Karl Dietmann

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.

A method for evaluating postural hypotension in conscious rabbits as a model to predict effects of drugs in man

Because of the importance of postural hypotension as a side effect of antihypertensive drugs in man, an experimental model has been developed that permits the investigation of blood pressure response to tilting. Conscious rabbits were placed on a tilting table and tilted rapidly from horizontal to vertical position. Blood pressure was recorded continuously throughout the whole period. The individual orthostatic reaction was expressed as an orthostatic index. The experimental data obtained with guancydine, clonidine, guanethidine, prazosin, and dihydralazine were compared with clinical observations with regard to the impairment of orthostatic reaction; dihydralazine did not agree, but there was a good agreement for guancydine, clonidine, guanethidine, and prazosin. Although complete agreement between the experimental data and clinical observations does not exist, the model seems to be sufficient to differentiate between drugs with low or high potential for postural hypotension.

Zur Regelung der Coronardurchblutung im akuten Sauerstoffmangel

SummaryThe coronary blood flow of 5 conscious dogs was recorded continuously with electromagnetic flowmeters. A temporary local hypoxia of the myocardium induced by means of a pneumatic blood vessel occuluder was followed by a reactive hyperemia.Theophylline prevented the increase in coronary blood flow during adenosine infusion but not the reactive hyperemia. This shows that the latter is not caused by a release of adenosine.ZusammenfassungAn fünf wachen Hunden wurde die Coronardurchblutung mit elektromagnetischen Durchflußmessern fortlaufend registriert. Mit einer pneumatischen Verschlußmanschette konnte eine temporäre, lokale Hypoxie des Herzmuskels erzeugt werden, der eine reaktive Mehrdurchblutung folgte.Theophyllin verhinderte die Zunahme der Coronardurchblutung bei Infusion von Adenosin, nicht aber die reaktive Hyperämie. Daraus wird geschlossen, daß letztere nicht durch eine Freisetzung von Adenosin zustande kommt.

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.

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.