Hypertension study in anaesthetized rabbits: protocol proposal for AT1 antagonists screening.

INTRODUCTION: The aim of this study was to establish an optimized fast and safe protocol for the pharmacological screening of AT(1) antagonists. MATERIALS AND METHODS: The pharmaceutical prototype AT(1) antagonist losartan, its active metabolite EXP3174 and the synthetic compound MMK1 were analysed in order to validate the protocol. Ang II was continuously infused while the animals received the drugs in two procedures. RESULTS: In the post-treatment procedure drugs were administered either in a single bolus dose or in a sequential manner. When losartan was administered in a single bolus dose, efficacy was evident until the 7th min (p=0.012) whilst EXP3174 infusion extended the efficiency up to the end of the study (p=0.006). In addition, the sequential injections of losartan prolonged the inhibitory time interval until the end of the study (p=0.045). In the pre-treatment procedure, results suggested a dose-dependent inhibitory effect for both antagonists. The pressor response to Ang II was unchanged after MMK1 administration either in the post- or in the pre-treatment mode. CONCLUSIONS: The proposed protocol appears to be safe, simple and fast for the pharmacological screening of AT(1) antagonists and enables the evaluation of new antagonists using lower doses than any other reported in the literature.

Platelet glycoprotein IIb HPA-3 polymorphism and acute coronary syndromes.

BACKGROUND: There is considerable research interest about the platelet GPIIb/IIIa receptor polymorphisms in CAD. METHODS: We investigated differences in the frequency of the polymorphism in the GPIIb subunit of the receptor HPA-3 (a and b allele) between patients with more extensive coronary thrombosis such as patients with ST segment elevation (STEMI) and those with less extensive coronary thrombosis such as those with non-ST elevation myocardial infarction (NSTEMI), unstable angina (UA) or chronic CAD. We studied 118 CAD patients, of which 38 suffered from STEMI, 62 from NSTEMI or UA and 18 from chronic CAD and 15 healthy individuals. Patients were followed-up for 21+/-6 months for occurrence of death, myocardial infarction and revascularization. RESULTS: Seventeen out of 38 (45%) patients with STEMI were homozygous for the HPA-3 b allele compared to 6 out 62 (10%) with NSTEMI-UA , 4 out of 18 (22%) with chronic CAD and 2 out of 15 (13%) healthy controls (chi(2)=16,4, p=0.03.) Homozygous patients for the HPA-3b exhibited a 5-fold higher risk for STEMI compared to heterozygous patients for HPA-3b or homozygous for HPA-3a allele (OR: 5.90, 95% CI: 2.15-16.54, p=0.01) after adjustment for age, sex and risk factors. The HPA-3 genotypes were not related with cardiovascular events during follow-up. CONCLUSIONS: Among patients with an acute coronary syndrome those being HPA-3b homozygous have a tendency to develop ST segment elevation myocardial infarction instead of non-ST segment elevation infarction or unstable angina. There is no association between the HPA-3 genotypes and future cardiovascular events.

Sleep-disordered breathing in a general heart failure population: relationships to neurohumoral activation and subjective symptoms.

The aim of this study was to determine the prevalence of sleep-related breathing disorders (SDB) in a UK general heart failure (HF) population, and assess its impact on neurohumoral markers and symptoms of sleepiness and quality of life. Eighty-four ambulatory patients (72 male, mean (SD) age 68.6 (10) yrs) attending UK HF clinics underwent an overnight recording of respiratory impedance, SaO2 and heart rate using a portable monitor (Nexan). Brain natriuretic peptide (BNP) and urinary catecholamines were measured. Subjective sleepiness and the impairment in quality of life were assessed (Epworth Sleepiness Scale (ESS), SF-36 Health Performance Score). SDB was classified using the Apnoea/Hypopnoea Index (AHI). The prevalence of SDB (AHI > 15 events h(-1)) was 24%, increasing from 15% in mild-to-moderate HF to 39% in severe HF. Patients with SDB had significantly higher levels of BNP and noradrenaline than those without SDB (mean (SD) BNP: 187 (119) versus 73 (98) pg mL(-1), P = 0.02; noradrenaline: 309 (183) versus 225 (148) nmol/24 h, P = 0.05). There was no significant difference in reported sleepiness or in any domain of SF-36, between groups with and without SDB (ESS: 7.8 (4.7) versus 7.5 (3.6), P = 0.87). In summary, in a general HF clinic population, the prevalence of SDB increased with the severity of HF. Patients with SDB had higher activation of a neurohumoral marker and more severe HF. Unlike obstructive sleep apnoea, SDB in HF had little discernible effect on sleepiness or quality of life as measured by standard subjective scales.