Wolfgang Schaumann

Pharmacological effects on coronary reactive hyperemia in conscious dogs

SummaryIn conscious dogs, blood flow in the circumflex branch of the left coronary artery was measured with electromagnetic flowmeters. Myocardial anoxia followed by reactive hyperemia was produced by occluding the artery with a pneumatic cuff for up to 120 sec. 1.The interval between the beginning and the maximum of reactive hyperemia increased with the duration of occlusion.2.Independent of the duration of occlusion, the excess flow during reactive hyperemia was 3–4 times as high as the flow deficit during occlusion.3.Threshold doses of dipyridamole and lidoflazine, while potentiating the dilatation of coronary vessels by adenosine, increased the excess flow only when the arterial occlusion lasted for more than 30 sec. The latter effect was abolished by theophylline.4.Threshold doses of coronary dilators such as Th 322 and carbochromen which do not potentiate adenosine, did not enhance reactive hyperemia for any duration of occlusion.5.Theophylline decreased the duration of reactive hyperemia but not the excess flow as expressed by the integral of the strength of hyperemia over time.6.When infused into the coronary artery, procaine caused a dose-dependent diminution of the reactive hyperemia.The results suggest that appreciable amounts of adenosine are liberated only during complete anoxia for more than 30 sec. Under physiological conditions, coronary resistance is probably regulated by a nervous mechanism and not by the liberation of adenosine.

β-Methyl-digoxin

SummaryGlycosides were injected into a ligated loop of the small intestine of guinea-pigs under urethane anaesthesia. From the residual radioactivity in the intestinal loop at various times after the injection the amount absorbed was determined and from that the rate of absorption, assuming exponential absorption.β-Methyl-digoxin was absorbed more rapidly than digoxin and its derivatives β-acetyl-digoxin and lanatoside C but slower than digitoxin.β-Methyl-digoxin was much better absorbed from a suspension than from a solution; this caused the difference from digitoxin to disappear to a large extent. The high rate of absorption of β-methyl-digoxin in humans is probably explicable in this way.The rate of absorption of β-methyl-digoxin was independent of the dose until the appearance of arrhythmias; it decreased with progressing intoxication. Absorption was delayed when cardiac output was decreased by barbital anaesthesia.The amount absorbed at the onset of arrhythmias can be calculated from the injected dose, the rate of absorption and the time. For β-methyl-digoxin and digoxin it corresponded to the effective doses determined by intravenous infusion and to the cardiotoxicity after intraduodenal injection. The cardiotoxicity of β-acetyl-digoxin and digitoxin was less than that expected from the amounts absorbed suggesting metabolic inactivation during absorption.The relative enteral activity is not only determined by the absorption but also by the rate of elimination. The rate at which the material should leave the intestine in order to maintain arrhythmia was calculated. It was considerably greater for digitoxin than for β-methyl-digoxin or digoxin.

The effect of cyclic adenosine- and guanosine 3',5'-monophosphate on the normal and drug-increased coronary blood flow.

Abstract Cyclic 3′,5′-AMP (cAMP), cyclic 3′,5′-GMP (cGMP) and their more lipo-phylic derivatives (cDBA, cMBA, cDBG) were studied in conscious, resting dogs prepared with chronically implanted electromagnetic flow probes and catheters. Coronary blood flow (CBF), heart rate, aortic blood pressure and in some cases, cardiac output were recorded. cAMP, cDBA and cMBA increased the normal and pharma-cologically elevated CBF while cGMP and its dibutyryl derivative were without effect. Pretreatment with theophylline, a phosphodiesterase inhibitor, diminished the effect of cAMP but enhanced the effect of cDBA and cMBA. The data suggest that cAMP cannot be considered as a second messenger responsible for the maintenance of coronary vascular tone. It may, however, be responsible for coronary vasodilation.

Extrarenal actions of aldosterone antagonists in guinea pigs

SummaryRenal and extrarenal effects of aldosterone antagonists on potassium balance were investigated in guinea pigs.1.Pretreatment with 2×120 μmoles/kg spironolactone orally for 3 days increased the tissue: plasma ratio of potassium in cardiac and skeletal muscle. Plasma potassium was unchanged.2.A single dose of 120 μmoles/kg spironolactone orally increased the urinary output of sodium. The renal excretion and clearance of potassium were unchanged.3.In the isolated heart, perfusion with spironolactone or canrenone induced an uptake of potassium. Canrenoate-K and aldosterone were inactive. It is concluded that in guinea pigs aldosterone antagonists favour a shift of potassium from the extra- to the intracellular space by a direct effect on cardiac and skeletal muscle.

Pharmacodynamics, pharmacokinetics and metabolism of digitoxin and derivatives in cats.

SummaryDerivatives of dihydro-digitoxin (DHD) were studied in the search for a glycoside with a primarily extra-renal clearance and a faster elimination rate than digitoxin. The positive inotropic doses of the derivatives of DHD were higher than those of digitoxin and digoxin. There was no significant difference in the therapeutic margin. After injection of 3H-digoxin in unaesthetized cats, no metabolites were found in the serum which did not bind with the antibody used for the RIA. After injection of 3H-digitoxin, and its derivatives, the radioactivity was cleared from the serum at a much lower rate than the concentrations assayed by RIA. The metabolites which did not bind to the digitoxin antibody were hydrophilic and had a low protein binding. Digitoxin-bisdigitoxoside (Dt-2) determined by RIA rapidly disappeared from the serum. The radioactivity remaining after 24 h was eliminated with a half-life of 219 h. Ten min after injection of DHD the serum contained no unchanged DHD, but 36% digitoxin suggesting that the reduction of digitoxin to DHD is reversible and that the conversion of DHD to Dt-2 is the rate limiting step in the metabolism of digitoxin. The total body clearance of digitoxin, its metabolites and derivatives determined by RIA increased in the order DHD-oxime ⩽ digitoxin > DHD ⩽ DHD-acetyloxime < DHD-methyloxime. The clearance and the elimination rate of DHD-methyloxime were significantly higher than those of digitoxin (P = 0.05).

Effect of Cyclic Nucleosid Phosphates on the Normal and Elevated Myocardial Blood Flow

Cyclic AMP (adenosine 3′, 5′ -monophosphate) and cyclic GMP (guanosine 3′, 5′ -monophosphate) were identified in mammalian tissue several years ago and it was suggested that these hormones might play a role in the reactivity of the smooth muscle of the coronary arteries. The present studies were designed to evaluate the effect of these agents and their more lipophilic derivatives on the normal and elevated coronary blood flow (CBF) of conscious dogs. Elevation of CBF was produced by intravenous injection of metrifudil (Th 322). Various amounts of the cyclophosphates up to 80 mg/dog x min were given by direct intracoronary infusion. The normal and pharmacologically enhanced CBF increased further when cyclic AMP and its dibutyryl derivative (cDBA) were given. The effect of cDBA was augmented after theophylline, whereas the effect of cyclic AMP was diminished after theophylline. This suggests that the increase in CBF by cyclic AMP is mainly due to a contamination by non-cyclic adenosine compounds, e.g. 5′ AMP which is a very potent coronary dilator. Cyclic GMP was without effect. The possible role of the cyclophosphates in the adaptation of CBF to myocardial metabolism will be discussed.