Evidence for the binding of beta-adrenoceptor blockers to microsomal Na+/K+-ATPase in guinea pig heart preparations.

We reported in a previous study that beta-adrenoceptor blockers inhibit the Mg2+-dependent ATP-hydrolytic function of Na+/K+-ATPase. To determine if this action is a result of binding of beta-blockers to the receptor sites that bind the digitalis glycosides, we performed displacement binding assays of eight beta-blockers with [3H]-ouabain (OUA) in guinea pig myocardial microsomal preparations. In the first series of experiments, 10-200 microM of the beta-blockers were displaced with 250 nM OUA. In the second set of experiments, 10-500 nM of OUA was displaced using 200 microM of the beta-blockers. The drugs showed concentration-dependent receptor occupancy at the different OUA levels. Propranolol (PPN), metoprolol (MTP), and sotalol (STL) showed the strongest binding; nadolol (NDL), indenolol (IDN), and atenolol (ATN) had intermediate binding; carazolol (CRZ) and celiprolol (CLP) had the weakest binding properties. The results suggest that beta-blockers may compete for the same binding sites with ouabain in their inhibition of the Na+/K+-ATPase. These actions may contribute to the mechanism for some of their cardiac effects, especially their proarrhythmic and arrhythmogenic actions.

Angiotensin-converting enzyme polymorphism and the risk of coronary heart disease in the Saudi male population.

OBJECTIVE: To determine the relevance of angiotensin I-converting enzyme (ACE) gene polymorphism for coronary artery disease (CAD) in the Saudi population. METHODS AND RESULTS: DNA of 84 male Saudi patients with established CAD, 36 male controls who underwent angiography, and 327 healthy Saudi male blood donors was amplified by polymerase chain reaction, using oligonucleotide primers flanking the insertion (I)/deletion (D) sites in the polymorphic region of intron 16 of the ACE gene. Polymerase chain reaction amplification resulted in 490-bp (II), 190-bp (DD), or 490- and 190-bp (ID) fragments. The genotype II distribution was 16.7% in the control group, 7.3% in the blood donor group, and 7.2% in the patients with CAD, and the distribution for DD was 58.3%, 47.1%, and 41.0%, respectively. Notably, 61.9% (P <.0001) of CAD patients presented with angina on admission, and 52.4% had diabetes mellitus. CONCLUSIONS: The results show no increased risk of CAD in association with either the II or DD genotypes in the Saudi population. However, further investigation of genotype II as a predictor for atherosclerosis rather than increased risk of coronary heart disease may be indicated.

Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+ -K+ ATPase.

The notion that the inhibition of the Mg2+ -dependent ATP-hydrolytic function of the myocardial Na+ -K+ ATPase by class I antiarrhythmic agents occurs as a result of their binding to the same receptor sites as the digitalis glycosides was tested by performing competitive binding assays of [3H]ouabain (OUA) with eight drugs: disopyramide, encainide, lidocaine, lorcainide, phenytoin, procainamide, quinidine, and tocainide in guinea pig heart microsomal preparations. In the first set of experiments, 10-200 microM concentrations of the drugs were preincubated with the enzyme and displacement assays performed with 250 nM OUA. The drugs showed receptor occupancy of 19-32% at 50 microM, 25-44% at 100 microM, and 37-56% at 200 microM. Then, 10-500 nM concentrations of OUA were preincubated with the enzyme, and competitive assays were performed using 200 microM concentrations of the drugs. OUA occupied 39-51% of the receptor sites at 100 nM, 44-67% at 250 nM, and 62-82% at 500 nM, displacing the drugs in a concentration-dependent fashion. The results show that antiarrhythmic drugs interact with the same or similar receptor sites as ouabain on the Na+ -K+ ATPase, pointing to a possible contribution of these interactions to the mechanism for their inhibitory actions on the enzyme, and perhaps their arrhythmogenic effects.

Relevance of apolipoprotein E polymorphism for coronary artery disease in the Saudi population.

BACKGROUND: The apolipoprotein E alleles epsilon2 and epsilon4 have been reported as independent risk factors for coronary artery disease (CAD) and as predictors for the development of atherosclerosis. METHODS AND RESULTS: We determined by polymerase chain reaction the distribution of apolipoprotein E polymorphism in 320 Saudi blood donors (BD), 96 CAD patients, and 40 control subjects who had undergone angiography. Compared to controls, only epsilon4 was elevated in CAD patients. More than 61% (P <.0001) of the patients had angina, and 52.1% (P <.05) were diabetic; both of these factors were strongly associated with the presence of allele epsilon2. The epsilon2 allele was also associated with hypertension, elevated serum triglycerides, and total cholesterol. On the other hand, the allele epsilon4 appeared to be associated with increased risk of CAD and was also associated with hypertension, 3-vessel disease, and restenosis. CONCLUSIONS: Accordingly, epsilon4 may be associated with increased risk of CAD, whereas epsilon2 appears to be a predictor of several risk factors for atherosclerosis.

Platelet alpha-adrenoceptor density in patients with left ventricular volume overload.

We have evaluated the possibility that, in patients with left ventricular heart disease, the effects of aortic and mitral regurgitation on platelet alpha 2-adrenoceptors may depend on the origin and severity of the overload. Receptor density and binding affinities were estimated by their specific binding to [3H]-yohimbine. In blood donor controls (CON), the receptor density was 4.72 +/- 0.41 fmol/10(6) platelets (n = 31). In the volume overloaded patients (n = 35), the total density was elevated by 57% (p < 0.05) accompanied by a 69% (p < 0.05) increase in plasma epinephrine. Compared with CON, patients with pure aortic regurgitation (AVR, n = 12) showed a 91% (p < 0.0001), pure mitral regurgitation (MVR, n = 15) 43% (p < 0.05) and mixed mitral and aortic valve regurgitation (MOL, n = 8) 23% increase in receptor density. Furthermore, the elevation of the density in the aortic disease was significantly greater (p < 0.05) than in the mixed overload group. There was a weak positive correlation between the increase in receptor density and the ejection fractions (r = 0.27), suggesting that the former may be dependent on the severity of the volume overload. The results show that in left heart valvular disease, aortic regurgitation leads to a highly significant increase in alpha-adrenoceptor density, while the effects of mitral valve disease exhibit borderline significance. These findings probably point to the differences in the extent of influence of the origin and severity of the two forms of left ventricular volume overload (LVO), as well as the ensuing hemodynamic changes on the cardiac contractile apparatus.