'The principles of a future pharmacology': Johann Christian Reil (1759-1813) and his role in the development of clinical pharmacology.

AIM: Johann Christian Reil was an eighteenth-century German physician and clinical academic with wide interests. These included building the scientific foundations of modern medical practice. In 1799, he published a work specifically calling for a scientific approach to pharmacology in medical practice. In this paper, I aim to present the key parts of that work for the first time in English translation. METHODS: Reil's 1799 work was translated into English and evaluated against current standards of practice in clinical pharmacology to highlight his 'modern' approach to our subject. RESULTS: Reil defines pharmacology and presents a series of eight rules or principles that should be followed by those wishing to evaluate drugs in humans. These rules highlight the need for scientific rigour, including the use of multiple controlled experiments, and call for the introduction of a specialized vocabulary to facilitate the exchange of ideas between pharmacological researchers. CONCLUSIONS: Although rarely mentioned in the pharmacological literature today, Reil's work in the late eighteenth century is an important precursor of our modern approach to the evaluation and testing of drugs in clinical practice. This English translation of the key sections of his work may now allow others to properly evaluate his contribution.

Management of patients at risk of adrenal crisis in the dental setting: a review of current practice in UK dental teaching hospitals.

Introduction Patients with impaired corticosteroid response due to Addison's disease or systemic glucocorticoid use are at risk of adrenal crisis when undergoing dental treatment. There is a lack of conclusive evidence to support dental teams in identifying patients at risk and their management to prevent an adrenal crisis.Aim To review the current practice in UK dental teaching hospitals regarding the management of patients at risk of adrenal crisis in the dental setting.Methods An electronic survey focused on patients who may be at risk of adrenal crisis due to systemic glucocorticoid therapy was sent to all 18 UK dental teaching hospitals. Information on the use of a policy or guidance was requested. Responses were evaluated for clinical decision-making, patient risk assessment and steroid cover dosing regimens.Results A 78% response rate was achieved. Only 29% of institutions had a written policy or guidance document. Variation exists in the threshold of steroid dose and duration of treatment in identifying patients at risk of adrenal suppression. Furthermore, the dose regime for steroid cover varied.Conclusion Further evidence on the management of patients at risk of adrenal crisis is required to inform national guidance and reduce variation in patient management.

Dynamic regulation of the endocannabinoid system: implications for analgesia.

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study.

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common "null" allele at the apo(a) locus.

Distributions of plasma lipoprotein(a) (Lp[a]) concentrations exhibit marked interracial differences. Apolipoprotein(a) (apo[a]), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4(K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the interracial variation in plasma Lp(a) levels, we compared apo(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese, and African Americans. Caucasians and African Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their apo(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African Americans than in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations but significantly different apo(a) allele size distributions. Therefore, interracial differences in the plasma concentrations of Lp(a) are not due to differences in the frequency distributions of apo(a) alleles. We also examined the relationship between apo(a) allele size and the presence of detectable plasma apo(a) protein in plasma. Apo(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, we conclude that there is no common "null" allele at the apo(a) locus.

Effect of individualizing starting doses of a statin according to baseline LDL-cholesterol levels on achieving cholesterol targets: the achieve cholesterol targets fast with atorvastatin stratified titration (ACTFAST) study.

AIMS: To investigate whether selecting the starting dose of atorvastatin according to baseline and target (<2.6 mmol/L) LDL-cholesterol (LDL-C) values would allow high-risk subjects to achieve target LDL-C concentration within 12 weeks, with the initial dose or a single uptitration. METHODS AND RESULTS: Twelve-week, prospective, open-label trial that enrolled 2117 high-risk subjects (statin-free [SF] or statin-treated [ST]). Subjects with LDL-C >2.6 mmol/L (100mg/dL) but

Genetic variation in the interleukin-10 gene promoter and risk of coronary and cerebrovascular events: the PROSPER study.

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.

Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).

BACKGROUND: Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity. Therefore, we hypothesized that raised leptin levels may identify men at increased risk of a coronary event in the West of Scotland Coronary Prevention Study (WOSCOPS). Methods and Results- Plasma leptin levels were measured at baseline in 377 men (cases) who subsequently experienced a coronary event and in 783 men (controls) who remained free of an event during the 5-year follow-up period of the study. Controls were matched to cases on the basis of age and smoking history and were representative of the entire WOSCOPS cohort. Leptin levels were significantly higher in cases than controls (5.87+/-2.04 ng/mL versus 5.04+/-2.09 ng/mL, P<0.001). In univariate analysis, for each 1 SD increase in leptin, the relative risk (RR) of an event increased by 1.25 (95% confidence interval [CI], 1.10 to 1.43; P<0.001). There was minimal change in this RR with correction for body mass index (RR, 1.24; 95% CI, 1.06 to 1.45; P=0.006) or with further correction for classic risk factors, including age, lipids, and systolic blood pressure (RR, 1.20; 95% CI, 1.02 to 1.42; P=0.03). Leptin correlated with C-reactive protein (r=0.24, P<0.001) and, even with this variable added to the model, leptin retained significance as a predictor of coronary events (RR, 1.18; 95% CI, 1.00 to 1.39; P=0.05) at the expense of C-reactive protein. CONCLUSIONS: We show, for the first time, in a large prospective study that leptin is a novel, independent risk factor for coronary heart disease.

Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.

BACKGROUND: We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. METHODS AND RESULTS: Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of >/=7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of >/=7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. CONCLUSIONS: We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-B metabolism in hypothyroidism.

T4 replacement at 150 micrograms/day in a group of six hypothyroid subjects led to the development of a euthyroid state and produced a fall in the cholesterol content of plasma and low and high density lipoproteins (LDL and HDL). The effect of T4 on apolipoprotein-B (apoB) metabolism was followed using radioiodinated very low density lipoprotein1 (VLDL1; 60-400 Svedberg units) and VLDL2 (20-60 Svedberg units). The pretreatment plasma concentration of VLDL1 apoB and its rates of synthesis and catabolism were similar to those in normal subjects. VLDL2 apoB was synthesized at a supranormal rate in hypothyroid subjects, and this led to a doubling of its circulating mass. Treatment did not significantly alter the kinetics of apoB in either VLDL1 or VLDL2. The concentration of intermediate density lipoprotein (IDL) apoB in untreated hypothyroids was 170% of normal and fell during T4 treatment due to stimulation of conversion of LDL (from 0.46 +/- 0.14 to 0.91 +/- 0.30 pools/day; mean +/- SD; P < 0.01). Direct IDL apoB clearance was not altered by treatment, whereas the fractional catabolic rate of LDL increased 76% (from 0.17 +/- 0.06 to 0.27 +/- 0.07 pools/day), leading to a 36% decrement in LDL mass. The stimulation of IDL to LDL conversion during therapy was probably due to a 3-fold increase in hepatic lipase activity (P < 0.02). This change together with the known effects of T4 on LDL receptors largely explained the lipoprotein abnormality in hypothyroidism and the effects of replacement therapy.

Neurotransmission in the sheep middle cerebral artery: modulation of responses by 5-HT and haemolysate.

In ring sections of the sheep middle cerebral artery, electrical field stimulation elicits a complex response due to the simultaneous release of vasodilator and vasoconstrictor neurotransmitters. Haemolysate abolishes the relaxant effects of the vasodilator neurotransmitter and causes a marked augmentation of the contractile response in both the presence (448 +/- 191%) and absence (409 +/- 134%) of an intact endothelium. The haemolysate also reverses relaxation induced by sodium nitroprusside or sodium nitrite but has no effect on relaxation induced by 8-Br-cGMP. The vasodilator neurotransmitter therefore appears to act directly on the smooth muscle to cause relaxation by the stimulation of guanylate cyclase. The vasoconstrictor neurotransmitters that are released are antagonised by prazosin (100 nM), ketanserin (100 nM) and atropine (100 nM), which suggests that the transmitters involved are noradrenaline, 5-hydroxytryptamine (5-HT), and acetylcholine, respectively. In the presence of these three antagonists at 10 microM, there was 86.9 +/- 4.8% inhibition. Incubation with 5-HT (10 microM) causes a marked augmentation of the contractile response (267 +/- 56%) to field stimulation that can be reduced by pretreatment with either desipramine or citalopram, inhibitors of noradrenergic and serotoninergic uptake mechanisms, respectively. The 5-HT appears to be taken up into noradrenergic nerves and released as an alternative neurotransmitter upon subsequent stimulation. These actions of haemolysate and 5-HT may be involved in the cerebral vasospasm observed following subarachnoid haemorrhage.

Koro: proposed classification for DSM-IV.

Koro, a culture-specific disorder consisting of complaints of genital retraction and fear of death associated with genital retraction, has been recognized in Asian cultures in single cases and in epidemic proportions. Koro has been described in non-Asian patients as well, leading to debate concerning the true nature of the syndrome. The authors review past attempts to define and classify koro and present a classification for DSM-IV that they believe could be used to classify other culture-bound syndromes as well.

Evidence based approach for the management of mixed hyperlipidaemia.

There is now a large body of evidence from multiple clinical trials confirming that lowering plasma low density lipoprotein (LDL)-cholesterol results in a clinically significant reduction in coronary heart disease (CHD) risk. These include the Scandinavian Simvastatin Survival Study and the West of Scotland Study. However, further analyses of the Helsinki Heart Study (HHS) have provided additional detail on the relationship between other lipid changes and incidence of CHD. In the HHS, the reduction of CHD events was related not only to the LDL-cholesterol lowering ability of the drug used, but also to its HDL-cholesterol raising and triglyceride lowering effects. Furthermore, a recent comparison of the levels of atheroma regression associated with different drug classes reveals that, while statins produce much greater changes in total and LDL-cholesterol, fibrates have the most marked effect on coronary artery minimum lumen diameter changes. In practice, the overall CHD risk of patients should be reduced by a co-ordinated approach to management of all the correctable risk factors. As part of this approach, the lipid profile should be assessed and normalised initially through the instigation of lifestyle changes, and if necessary, the adjunctive use of lipid regulating drugs. While the lowering of LDL-cholesterol is clearly important, the significance of lowering plasma triglyceride should not be overlooked.

Predictors of plasma lipoprotein(a) concentration in the West of Scotland Coronary Prevention Study cohort.

An elevated plasma lipoprotein(a) (Lp(a)) concentration is an independent risk factor for coronary heart disease (CHD). Plasma Lp(a) levels are believed to be predominantly controlled by the APO(a) gene, which encodes the apo(a) glycoprotein moiety of the Lp(a) particle. However, other parameters in the lipoprotein profile as well as co-existing disease states or personal traits have been proposed as co-varieties. In order to examine these potential controlling factors in greater detail than previously possible, 1760 unrelated Caucasian subjects were studied, from which were identified 907 with a single expressing APO(a) allele. This strategy was followed to obviate the difficulty in dealing with the co-expression of different apo(a) isoforms and the resulting compound plasma Lp(a) level. After cube-root transformation of the plasma Lp(a) levels to normalise their distribution, a series of correlates were computed. There was no good correlation between Lp(a) concentration and any other measured lipid or lipoprotein in the lipid profile or with any other variable examined, with the important exception of the length of the expressed apo(a) isoform (r = -0.491, P = 0.0001). We conclude that in this population the plasma Lp(a) concentration is not predicted by the plasma lipid profile, alcohol intake, or smoking status but is predicted, albeit incompletely, by the length polymorphism of the APO(a) gene.

Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than total lipoprotein(a) mass? A nested case control study from the West of Scotland Coronary Prevention Study.

The clinical utility of a new assay for plasma lipoprotein(a)-cholesterol (Lp(a)-C) was assessed in parallel with our routine Lp(a) mass measurements in a nested-case control study of subjects within the placebo arm of the West of Scotland Coronary Prevention Study (WOSCOPS). A total of 238 control patients and 108 patients who had suffered a serious vascular event during the course of the WOSCOPS were examined. Lp(a) mass was assessed within 2 years of sampling by an ELISA method on baseline EDTA plasma samples which had been stored at -70 degrees C. Subsequently, the Lp(a) mass was re-measured by an immunoturbidimetric assay approximately 8 years after sampling. On the same stored aliquot the Lp(a)-C was measured. These analyses allowed us to assess whether the Lp(a)-C assay could provide any additional information over and above that which would be obtained from our Lp(a) mass assays. In addition the apo(a) isoform sizes of these subjects were measured using a high resolution immunoblotting system. The Lp(a)-C and Lp(a) mass measurements provided exactly the same information in the study, as they were equally non-discriminatory between cases and controls. The only difference between the two patient groups was the percentage of 'null' apo(a) alleles (control: 25.6% versus cases: 19.4%). We conclude that these results reinforce the concordance of the two assay systems and confirm that the Lp(a)-C assay provides no added information over and above that gained from traditional Lp(a) mass assays, which may be faster and less expensive.

Effects of ciprofibrate on LDL metabolism in man.

This study examined the effects of ciprofibrate therapy (100 mg/day) on plasma lipids, lipoproteins and low density lipoprotein (LDL) kinetic heterogeneity in moderately hypercholesterolaemic subjects. The drug lowered plasma triglyceride and cholesterol by 41% and 17%, respectively. Very low density lipoprotein (VLDL) cholesterol fell by 38%, LDL cholesterol fell by 22%, while the content of the lipid in high density lipoprotein (HDL) increased by 11%. LDL structural and metabolic heterogeneity were assessed before and during therapy in eight subjects. Density gradient centrifugation was used to fractionate LDL into three species. LDL-I, the least dense, was not affected by therapy whereas LDL-II and LDL-III were decreased by 28% (P < 0.01) and 31% (N.S.). Baseline turnover studies revealed that LDL catabolism was subnormal and this was the cause of the raised cholesterol in these subjects. Ciprofibrate therapy increased the apoLDL fractional catabolic rate (FCR) by 19%, principally by inducing a 38% enhancement (P < 0.03) in apoLDL removal by the receptor pathway. ApoLDL kinetics exhibited metabolic heterogeneity both before and during drug therapy. Analysis of plasma decay curves for the LDL tracer and urinary excretion data indicated that the lipoprotein comprised two metabolically distinct species, one with an FCR of about 0.50 pools/day (Pool A), the other with an FCR of about 0.18 pools/day (Pool B). Drug therapy decreased synthesis of and hence reduced the plasma mass of apoLDL in the slow metabolised pool B. This perturbation in synthesis was linked to the change in plasma triglyceride concentration. The resultant reduced proportion of pool B vs. pool A material accounted for the observed promotion of LDL receptor-mediated clearance. Ciprofibrate, therefore, produced beneficial changes in the plasma levels of VLDL, LDL and HDL and in the metabolism of LDL.

The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

Pharmacological characterization of postjunctional alpha-adrenoceptors in cerebral arteries from the sheep.

1. The responsiveness to noradrenaline was characterized in cerebral arteries from the sheep, since this species was large enough to permit a comparison of arteries from different parts of the cerebral vasculature. 2. Noradrenaline caused contraction of the basilar artery, middle cerebral artery and small pial arteries by stimulation of alpha 1-adrenoceptors. 3. The maximum contraction to noradrenaline was small in the basilar artery (28% of the 5-hydroxytryptamine (5-HT) maximum) but larger in the middle cerebral artery (78% of the 5-HT maximum) and pial artery (92% of the 5-HT maximum) of the sheep. 4. Cocaine (10 microM) potentiated noradrenaline-induced contractions in the sheep middle cerebral artery but not in the sheep basilar artery. 5. The noradrenaline contraction, relative to the 5-HT contraction, was not affected by removal of the endothelium in either the sheep basilar or middle cerebral artery. 6. The results showed a variation within the sheep cerebral vasculature in the response to noradrenaline which cannot be explained by regional differences in alpha-adrenoceptor subtypes, noradrenaline uptake mechanisms or endothelial function.

Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.