpected finding. Initially there was resistance to their use as the reduction of cardiac output and increase in peripheral resistance from beta-blockade was considered an undesirable pharmacological action for a drug in the treatment of hypertension. However, beta-blockers have now become established in the treatment of hypertension and have been recommended as a first line choice in various guidelines, although their exact mode of action remains a matter for debate. In broad terms beta-blocking drugs are at least of similar efficacy to the other major classes of antihypertensive drugs. They may be usefully combined with other anti-hypertensives, as is often required. There is some evidence that the beta-1 selective agents are more efficacious than the non-selective beta-blockers. Notwithstanding some observations to the contrary beta-blockers are often effective antihypertensive agents in the elderly and in black patients; the combination of being elderly and black, however, appears to result in a reduced fall in blood pressure. If they are given early in pregnancy they lead to a low birth weight. Co-existant disease may influence the choice of a beta-blocker to treat hypertension. Beta-blockers are valuable agents in ischaemic heart disease, notably the control of chronic angina pectoris and to improve prognosis post-myocardial infarction. While initial dose titration has to be extremely careful, heart failure is now a strong indication for the use of a beta-blocker, as prognosis is much improved. Diabetes should no longer be regarded as a contra-indication to the use of a beta-1 selective agent. Recent work confirms that beta-blockers should be given to patients undergoing surgery who have a high cardiac risk. Outcome studies suggest overall that in younger patients beta-blockers reduce the incidence of strokes and myocardial infarction. There is no convincing evidence of a difference between the ACE inhibitor captopril and the combination of diuretic and a beta-blocker. In high risk patients, i.e. those with diabetes, no difference was seen between captopril and atenolol. Diuretics may result in better outcome measurements in the elderly compared to beta-blockade but in combination, "conventional treatment" is as effective in terms of total mortality, strokes and myocardial infarction as ACE inhibitors or calcium antagonists. Co-existant asthma remains an important contraindication to beta-blockade, but not chronic obstructive airways disease where a beta-blocker should be used with caution if it is indicated, e.g. post-infarction. Quality of life measurements, at least with beta-1 selective agents compare favourably with other anti-hypertensive drugs. Beta-blockers, without partial agonist activity, should not be stopped abruptly, particularly in patients with, or at high risk of, co-existant ischaemic disease because of the danger of post-beta-blockade cardiac sympathetic hypersensitivity; alternatively bed rest should be instituted to reduce the risk of sympathetic stimulation.

I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly.

In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t(1/2)) of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t(1/2) values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.

New approaches to the uses of beta blocking drugs in hypertension.

After a slow start, beta-blockers have become widely used as first-line agents in the treatment of hypertension, and recommended as such in recently published guidelines. There is evidence that the beta1-selective agents are more efficacious than non-selective blockers that inhibit both beta1 and beta2 receptors. Notwithstanding some earlier evidence to the contrary, it appears that beta1-selective drugs are equi-effective in young and elderly whites, younger, ie, under mid 60s, blacks. It is with the combination of age and being black that beta-blockers are usually less useful than some other groups of antihypertensive drugs, most notably calcium antagonists and diuretics. Primary prevention studies indicate beta-blockers reduce the incidence of cerebro-vascular disease and coronary heart disease in younger patients but they appear less effective than diuretics in the elderly. Beta-blockers are particularly indicated in patients who have experienced a myocardial infarction where they are often under used. There is some evidence that even in post-infarction patients with co-existent chronic obstructive airways disease, usually regarded as a contra-indication, experience an improved 2-year survival with the use of beta-blockers. Recently they have also been demonstrated to improve prognosis in heart failure patients, previously regarded as a contra-indication. Likewise, recent studies have shown that atenolol was at least as effective as captopril in improving the outlook in hypertensive patients with non-insulin dependent diabetes. While earlier comparisons with the non-selective lipid soluble propranolol indicated otherwise, comparisons with beta1-selective agents have indicated a similar effect on quality of life assessments with angiotensin-converting enzyme inhibitors.

Moxonidine: a new antiadrenergic antihypertensive agent.

Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show that much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. Pretreatment with imidazoline I1 blockade from efaroxan abolishes the antihypertensive action of microinjection of moxonidine into the RVLM in the spontaneously hypertensive rat (SHR), while alpha2 blockade from SKF 86466 is much less effective. Microinjection of efaroxan into the RVLM prevents the fall of BP in the SHR from intravenous moxonidine. Moxonidine binds with an affinity for the imidazoline I1 receptor that is 33 times more effective than is alpha2-receptor binding. There is only a few fold preference for binding at the imidazoline I1-receptor for clonidine. Moxonidine results in a fall in adrenaline, noradrenaline and renin levels in humans, as might be expected from central inhibition of sympathetic tone. Moxonidine gives a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. There is a reduction in left-ventricular end systolic and diastolic volumes. There is a regression of left-ventricular hypertrophy after moxonidine was given for 6 months. Following oral administration the half-life (Tmax) is about 1 h. Moxonidine is highly bioavailable, approaching 90%. Moxonidine is largely excreted unchanged, biotransformation is unimportant. It has a T(1/2) of 2.5 h, renal insufficiency prolongs the T(1/2). However, suggesting possible retention in the central nervous system (CNS) the antihypertensive effect lasts longer than would be expected from the half-life. Moxonidine has been shown to be suitable for administration once daily. Moxonidine is an effective antihypertensive drug. In the course of its evaluation it has been compared with representatives from each important class of antihypertensive drugs, with diuretics, both alpha- and beta-blocking drugs, clonidine, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors. These studies have shown that BP control is overall similar with moxonidine and these other agents. Moxonidine has a favourable side-effect profile, at least in part due to its lack of effect on central alpha2 receptors.

Pharmacology and clinical use of moxonidine, a new centrally acting sympatholytic antihypertensive agent.

Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I1 blockade from efaroxan, but alpha(2) blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that moxonidine binds with an affinity for the imidazoline I1 receptor that is thirty-three times more effective than is alpha(2) receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with moxonidine. After oral administration Tmax is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T1/2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with moxonidine and these other agents. The side effect profile of moxonidine is favourable, its lack of effect on central alpha(2) receptors is important in this regard.

In vitro adrenaline and collagen-induced mobilization of platelet calcium and its inhibition by naftopidil, doxazosin and nifedipine.

AIMS: The aim of the study was to obtain further information regarding the modes of action of doxazosin, naftopidil and nifedipine on platelet function. METHODS: We conducted an in vitro study of drug influences on adrenaline and collagen-induced mobilization of platelet calcium. RESULTS: In the presence of fibrinogen (300 micrograms ml-1) both collagen (5 micrograms ml-1) and adrenaline (16 microM) stimulated the aggregation of washed platelets. Collagen induced a transient rise (+4.97 +/- 0.63 microM) in platelet Ca2+ concentration, [Ca2+]i, as measured using the photoprotein aequorin, which coincided with the onset of aggregation. Adrenaline induced a smaller rise (+3.6 +/- 0.96 microM) which, however, occurred after the onset of aggregation. Naftopidil, an alpha 1-adrenoreceptor antagonist produced a concentration-dependent inhibition of collagen-induced Ca2+ mobilization, maximum inhibition (22.9 +/- 4%, P < 0.05) occurring with 40 microM naftopidil. The inhibition of Ca2+ mobilization was not reflected by a concentration-dependent inhibition of platelet aggregation, although 40 microM naftopidil produced statistically significant inhibition (23.3 +/- 11.7%, P < 0.05). The adrenaline-induced rise in [Ca2+]i was inhibited dose dependently by naftopidil (e.g. 40 microM naftopidil, 100 +/- 0%, P < 0.05), as was aggregation (40 microM naftopidil, 100 +/- 0%, P < 0.05). Doxazosin, another alpha 1-adrenoreceptor blocker, inhibited Ca2+ mobilization induced by collagen to similar extents as for naftopidil (30 microM doxazosin, 17.4 +/- 2.5%, P < 0.05), but did not inhibit platelet aggregation. It also inhibited the adrenaline-induced rise in [Ca2+]i in a concentration-dependent manner (30 microM doxazosin, 37.6 +/- 13.7%, P < 0.05), significant inhibitions of platelet aggregation also being produced (30 microM, 49.6 +/- 17.2%, P < 0.05). As expected, the calcium channel blocker nifedipine produced concentration-dependent inhibitions of both collagen-induced Ca2+ mobilization (e.g. 28 microM nifedipine, 47.8 +/- 2.7%, P < 0.05) and aggregation (28 microM, 55.1 +/- 9.2%, P < 0.05). CONCLUSIONS: These data indicate that the alpha 1-adrenoreceptor blockers, naftopidil and doxazosin, inhibit Ca2+ mobilization, this mechanism being possibly the means whereby these drugs inhibit platelet aggregation.

Influence of the alpha-adrenoreceptor naftopidil and doxazosin, on adrenaline-induced serotonin platelets: comparison with the antagonists, collagen and efflux by human effects of nifedipine.

Collagen (5 microg/ml) stimulation of washed platelets increased endogenous serotonin (5-HT) release to the medium from 13.88 1.39 to 188.67 26.37 pmol/108 platelets ( P < 0.001). Adrenaline (16 microM) also increased 5-HT release, from 11.0 1.46 to 110.6 29.9 pmol/108 platelets ( P < 0.02). Naftopidil enhanced collagen-induced 5-HT efflux; significant increases occurred with 2 microM (+71.6%, P < 0.01), 10 microM (+89.1%, P < 0.01) and 40 microM (+69.7%, P < 0.01). With 0.4 muM and 2 microM naftopidil, adrenaline-induced 5-HT release was enhanced, albeit non-significantly, whilst with 10 microM and 40 muM naftopidil release was reduced (40 microM,-58.5%, P < 0.05). Doxazosin increased collagen-induced 5-HT release, significant increases being recorded with 7.5 microM (+81.7%, P < 0.05) and 30 microM (+78.4%, P < 0.05). Adrenaline-induced 5-HT release was also increased by doxazosin, but not significantly. Collagen-stimulated 5-HT release was inhibited by nifedipine (7 microM,-38.8%, P < 0.05; 28 microM, -61.2%, P < 0.001). These data suggest that the-antagonists, naftopidil and doxazosin, and the Ca2+ channel blocker, nifedipine, influence agonist-induced platelet 5-HT release through different mechanisms. Thus naftopidil and doxazosin may possess 5-HT transporter-blocking activity. The observation that naftopidil inhibited, adrenaline-induced 5-HT release may indicate that naftopidil also inhibits adrenaline uptake and exchange with dense granular 5-HT, with consequent inhibition of 5-HT release and platelet aggregation. The data obtained with nifedipine are consistent with 5-HT release being reduced as a result of its inhibitory action on platelet Ca2+ mobilisation.

The use of moxonidine in the treatment of hypertension.

BACKGROUND: Imidazoline I1-receptor agonism represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Adrenaline, noradrenaline and renin levels are reduced, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that moxonidine results in an acute decrease in blood pressure due to a fall in systemic vascular resistance, whereas the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months of treatment. PHARMACOKINETICS: Following oral administration, maximum concentration is reached at about 1 h, and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, and biotransformation is unimportant. The half-life of moxonidine is 2.5 h, which is prolonged by renal insufficiency. However, the antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the central nervous system. DRUG EFFECTS: Decreases of about 20-30 mmHg systolic and 10-20 mmHg diastolic blood pressure have been found in open studies with moxonidine. The dosage of 0.2-0.4 mg moxonidine daily controls hypertension in most patients. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and angiotensin converting enzyme inhibitors. Blood pressure control has been observed to be similar with moxonidine and these other agents. Generally, the overall incidence of side-effects has been found to be similar, although the incidence of side-effects with clonidine is greater than that seen with moxonidine. CONCLUSIONS: A meta-analysis of controlled studies with moxonidine found that moxonidine gave similar reductions in blood pressure in both men and women, in those aged below 50, 50-60 and over 60 years, and regardless of body weight. As often seen with some other drugs, higher systolic blood pressures are associated with larger reductions in systolic blood pressure and the same appears to be the case with diastolic blood pressure.

Effective antihypertensive therapy: blood pressure control with moxonidine.

Stimulation of the imidazoline I1-receptor represents a new mode of antihypertensive action, inhibiting peripheral alpha-adrenergic tone by a central mechanism. Moxonidine is an imidazoline I1-receptor modulator. Acute hemodynamic studies indicate that moxonidine results in an acute fall of both blood pressure and systemic vascular resistance, whereas heart rate, cardiac output, stroke volume, and pulmonary artery pressures are not affected. The ejection fraction is not significantly affected. Left ventricular end-systolic and -diastolic volumes are reduced. There is regression of left ventricular hypertrophy after 6 months of treatment. Epinephrine, norepinephrine, and renin levels are all reduced, a finding consistent with central inhibition of sympathetic tone. After oral administration Tmax is about 1 h and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged; biotransformation is unimportant. The T1/2 is 2.5 h, prolonged by renal insufficiency. The antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the CNS. Open studies with moxonidine have revealed decreases on the order of 20-30 mm Hg systolic and 10-20 mm Hg diastolic blood pressure. Most patients are controlled by 0.2-0.4 mg daily. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with diuretics, clonidine, calcium antagonists, angiotensin-converting enzyme inhibitors, and both alpha- and beta- blocking drugs. Blood pressure control has been similar with moxonidine and these other agents. The overall incidence of side effects was similar, although moxonidine has a lower incidence of side effects than clonidine. Meta-analysis of controlled studies with moxonidine indicates that moxonidine causes similar decreases in blood pressure in both male and female subjects, in those below 50 years, those 50-60 years, and those over 60 years old, regardless of body weight. As with some other drugs, higher systolic blood pressure are associated with larger falls of systolic blood pressure, and the same is true for diastolic blood pressure.

The potentiation of adrenaline-induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.

1. Aggregation in platelet-rich plasma from normotensive men was induced by adrenaline (0.25-16 microM), ADP (0.25-16 microM), collagen (0.25-8 micrograms ml-1) or serotonin (10 microM) alone, or by previously sub-threshold concentrations of adrenaline (0.03-1 microM) in combination with sub-threshold concentrations of serotonin (2.5 microM), ADP (0.5 microM) or collagen (0.125 micrograms ml-1). The effects of the alpha 1-adrenoceptor blockers naftopidil and doxazosin on platelet aggregation were investigated. 2. The dose-response curves for collagen and ADP were unaffected by either drug. However, naftopidil (40 microM) inhibited serotonin-induced platelet aggregation (23.9%, 95% confidence interval (CI) 10.7 to 37.1%; P < 0.01) and caused a slight shift to the right of the adrenaline dose-response curve with a mean increase in the EC50 value of 0.5 microM (95% CI 0.07 to 0.93 microM; P < 0.05). Doxazosin had no effect on serotonin or adrenaline-induced aggregation. 3. A marked potentiation of the aggregation induced by subthreshold concentrations of adrenaline resulted from the prior addition of low concentrations of ADP, collagen or serotonin. 4. These potentiated responses were inhibited in a dose-dependent manner by naftopidil and to a lesser extent doxazosin. The maximum inhibitions (%) produced by naftopidil (40 microM) on the responses of adrenaline potentiated by ADP were 58.3% (95% CI 36.8 to 79.8%; P < 0.001), serotonin 58.9% (95% CI 40.0 to 77.8%; P < 0.001), and collagen 70.9% (95% CI 52.5 to 89.3%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical experience with moxonidine.

Moxonidine is an imidazoline receptor modulator, specific for the I1-imidazoline receptor. The stimulation of imidazoline receptors represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Acute hemodynamic studies reveal moxonidine produces an acute fall of blood pressure and systemic vascular resistance. Heart rate, cardiac output, stroke volume, and pulmonary artery pressures are not affected. Left ventricular end-systolic and diastolic volumes are reduced. Ejection fraction is not significantly affected but 6-month studies showed a regression of left ventricular hypertrophy. After oral administration the maximum concentration of moxonidine is reached in about 1 hour, and elimination half-life is 2.5 hours, prolonged by renal insufficiency. The antihypertensive effect lasts longer than would be expected from the half-life. Open studies with moxonidine have revealed falls between 20 and 29 mmHg systolic, and between 10 and 19 mmHg diastolic blood pressure. In the largest study, over 12 months in 141 patients, most patients were controlled by 0.2 mg daily (58%) or 0.2 mg b.i.d. (38%). Moxonidine has been compared with representatives from each important class of antihypertensive drugs. In a crossover trial of clonidine in 20 patients, blood pressure control was similar, but the incidence of tiredness and dry mouth was less on moxonidine, as was the total number of patients experiencing side effects, 85% versus 30% (p < 0.01). In a larger parallel group study of moxonidine (n = 122) and clonidine (n = 30), blood pressure control was similar, but the overall incidence of side effects was less on moxonidine. In comparative studies of moxonidine with atenolol, ACE inhibitors, dihydropyridine calcium antagonists, hydrochlorothiazide, and alpha 1 blockade, the blood pressure control with representatives of these various classes of drugs was similar to moxonidine.

Platelet function in patients with hypercholesterolaemia.

Platelets and plasma lipoproteins, particularly low density lipoprotein, have important roles in atherogenesis. Evidence from several sources suggests that important interactions occur between these individual components of the atherogeneic process. Here we review work from our own laboratory on platelet function in normal individuals and patients heterozygous for familial hypercholesterolaemia (FH). Data is presented on the role of platelet noradrenaline and also on altered cellular signalling in platelets from FH individuals who have plasma low density lipoprotein concentrations which are approximately double those seen in normal subjects.

An Examination of Some Factors which Influence the Stability of in Vitro Platelet Responses.

Platelet sensitivity to ADP and adrenaline was determined after storage of platelet-rich plasma (PRP) under various conditions to establish those yielding optimal platelet stability. The effects of the exclusion of air from the storage syringes, temperature, PRP dilution and duration of storage were tested. Storage at room temperature (22° C) in the absence of air stabilised PRP pH over 24 h and stabilised platelet sensitivity to ADP up to 4 h. Storage at 4°C and 13 C caused platelet activation and eventually spontaneous aggregation, as evidenced by significant reductions in platelet counts. Samples stored at 37° C were less responsive to ADP and adrenaline than samples maintained at 22 C. Platelet count adjustment to 200 × 10(9)/L reduced platelet sensitivity as reflected by increased agonist EC(50) values and threshold concentrations. Positive correlations between agonist EC(50) values (and between threshold concentrations) for diluted and undiluted samples were obtained, indicating that platelet count adjustment did not affect the ranking order of platelet sensitivity within the subject group. No correlations between platelet count and indices of platelet sensitivity were seen suggesting that differences in platelet aggregation arise from intrinsic differences in platelet sensitivity rather than differences in platelet count. With time of storage the responses to ADP (EC(50) and threshold concentration) and adrenaline (EC(50)) declined to a greater extent for undiluted PRP than for diluted PRP. No changes in the platelet-poor plasma concentrations of the dense granular component, serotonin, occurred in diluted or undiluted samples over 24 h. We conclude that in order to ensure optimal stability of platelets, PRP should be stored at room temperature (22°C) in the absence of air and tested within 4 h of preparation. A decision on platelet count adjustment is also required dependent upon the experimental objectives.

Carvedilol in ischaemic heart disease.

beta-adrenoceptor-blocking drugs, first introduced for the treatment of symptomatic angina pectoris, have been found effective across the whole spectrum of ischaemic disease. Labetalol was the first combined-action beta-blocking drug to be described and was shown to be capable of increasing exercise tolerance in patients with angina pectoris. Carvedilol also possesses a peripheral vasodilating action mainly due to an alpha 1-adrenoceptor blockade. Haemodynamic studies with carvedilol in patients with ischaemic heart disease have shown a reduction in peripheral vascular resistance in contrast to propranolol which increases systemic resistance and reduces cardiac output. Additionally, in ischaemic heart failure there is evidence of improved myocardial function, as shown by an increase in ejection fraction, after the administration of carvedilol. Carvedilol has been shown to improve exercise tolerance in patients with angina pectoris and reduce the occurrence of episodes of silent myocardial ischaemia. Carvedilol, unlike many beta-blocking drugs, does not adversely affect the plasma lipid profile qualitatively or quantitatively. In contrast to many non-selective beta-blocking drugs, carvedilol has a more favourable haemodynamic profile, and its lack of adverse influence on the plasma lipid profile may be important in its long-term use.