Summary: We studied thirteen patients before and after a five‐minute infusion of intravenous dipyridamole (Persantin) (0.6 mg/kg). In ten patients with no evidence of ischaemic heart disease there were only modest increases in cardiac output (+17%) and heart rate (+16%), and decreases in systemic resistance (‐24%), pulmonary capillary pressure (‐19%), and mean blood pressure (‐10%), five minutes after dipyridamole. Values returned towards control levels ten minutes later; there were no symptoms. By contrast, two patients with ischaemic heart disease developed acute coronary insufficiency after dipyridamole. ECG changes indicated acute ischaemia in the region of the previous infarct. Used diagnostically in a third patient, with the patient's consent, dipyridamole produced symptoms and haemodynamic changes of angina pectoris. We concluded that dipyridamole caused moderate peripheral vasodilatation in the patients without evidence of coronary artery disease. The findings in the patients with ischaemic heart disease are consistent with the hypothesis that dipyridamole produced a shunting of blood away from ischaemic areas in the myocardium by reducing coronary vascular resistance more in well perfused areas than in ischaemic areas–a “coronary steal” effect. Recent reports suggest that dipyridamole (Persantin) reduces platelet aggregation1–4. This effect has been the rationale for the use of dipyridamole with anticoagulants in the prevention of thromboembolic complications of prosthetic valve replacement5 and in the treatment of acute renal failure due to glomerulonephritis6 and rejection of the transplanted kidney7. It is possible that repeated attacks of “crescendo” angina pectoris and acute coronary insufficiency, which frequently culminate in myocardial infarction, could be due to recurrent embolisation of platelet aggregates forming on an atheromatous plaque in a major coronary vessel. If this hypothesis is correct, infusions of dipyridamole might be useful therapeutically. We undertook a study of the effects of dipyridamole on plateletss and in the course of this we noted important and unexpected circulatory effects of the drug in two patients with coronary artery disease. This prompted us to investigate the circulatory effects of dipyridamole and this paper reports our findings; some of the results have already been recorded briefly9,10.

I Aminophylline inhibits the coronary vasodilator actions of adenosine. Our previous studies suggested that low dose infusions of aminophylline reduce coronary blood flow in the isolated heart. In the present study we investigated the actions of aminophylline on coronary blood flow and myocardial contractility in a transplanted heart model. Drugs were given by close coronary arterial infusion.2 Aminophylline in low doses (200 pg/min) reduced coronary blood flow by 21 ± 2% (mean ± s.e. mean) but did not alter myocardial contractility or heart rate. Higher doses (500 and 1000,ug/min) increased coronary blood flow and myocardial contractility without changing heart rate. 3 a-Adrenoceptor blockade with phenoxybenzamine did not affect the response to a low dose of aminophylline (200 pg/min). 4 Propranolol in doses of 10 and 30,ug/min blocked ,B-adrenoceptors but did not change coronary blood flow. The higher dose reduced myocardial contractility. 5The effects of a high dose of aminophylline (1000,g/min) on coronary blood flow were not changed by either a-or ,B-adrenoceptor blockade, although propranolol (30,ug/min) reduced the augmentation in myocardial contractility. 6 The results show that when given in doses which do not alter myocardial contractility, aminophylline reduces coronary blood flow in the isolated heart and that this is not mediated through an a-adrenoceptor mechanism, They also show that the increases in coronary blood flow and positive inotropic effects obtained with higher doses of aminophylline are not mediated through catecholamines and suggest that higher doses of aminophylline have a small direct coronary vasodilator action. The low dose vasoconstrictor response may be produced by inhibition of the coronary vasodilator action of locally produced adenosine.

Coronary blood flow and vascular reactivity were studied at intervals after donor dog hearts were transplanted into the necks of recipient dogs. Coronary blood flow was measured with an electromagnetic flow transducer on the carotid artery of the recipient dog, and coronary vascular reactivity was assessed from the response of the coronary vessels to the vasodilator drugs, dipyridamole and adenosine. During the first 4 days after the transplant, resting coronary blood flow and vascular resistance did not change. Responses to dipyridamole and adenosine were unchanged during the first 2 days but were reduced on the third and fourth days. Increased vascular permeability to circulating Evans blue dye and deposition of colloidal carbon in venules occurred in association with small increases in left ventricular myocardial water content 3 and 4 days after the transplant. These changes indicate that an inflammatory response accompanies the onset of histological evidence of rejection at 3 and 4 days. The reduced vascular reactivity of the transplanted heart at 3 and 4 days may be related to morphological changes in arterioles rather than to gross edema formation during rejection. KEY WORDScoronary blood flow Evans blue dye coronary vascular reactivity permeability studies in the heart dipyridamole acute rejection adenosine colloidal carbon transplantation• The early phase of acute rejection of organ allografts is accompanied by evidence of increased vascular permeability (1, 2) and mononuclear cell infiltration. Similar changes are present in the early rejection of the transplanted heart (3-5), indicating alterations in the walls of the coronary blood vessels. The response of these altered vessels to coronary vasodilator drugs is not known but may be of clinical importance in the management of rejection crises associated with a reduced coronary blood flow (6). In earlier studies we have shown that the response of the coronary vasculature to vasodilator drugs is normal in the immediate posttransplantation period (7,8). In the present study, we measured the coronary blood flow in the heart from the time of the transplant until there was early histological evidence of rejection and we assessed coronary vascular reactivity by recording the increases in coronary blood flow produced by the vasodilator drugs, dipyridamole and adenosine. Changes in coronary artery reactivity were correlated with histopathological changes and permeability studies in coronary arterial and cardiac microcirculation in the early phases of rejection. Methods EXPERIMENTAL MODELThe donor dog's heart was transplanted into the neck of the recipient dog according to a modification of the technique described previously (7). All the dogs were anesthetized with sodium thiopental (20 mg/kg, iv) and maintained on a gas mixture of nitrous oxide and oxygen (2:1). The recipient dogs (20-25 kg) also received halothane (0.5-1.0%).The neck of the recipient dog was dissected to expose the carotid artery and the external jugular vein. Arterial and venous polyvi...

Intracoronary administration of isoprenaline, adrenaline, and the noradrenaline in the Langendorff-type transplanted dog heart transiently decreased coronary blood flow measured from the inflow vessel; flow then increased. The reduction in coronary flow coincided with increased myocardial contractility and was prevented by keeping the left ventricle empty. Propranolol prevented changes in flow and contractility. It is concluded that positive inotropic changes result in the ejection of accumulated Thesbesian flow from the ventricle and affect coronary flow measurements and that the interpretation of flow changes requires a steady state.