A Bonaccorsi’s research while affiliated with Mario Negri Institute for Pharmacological Research and other places

An investigation was conducted to study whether animals with experimental cardiovascular disorders were more sensitive to the cardiotoxic effects of nortriptyline (NT) than normal animals. Since increased toxicity might be due to hypersensitivity of the target organ (the heart) and/or to increased blood levels of the drug, NT blood levels and an electrocardiogram (ECG) were simultaneously recorded in unanesthetized rabbits during NT intravenous infusion. Nortriptyline induced marked ECG alterations such as tachycardia, arrhythmias, impaired conduction, ST and T wave abnormalities, although only the increase in PQ and QRS intervals were directly correlated with NT blood levels (p < 0.01). A one-compartment model described the pharmacokinetics and pharmacodynamics of NT disappearance. Nortriptyline blood levels of about 0.5 caused a 10% increase in PQ and QRS. A 20% complex widening occurred at 1 . The pharmacokinetics and cardiac effects of NT did not significantly differ in rabbits with experimental myocardial infarction (isoprenaline 50 × 2 days), hyperthyroid rabbits (triiodothyronine 0.1 × 15 days), or controls.

A radioactive microsphere method for the determination of cardiac output distribution has been adapted to the mouse. Microspheres injected into the left ventricle are distributed to the tissues proportionally to theirs blood flow and trapped by the microvasculature during the first passage. The assumptions for the application of this method were checked. Two determinations of cardiac output distribution can be made in the same animal and the effect of noradrenaline was evaluated.

Radioactive microspheres, 15 μ in diameter, labelled with 57Co and 58Co, were used for simultaneous determination of cardiac output and its distribution in the same unanesthetized rat. Spheres were injected into the left ventricle and a reference sample obtained from the femoral artery. Both sites were cannulated the day before the experiment under pentobarbital anesthesia. The findings for cardiac output and major organ distribution agree with most published reports obtained in the rat in different experimental conditions. To test the sensitivity of this method to modifications of the peripheral vascular bed, we compared the effects of exposure to three different temperatures, 23°, 4°, and 38°C, on organ blood flow. The most important circulatory changes occurred in the regions involved in heat regulation such as the tail, ears, and paws.

The contribution of platelets to the cardiovascular effects of ADP was investigated in rats in different experimental conditions. Following rapid i. v. bolus injections of ADP (from 0.001 to 0.03 mg/kg b. w.) only a dose-related fall in blood pressure could be detected. Increasing the dose of ADP (up to 1 mg/kg b. w.), platelet fall and changes in cardiac rhythm (bradycardia, A. V. blocks and ectopic beats) became evident. All these phenomena were rapidly reversed. Inhibition of platelet aggregation by a pyrimido-pyrimidine compound (SH 869) or thrombocytopenia induced by Busulfan or antiplatelet antiserum did not significantly protect the animals from the cardiovascular effects of ADP. The fall in blood pressure, however, was reduced. Adenosine, at equimolar concentrations, caused ECG changes similar to those induced by ADP with no platelet aggregation and a less pronounced blood pressure fall. These results suggest that most of the cardiovascular modifications induced by rapid injection of ADP are largely independent of platelets. Platelets appeared to play a more important role when ADP was given for a longer period of time. A slow i. v. infusion of ADP (6 mg/kg b. w. for 10 min) was accompanied by platelet fall, cardiovascular collapse and ECG alterations typical of myocardial ischaemia. All these effects persisted throughout the ADP infusion but disappeared soon after its termination. They were almost completely inhibited in rats given SH 869 or made thrombocytopenic. In conclusion, platelets seem to contribute to the cardiovascular effects of ADP only in certain experimental conditions. In others, the nucleotide’s direct effects seem more important.

We investigated the role played by platelet aggregates in cardiovascular alterations induced by ADP in the rat by following the localization of Cr51-platelets in different circulatory districts. An intravenous infusion of ADP (3 mg/kg/5min ) caused cardiovascular collapse accompanied by a 50% fall in platelet count and Cr51 blood radioactivity. Cr51-platelet content increased five fold in the lung. When ADP was infused into the left ventricle only a moderate decrease in systemic blood pressure was observed although the platelet fall was similar to that observed after i.v. infusion. Significantly higher radioactivity than controls was found in the heart, kidney, femoral muscle and brain, but not in the lung. It is suggested that selective platelet trapping in the pulmonary circulation in addition to the direct vasodilating activity of ADP were the major causes of cardiovascular shock during ADP infusion in the rat.

Acetylsalicylic acid (ASA) did not prevent the arrhythmias induced in rats by a bolus intravenous injection of ADP, an effect independent of platelets. ASA was also unable to protect the rats from the platelet-mediated cardiovascular effects and myocardial ischaemia induced by a prolonged ADP infusion. It is suggested that the release of vasoactive substances inhibited by ASA does not play a major role in the cardiovascular effects of ADP in rats.

The contribution of platelets to the cardiovascular effects of ADP was investigated in rats in different experimental conditions. Following rapid i. v. bolus injections of ADP(from 0.001 to 0.03 mg/kg b. w.) only a dose-related fall in blood pressure could be detected. Increasing the dose of ADP (up to 1 mg/kg b. w.), platelet fall and changes in cardiac rhythm (bradycardia, A. V. blocks and ectopic beats) became evident. All these phenomena were rapidly reversed. Inhibition of platelet aggregation by a pyrimido-pyrimidine compound (SH 869) or thrombocytopenia induced by Busulfan or antiplatelet antiserum did not significantly protect the animals from the cardiovascular effects of ADP. The fall in blood pressure, however, was reduced. Adenosine, at equimolar concentrations, caused ECG changes similar to those induced by ADP with no platelet aggregation and a less pronounced blood pressure fall. These results suggest that most of the cardiovascular modifications induced by rapid injection of ADP are largely independent of platelets. Platelets appeared to play a more important role when ADP was given for a longer period of time. A slow i. v. infusion of ADP (6 mg/kg b. w. for 10 min) was accompained by platelet fall, cardiovascular collapse and ECG alterations typical of myocardial ischaemia. All these effects persisted throughout the ADP infusion but disappeared soon after its termination. They were almost completely inhibited in rats given SH 869 or made thrombocytopenic . In conclusion, platelets seem to contribute to the cardiovascular effects of ADP only in certain experimental conditions. In others, the nucleotide’s direct effects seem more important.

Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally. Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions. Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion. Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 μg/ml for desipramine and from 0.04 to 1.2 μg/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40° rotation were 1.35 μg/ml (desipramine) and 1.75 μg/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 μg/ml for desipramine and 3.6 μg/ml for protriptyline. Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.