Friedel Seuter

Inhibition of Platelet Aggregation by Acetylsalicylic Acid and other Inhibitors

Effects on platelet aggregation were examined of acetylsalicylic acid (ASA), indomethacin and a number of other agents including dipyridamole, phenylbutazone and sulfinpyrazone under standardized conditions. The Born turbidometric method of measuring platelet aggregation was used with collagen as the stimulus for aggregation. ASA and indomethacin were shown to be among the most potent inhibitors of aggregation, being active at minimal effective concentrations of 1-3 mug/ml using a 10 min time of pre-incubation with the platelet-rich plasma (degree of aggregation inhibition was time dependent). Most of the other agents tested were also active in vitro and both prostaglandin E1 and adenosine were more potent than ASA or indomethacin. However, these agents were shown not to exert significant inhibitory effects when administered orally to rats (dose 10 and 30 mg/kg). ASA proved to be effective in doses as low as 3 mg/kg, and indomethacin in doses as low as 1 mg/kg orally. The inhibitory effects of ASA on aggregation remained for several days after a single oral dose, whereas the effects of indomethacin disappeared within 24 h.

Protective effect of a novel thromboxane antagonist, BAY-U3405, on canine myocardial damage after coronary artery occlusion and reperfusion

The effects of a novel thromboxane antagonist, (3R)‐3‐(4‐fluorophenylsulfonamido)‐1,2,3,4‐tetrahydro‐9‐carbazolepropanoic acid (BAY‐U3405), on myocardial damage due to ischemia and reperfusion (added to accelerate the initiated injury) were studied in anesthetized dogs. The left anterior descending (LAD) coronary artery was occluded for 6 hours and reperfused for 30 minutes. BAY‐U3405, 1 mg/kg, was injected intravenously 15 minutes after LAD occlusion, followed by continuous infusion of 10 mg/kg/hour starting at 30 minutes after occlusion. The drug had no hemodynamic effects. During the experiments 6 of 14 animals died of ventricular fibrillation (VF) in the placebo‐vehicle controls (3 during occlusion and 3 during reperfusion); in the drug‐treated group 5 of 13 dogs died of VF (all during occlusion none during reperfusion). This difference in total mortality and cause was not statistically significant. Reperfusion arrhythmias were largely suppressed by BAY‐U3405: 201 ± 43 versus 689 ± 98 irregular beats during 30 minutes (p < 0.001) in the experimental and control groups, respectively. Coronary collateral flow, obtained from a load‐line analysis by measurement of retrograde coronary flow, and collateral index were similar in both groups. Therefore, BAY‐U3405 did not alter collateral blood supply to the ischemic myocardium. Infarct size, determined with tetrazolium staining, was reduced by 65% (p < 0.01) after its administration. These results suggest that thromboxane antagonism by BAY‐U3405 may delay infarct expansion and reduce the frequency of ventricular arrhythmias during reperfusion of previously ischemic myocardium.

Experimental Hypertension and Therapeutic Progress: Vasodilation and Beyond

Inhibition of atrial natriuretic peptide (ANP) degradation by enkephalinase is known to increase endogenous ANP levels and to induce similar functional effects as administration of exogenous ANP. The influence of this principle on cardiac function in rats with hypertension-induced heart failure was investigated. We used 13-month-old male stroke-prone spontaneously hypertensive rats (SHR) with heart failure and hypertrophy. Groups of 12 rats were treated either with the enkephalinase inhibitor sinorphan (SIN; 31.5 mg/kg bj.d.), 50 ppm hydrochlorothiazide (HCTZ), in the feed or vehicle only for 14 days. SIN and HCTZ had similar acute natriuretic effects. Chronic treatment failed to affect natriuresis. SIN increased plasma and urinary cyclic guanosine monophosphate (cGMP). Unlike HCTZ, SIN reduced left ventricular enddiastolic pressure and heart weights. HCTZ failed to affect cardiac function or hypertrophy, but increased plasma renin activity. These reSults suggest that therapeutic use of ANP can improve cardiac function and structure in hypertension-induced cardiac failure. It was also shown that standard natriuretic treatment was ineffective.