Statins for prevention of stroke.
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Aged↗
Biomedical subjects
G J Blauw
Publications and source records attributed to G J Blauw.
Total cholesterol and risk of mortality in the oldest old.
BACKGROUND: The impact of total serum cholesterol as a risk factor for cardiovascular disease decreases with age, which casts doubt on the necessity for cholesterol-lowering therapy in the elderly. We assessed the influence of total cholesterol concentrations on specific and all-cause mortality in people aged 85 years and over. METHODS: In 724 participants (median age 89 years), total cholesterol concentrations were measured and mortality risks calculated over 10 years of follow-up. Three categories of total cholesterol concentrations were defined: < 5.0 mmol/L, 5.0-6.4 mmol/L, and > or = 6.5 mmol/L. In a subgroup of 137 participants, total cholesterol was measured again after 5 years of follow-up. Mortality risks for the three categories of total cholesterol concentrations were estimated with a Cox proportional-hazards model, adjusted for age, sex, and cardiovascular risk factors. The primary causes of death were coded according to the International Classification of Diseases (ICD-9). FINDINGS: During 10 years of follow-up from Dec 1, 1986, to Oct 1, 1996, a total of 642 participants died. Each 1 mmol/L increase in total cholesterol corresponded to a 15% decrease in mortality (risk ratio 0.85 [95% CI 0.79-0.91]). This risk estimate was similar in the subgroup of participants who had stable cholesterol concentrations over a 5-year period. The main cause of death was cardiovascular disease with a similar mortality risk in the three total cholesterol categories. Mortality from cancer and infection was significantly lower among the participants in the highest total cholesterol category than in the other categories, which largely explained the lower all-cause mortality in this category. INTERPRETATION: In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed.
Aged↗
Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors.
BACKGROUND AND PURPOSE: To estimate the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors ("statins") on stroke ris, we combined the data of the randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors published so far. METHODS: The studies were identified using the Medline CD+ and Current Contents databases from January 1980 through May 1996, inclusive. All studies were evaluated on the use of a placebo control, monotherapy, and double blindness. When the type of stroke or the occurrence of clinical events or adverse effects were incompletely or not reported, the investigators were contacted personally. For each trial, the number of strokes in the treatment arm was compared with the number of strokes expected on all observations under the assumption that drug treatment had no effect. RESULTS: A total of 462 strokes among 20438 participants in 13 trials could be analyzed. A total of 181 strokes were observed in patients randomized to treatment with an HMG-CoA reductase inhibitor and 261 strokes in patients randomized to placebo. A lower than expected number of strokes was observed in the treatment groups of all but one trial (P = .001). Treatment with an HMG-CoA reductase inhibitor led to an overall risk reduction of 31% (odds ratio, 0.69; 95% confidence interval, 0.57 to 0.83). CONCLUSIONS: The combined data suggest that treatment with HMG-CoA reductase inhibitors prevents stroke in middle-aged persons. Because stroke is especially common in older age, these data reinforce the need for clinical trials to evaluate the effect of HMG-CoA reductase inhibitors in preventing stroke in the elderly.
Aged↗
Hypoxic syncope.
INTRODUCTION: Syncope at altitude of otherwise healthy individuals is a well-known phenomenon (22). We report on the cardiovascular effects observed in subjects exposed to hypoxia to illustrate the role of the sympathetic-adrenergic system in hypoxic syncope. This study describes unexpected episodes of (near) syncope during two crossover trials at simulated altitude in a low pressure chamber. METHODS: In study A, 30 healthy male volunteers underwent 4 exposures to short-term (20 min) acute severe hypoxia (20,000 ft or 6096 m) to assess psychological performance. In study B, five volunteers were studied during prolonged exposure (1 h) to moderate hypoxia (13,500 ft or 4115 m) with and without concomitant low dose infusion with atrial natriuretic peptide to investigate the effects on pulmonary gas exchange. RESULTS: In study A (acute severe hypoxia), 6 out of 120 exposures (5%), in 5 subjects, were accompanied by lightheadedness, pallor, sweating, and bradycardia. Two subjects (2%) had syncope with cardiac asystole. In study B during moderate hypoxia without atrial natriuretic peptide, adverse reactions were absent and the (nor)epinephrine levels remained unchanged. Concomitant infusion with atrial natriuretic peptide resulted in near syncope (recumbent in 3, standing in 2) at an oxygen saturation of 82%. While the epinephrine level had eightfold increased, mean arterial pressure fell from 94 to 40 mm Hg and heart rate from 79 to 44 bpm. The norepinephrine level remained unchanged illustrating a dissociated sympathetic-adrenergic response. All subjects with syncope recovered spontaneously within few minutes in Trendelenburg's position with oxygen supplied. None suffered from prolonged side effects. CONCLUSION: It is concluded that exposure to acute severe hypoxia is a sufficient cause for syncope in healthy individuals. Enhanced vasodilatation to epinephrine may contribute to the withdrawal of sympathetic and enhancement of parasympatic activity, leading to vascular collapse, bradycardia or asystole (Bezold-Jarisch reflex). Patients fully recover in Trendelenburg's position with supplemental oxygen and further clinical examinations are not necessary.
Adult↗
End of New Zealand asthma epidemic.
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Asthma↗
Asthma deaths in New Zealand: whodunnit?
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Adolescent↗
Assessment of peripheral vascular effects of antimigraine drugs in humans.
The vascular beds of the forearm and finger can be used to study the peripheral effects of antimigraine drugs under normal and pathologic circumstances. We have investigated the novel antimigraine drug sumatriptan, a selective agonist for 5HT1 receptors. Its antimigraine effect may be attributed, at least in part, to constriction of cranial arteriovenous anastomoses (AVAs). In assessing the peripheral vascular effects of sumatriptan we used a forearm and finger blood flow model. Forearm blood flow (FBF) is mainly determined by resistance vessels, whereas finger blood flow (FiBF) mainly involves skin vessels, which contain many AVAs. Changes in FBF and FiBF can be assessed using venous occlusion plethysmography. Changes in AVA flow are determined by measuring the patency of the vascular beds of the forearm and hand to well-defined radiolabelled microspheres, which are injected into the brachial artery. We report the effects of sumatriptan on FBF, FiBF and AVA flow when administered into the brachial artery of healthy volunteers, and discuss the peripheral vascular effects of therapeutic doses of sumatriptan when given subcutaneously in migraine patients during and between attacks.
Adult↗
Hypoxia-induced arterial endothelin does not influence peripheral vascular tone.
The effect of hypoxia (SpO2 80%) on the arteriovenous production of endothelin-1 (ET) in the forearm was investigated in six healthy volunteers. In eight other subjects the local vascular effects of a low physiologic dose of intra-arterially administered ET (0.5 pg/kg/min) was studied during normoxia. Forearm blood flow (FBF) was measured by venous occlusion plethysmography, and arterial and venous plasma concentrations of ET were measured. FBF was not significantly influenced during hypoxia. After 15 min of hypoxia the arterial plasma level of ET increased from 2.5 +/- 0.1 to 3.3 +/- 0.3 ng/L (p < 0.05), whereas the venous plasma level remained unchanged. Intra-arterial infusion of ET increased the arterial plasma level of ET in the forearm from 2.2 +/- 0.3 to 4.9 +/- 0.4 ng/L. This increase in ET concentration did not influence FBF. It is concluded that hypoxia is a stimulus for ET release from the pulmonary vascular bed and that the resulting increase arterial plasma ET level does not influence peripheral vascular tone.
Adult↗
beta-Adrenergic receptors contribute to hypoxaemia induced vasodilation in man.
1. It was the aim of the present study to investigate the role of the beta-adrenergic receptor in hypoxaemia induced vasodilatation in the human forearm. 2. The study was performed in 12 non-smoking male volunteers. In six subjects the local vascular effects of intra-arterially (i.a.) infused propranolol (0.1 mu kg-1 min-1) was determined during normoxaemia and hypoxaemia (peripheral oxygen saturation; SpO2 80%), and compared with the contra-lateral (control) arm. beta-adrenergic receptor blockade by propranolol was confirmed by i.a. infusions of adrenaline. In six other subjects the effects of incremental hypoxaemia (SpO2 90, 85, 80%) on forearm- and finger blood flow was investigated. A difference between these vascular beds is the absence of vascular beta-adrenergic receptors in the finger. Forearm- and finger blood flow were measured by venous occlusion plethysmography. Plasma levels of (nor-)adrenaline were determined in both arterial and venous blood samples. Hypoxaemia was attained by gradual decompression of a hypobaric chamber and individually adjusted. 3. During normoxaemia the single infusion of propranolol did not influence forearm vascular resistance. In contrast, during hypoxaemia a net vasoconstriction was observed in the arm treated with propranolol, which was significantly different (P = 0.009) from the vasodilatation in the control arm (mean difference in response 40%; 95% confidence interval 13.2-66.8). The net arterio-venous spillover of noradrenaline from the forearm increased after the first 15 min of hypoxaemia (P < 0.05) and returned to baseline in the next 15 min. Arterial and venous plasma levels of adrenaline during hypoxaemia remained unchanged compared with normoxaemia. In the second set of experiments incremental levels of hypoxaemia induced a vasoconstriction in the finger, which was significantly different (P = 0.025) from the vasodilatation in the forearm (mean difference in response 300%; 95% confidence interval 63-537). 4. The data indicate that beta-adrenergic receptors contribute to hypoxaemia induced vasodilatation, despite unaltered adrenaline plasma concentrations.
Adult↗
No functional involvement of 5-hydroxytryptamine1A receptors in nitric oxide-dependent dilatation caused by serotonin in the human forearm vascular bed.
The vascular effects of serotonin (5-hydroxytryptamine, 5-HT) are complex and heterogeneous. In human forearm, we showed that low doses of 5-HT cause marked but transient vasodilatation followed by a persistent vasodilator response. In in vitro and in animal experiments, 5-HT induced release of nitric oxide (NO) through stimulation of endothelial 5-HT1-like receptors. In the present study, we investigated involvement of the "NO pathway" and possible involvement of the 5-HT1A receptor subtype in 5-HT-induced persistent vasodilator response. In 8 healthy volunteers, we infused 5-HT (0.1, 0.3, and 1 ng/kg/min) and the selective 5-HT1A receptor agonist flesinoxan (15, 45, and 150 ng/kg/min) intraarterially (i.a.) with NG-monomethyl-L-arginine (L-NMMA 30 micrograms/kg/min) or saline. Forearm blood flow (FBF) was measured by automated R-wave-triggered venous occlusion plethysmography. Forearm vascular resistance (FVR) was derived from simultaneously recorded i.a. blood pressure (BP) and FBF. 5-HT dose-dependently decreased FVR (p < 0.001). The persistent vasodilator response to 5-HT appears to be mediated by NO release, as suggested by its complete abolition by L-NMMA (p < 0.001). Flesinoxan decreased FVR slightly, but only at high doses (p < 0.05). The present findings indicate that 5-HT1A receptors are not functionally involved in 5-HT-mediated vasodilatation in human forearm.
Adult↗
Interactions between serotonin and endogenous and exogenous noradrenaline in the human forearm.
We investigated the interactions between serotonin (5-hydroxytryptamine, 5-HT) and exogenous or endogenous noradrenaline (NA) in the forearm of normotensive volunteers (n = 24), using venous occlusion plethysmography. Endogenous release of NA was stimulated by lower body negative pressure (LBNP; -10, -20 and -40 mmHg) and by intra-arterial (i.a.) infusions of tyramine (0.1 to 1 microgram/kg/min). Exogenous NA was infused in cumulative doses (0.3 to 10 ng/kg/min). All experiments were performed in the presence of either vehicle (0.4 mL/min), sodium nitroprusside (SNP; 3 or 5 ng/kg/min), or 5-HT (0.1 or 1 ng/kg/min). NA or 5-HT (1 ng/kg/min) were also infused with the selective 5-HT2 receptor antagonist ritanserin (500 ng/kg/min). Angiotensin II (Ang II; 0.03 to 0.3 ng/kg/min) was given as a vasoconstrictor control (n = 6). Vasoconstriction to exogenous NA was significantly enhanced by 5-HT (1 ng/kg/min; p < 0.05) in one group of subjects, but this could not be reproduced in a second group. In contrast, the vasoconstrictor responses to endogenous NA remained unaffected by 5-HT. SNP caused the same degree of vasodilation as 5-HT, and was followed by a similar response to NA. Ritanserin did not alter the vasoconstriction to infused NA, nor vasoconstriction to infused NA when combined with 5-HT. The vasoconstrictor response to Ang II was not influenced by 5-HT (0.1 ng/kg/min). Apparently, a synergistic effect between 5-HT and NA in the periphery involves a nonspecific mechanism. The latter seems to be confined to infused NA. The precise role of the 5-HT2 receptor in this interaction could not be elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Serotonin-induced vasodilatation in the human forearm is mediated by the "nitric oxide-pathway": no evidence for involvement of the 5-HT3-receptor.
The "nitric oxide (NO)-pathway" is presumed to be involved in acetylcholine (ACh)- and serotonin (5-hydroxytryptamine, 5-HT)-mediated vasodilatation. In addition, both the 5-HT-induced transient and persistent vasodilator responses in the forearm vascular bed are abolished by the 5-HT3/5-HT4-receptor antagonist ICS 205-930 ([1H]-indol-3-carbonic-acid-tropine-ester HCl, tropisetron). We studied 5-HT-mediated vasodilatation in the forearm vascular bed of normotensive volunteers, using venous occlusion plethysmography. Intraarterial (i.a.) infusions of 5-HT, ACh, and sodium nitroprusside (SNP) all caused an increase in forearm blood flow (FBF). Single infusions of ondansetron and granisetron also caused an increase in FBF. Infusion of the NO scavenger and guanylate-cyclase antagonist methylene blue (MB) did not change FBF, whereas the arginine analogue NG-monomethyl-L-arginine (L-NMMA) caused a decrease in FBF, which became less pronounced when infusions were repeated. Unlike ICS 205-930, concomitant infusions of the selective 5-HT3-receptor antagonists ondansetron (OND) and granisetron (GRAN) did not antagonize the transient or persistent vasodilator responses to 5-HT. These findings suggest the involvement of a 5-HT4-receptor. L-NMMA and MB both reduced the persistent vasodilator response to 5-HT, indicating involvement of the NO pathway. Neither MB nor L-NMMA influenced the endothelium-independent vasodilator response to SNP. ACh-induced vasodilatation was markedly potentiated by MB but was not affected by L-NMMA. The mechanism by which MB enhances the vasodilator response to ACh remains unclear.
Adult↗
Serotonergic receptors and drugs in hypertension.
The possible role of 5-hydroxytryptamine (5HT) and 5HT-receptors in hypertension, already suggested by Page in 1954, has been subject to a renaissance of interest owing to the development of antihypertensive drugs which interact with 5HT-receptors. These drugs, like ketanserin, urapidil and flesinoxan are used as tools to study the role of 5HT and its receptors in hypertension. Some arguments would plead in favour of a certain role of 5HT and 5HT-receptors in the pathogenesis and maintenance of hypertension: hyperresponsiveness of blood vessels from hypertensive patients and animals to 5HT-induced constriction; the antihypertensive/vasodilator activity of the 5HT2-receptor antagonist ketanserin; enhanced sensitivity of platelets from hypertensives to 5HT. However, there are also several arguments which do not support a causal role of 5HT in hypertensive disease: 5HT is not a generally accepted pressor agent, whereas its concentration in the circulating blood is subthreshold; the 5HT2-receptor antagonist ketanserin is the only agent of this type which lowers blood pressure, other 5HT2-receptor blockers (ritanserin; LY 53587) being inactive. The various data and arguments available do not unequivocally support a relevant role of peripheral 5HT and its receptors in hypertensive disease. 5HT2-receptor blockade may, however, have a favourable effect on the microcirculation under pathological conditions. The stimulation of central 5HT1A-receptors by drugs like urapidil, 8-OH-DPAT or flesinoxan, has been demonstrated to induce peripheral sympathoinhibition and a fall in blood pressure. This mechanism appears to be a novel target for centrally acting antihypertensives, clearly different from that of clonidine and related drugs, which are centrally acting alpha 2-adrenoceptor agonists.
Adrenergic alpha-Antagonists↗
The acute and chronic antihypertensive effects of ketanserin cannot be explained by blockade of vascular serotonin, type 2, receptors or alpha 1-adrenergic receptors.
The mechanism underlying the antihypertensive effect of acute and chronic administration of ketanserin was investigated in eight hypertensive patients. Intrabrachial artery infusions of serotonin and the selective alpha 1-adrenergic receptor agonist methoxamine were given before and 1 hour after a single oral dose of 20 mg ketanserin and after 4 weeks of treatment with 20 to 40 mg twice daily. Blood pressure was reduced by ketanserin both after the initial dose (p less than 0.01) and after 4 weeks of treatment (p less than 0.01). During placebo, serotonin, 1 ng/kg/min, increased forearm blood flow by 51% +/- 9% (p less than 0.01), whereas the highest dose induced a decrease in flow (-33% +/- 6%; p less than 0.01). Methoxamine elicited a vasoconstriction (p less than 0.001). These effects of serotonin and methoxamine were not influenced by either the initial dose of ketanserin or after 4 weeks of treatment. It is concluded that serotonin cannot be considered a general endogenous pressor agent in these patients. The antihypertensive effects of ketanserin cannot be attributed to either vascular alpha 1-receptor or serotonin, type 2, receptor blockade.
Adult↗
Arterial and venous effects of atrial natriuretic peptide in the human forearm.
Atrial natriuretic peptide (ANP) has direct vasodilating properties in addition to its diuretic and natriuretic effects. Furthermore, vascular permeability may be influenced. Because relatively little is known about the venous and capillary actions of ANP in humans, we investigated the spectrum of vascular actions of ANP in the human forearm. In seven healthy subjects, ANP was infused intraarterially in consecutive doses of 0, 10, 50, and 250 ng/100 mL tissue/min together with vehicle or norepinephrine 1 ng/kg/min. In seven other subjects, 0.5 ng/kg/min angiotensin II and 10 ng/kg/min serotonin were used as a constrictor. Venous occlusion plethysmography was used to measure forearm blood flow, venous compliance, capillary filtration rate, and maximum venous outflow. Intraarterial infusion of ANP induced a dose-dependent increase of forearm blood flow but the relative increases were not influenced by concomitant vasoconstriction. Venous compliance was not affected by the infusions, but serotonin and angiotensin II decreased the changes of both forearm volume and venous pressure. ANP antagonized these effects of angiotensin II. Capillary filtration rate was not affected by ANP infusion. ANP alone had no effect on the maximum venous outflow, but it attenuated the decrease induced by norepinephrine and angiotensin II. These results indicate that in the human forearm ANP has predominantly arterial effects, whereas the venous actions become manifest only in the presence of vasoconstriction. The venous effect of ANP may therefore gain importance in disease states with elevated levels of vasoconstrictors, for instance, in congestive heart failure.
Adult↗
The role of serotonin in cardiovascular diseases and their treatment.
Serotonin (5HT), discovered in the 1950s, has been the subject of renewed interest for several years, in particular due to the subdivision of 5HT receptors into various types. Concomitantly, several more or less selective agonists and antagonists for these various receptor subtypes have been developed. Although the physiologic relevance of 5HT remains largely unknown, its role in certain pathologic processes is widely accepted. Certain symptoms of the carcinoid syndrome, thromboembolic processes at the level of the microcirculation, and possibly also coronary spasm and peripheral vascular disease are likely to be associated, at least in part, with endogenous 5HT and serotonergic mechanisms. However, a primary and causative role for such mechanisms in essential hypertension seems unlikely. The blockade of peripheral 5HT2 receptors with drugs may offer advantages, in particular in those disorders where an interaction between predamaged blood vessels and platelets is involved. Such a therapeutic approach seems to be a more generally applicable principle than the lowering of blood pressure as such, which appears not to be a general phenomenon provoked by 5HT2-receptor blockade.
Animals↗
The role of 5-hydroxytryptamine and 5-hydroxytryptaminergic mechanisms in hypertension.
1. The possible role of 5-hydroxytryptamine (5-HT) and 5-HT-receptors in hypertension, already suggested by Page in 1954, has been subject to a renaissance of interest owing to the development of antihypertensive drugs which interact with 5-HT-receptors. These drugs, like ketanserin, urapidil and flesinoxan are used as tools to study the role of 5-HT and its receptors in hypertension. 2. The following arguments would plead in favour of a certain role of 5-HT and 5-HT-receptors in the pathogenesis and maintenance of hypertension: hyperresponsiveness of blood vessels from hypertensive patients and animals to 5-HT-induced constriction; the antihypertensive/vasodilator activity of the 5-HT2-receptor antagonist ketanserin; enhanced sensitivity of platelets from hypertensives to 5-HT. 3. However, at least as many arguments would deny a role of peripheral 5-HT in hypertension, like for instance: the fact that 5-HT is not a generally accepted pressor agent, whereas its concentration in the circulating blood is subthreshold; the hyperresponsiveness of vessels from hypertensives is not specific for 5-HT; the elevated local concentration of 5-HT released by platelets is mainly limited to the microcirculation; the 5-HT2-receptor antagonist ketanserin is the only agent of this type which lowers blood pressure, other 5-HT2-receptor blockers like ritanserin and LY 53587 being inactive. 4. The various data and arguments available do not unequivocally support a relevant role of peripheral 5-HT and its receptors in hypertensive disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pharmacological profile of antihypertensive drugs with serotonin receptor and alpha-adrenoceptor activity.
During the last few years, several antihypertensive drugs with multiple actions have been introduced. Most of these hybrid drugs are beta-adrenoceptor blockers with an additional vasodilator component, such as labetalol, dilevalol, carvedilol and celiprolol. A second category of antihypertensive drugs with multiple actions consists of agents which interact simultaneously with serotoninergic receptors and alpha-adrenoceptors. Urapidil, ketanserin, and a few experimental compounds related to these drugs are examples of this type of antihypertensive. They may be characterised pharmacologically as follows: (1) Ketanserin is a selective antagonist of serotonin 2 receptors with an additional much weaker alpha 1-adrenoceptor antagonistic activity. Its well documented antihypertensive activity cannot be explained by either serotonin 2-receptor blockade or alpha-adrenoceptor antagonism alone. An unknown type of interaction between serotonin 2-receptor and alpha 1-adrenoceptor blockade appears to be necessary, either in the periphery or in the CNS. (2) Urapidil is a selective alpha 1-adrenoceptor antagonist and, as such, a peripheral vasodilator. In addition, it displays central hypotensive activity, probably caused by the stimulation of serotonin 1A receptors in the CNS. This component is probably additive to the peripheral effect, and is also the background to the lack of reflex tachycardia seen with urapidil. The modes of action of both types of drugs are discussed in connection with the role of serotonin and its receptors in the cardiovascular system, both at the peripheral and the CNS levels.
Adrenergic alpha-Antagonists↗