J.R. Boissier

Cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 115): II. Central sympathetic structures

Abstract In order to discover whether 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155) has a central site of action, the influence of the drug on spontaneous discharges of sympathetic nerves, and on evoked discharges elicited by chemostimulant drugs or electrical stimulation of sympathetic structures of the brain stem was investigated. In dogs, ST 155 induced bradycardia and hypertension which was usually followed by hypotension. Discharges in splanchnic and inferior cardiac nerves were strikingly reduced or even abolished by ST 155, recovery appearing sometimes after three hours. The site of action appeared to be central because the phenomenon was also observed in debuffered dogs. However, activity in sympathetic nerves could still be evoked by chemo receptor stimulating drugs. Injected intracisternally, ST 155 induced a decrease in blood pressure and a reduction in sympathetic discharges. In cats, the same reduction of spontaneous electrical activity of sympathetic nerves was observed. In addition, increase in blood pressure and evoked discharges induced by hypothalamic and medullary pressor areas stimulation were decreased, but the effects of supramaximal stimulation were not modified. In rats, action potentials in the splanchnic nerve, as well as the evoked discharges elicited by hypothalamic and medullary stimulations were reduced by ST 155. ST 155 appears to be a very potent inhibitor of the spontaneous sympathetic centre in the brain stem, but is less effective on reflexly or centrally evoked discharges.

Centrally mediated decrease in sympathetic tone induced by 2(2,6-dichlorophenylamino)-2 imidazoline (S.T. 155, Catapresan)

Abstract 2(2, 6-dichlorophenylamino)-2 imidazoline hydrochloride (S.T. 155) induced in dogs a long lasting hypotension following a brief increase in blood pressure. At low doses, S.T. 155 decreased strikingly the discharges in the splanchnic and inferior cardiac nerves; this was also obtained in debuffered animals. This reduced sympathetic tone appeared to be the cause of the fall in blood pressure.

Cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155): I. Peripheral sympathetic system

Abstract The effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155) have been investigated on the peripheral sympathetic system. ST 155 induced an initial rise in blood pressure in normal and reserpinized or adrenalectomized animals, a contraction of the nictitating membrane of cats and isolated seminal vesicles of guinea pigs and a vasoconstriction in isolated ears of rabbits: all these actions were abolished by phentolamine, suggesting that ST 155 exerts these effects by direct stimulation of α-adrenergic receptors. No β-adrenergic blocking properties could be demonstrated. Low doses of ST 155 potentiated but higher doses decreased or even reversed the hypertensive actions of adrenaline and noradrenaline. The effects of the stimulation of the whole sympathetic system in pithed rats were reduced by ST 155, but the preganglionic stimulation of the nictitating membrane remained unaltered. These results are discussed and it is concluded that although ST 155 induced a certain degree of α-adrenergic blockade, this effect is not sufficient to account for the hypotensive action of the drug.

β-Adrenergic blockade and atrio-ventricular conduction impairment

Atrio-ventricular conduction and its modifications induced by six β-adrenergic blocking agents have been investigated in the dog. Premature atrial stimuli (St2) were applied at variable intervals following regular stimuli (St1) ensuring atrial pacing; atrial (AERP), nodoventricular (NERP) and global (GERP) effective refractory periods as well as global functional refractory period (GFRP) were determined before and after administration of each of the six drugs. When β-blockade was produced with d,1-propranolol which has membrane stabilizing effects (MSE) but no intrinsic sympathomimetic activity (ISA) or with sotalol, which has neither MSE nor ISA, all parameters were significantly increased. When β-blockade was achieved with pindolol or practolol, which have ISA but no MSE, all parameters remained unchanged, as was also the case with d-propranolol which has MSE but only a poor β-adrenolytic potency and no ISA. Alprenolol showed intermediate effects. Thus, it appears that β-blockade and not MSE, is responsible for the onset of A-V conduction impairment but that ISA, probably through a metabolic mechanism, affords protection against this impairment. On the other hand, measurement of ventricular effective refractory period (VERP) has shown that at the Purkinje-free wall junction, it is MSE which is mainly involved in conduction impairment.

Effects of atenolol on regional myocardial blood flow and ST segment elevation in the canine myocardium.

1 The effects of atenolol on regional myocardial blood flow (RMBF) and on ST segment elevation were studied both in normal and ischaemic regions of the myocardium in dogs. Some of the experiments were performed with cardiac pacing or after bilateral stellectomy.

Comparative study of six β‐adrenoceptive antagonists on airway resistance and heart rate in the guinea‐pig

1 The effects of six β‐adrenoceptive antagonists [(±)‐propranolol, (+)‐propranolol, (±)‐sotalol, (±)‐practolol, (±)‐pindolol and (±)‐procinolol] were studied on airway resistance and heart rate in guinea‐pigs and dose‐response curves constructed. 2 All β‐adrenoceptive antagonists decreased heart rate and increased airway resistance. A significant correlation was found between the increase in airway resistance and the degree of bradycardia induced by all drugs except practolol. The orders of activity of the six drugs in inducing significant variations of the two parameters were respectively, for airway resistance: (±)‐procinolol>(±)‐pindolol>(±)‐propranolol>(±)‐sotalol>(±)‐propranolol>(±)‐practolol, and for heart rate: (±)‐pindolol>(±)‐procinolol>(±)‐propranolol>(±)‐sotalol>(±)‐propranolol>(±)‐practolol. 3 (±)‐Sotalol, (±)‐pindolol and (±)‐procinolol‐induced changes in airway resistance and heart rate reached plateau values, which were not modified by increasing the dose. Since sotalol and procinolol have only very weak partial agonist and cardiac depressant properties, it appears that these changes can mainly be accounted for by the suppression of sympathetic tone. It is probable that this is also the case with pindolol. 4 On the other hand, (±)‐propranolol and (±)‐propranolol induced dose‐related changes in airway resistance and heart rate. Thus, a direct and nonspecific effect of both drugs on the bronchial muscle, similar to that observed on the heart appears to be implicated, together with sympathetic tone suppression in these variations. 5 (±)‐Practolol‐induced effects on airway resistance and heart rate were different from those observed with the five other β‐adrenoceptive antagonists.

Differential inotropic--chronotropic action of thyronamine.

Abstract J.R. BOISSIER, J.F. GIUDICELLI, S. LARNO and C. ADVENIER, Differential inotropic-chronotropic action of thyronamine , European J. Pharmacol. 22 (1973) 141–149. The cardiovascular and hemodynamic effects of thyronamine have been investigated in anesthetized dogs. Thyronamme produced dose-related increases in myocardial contractile force, cardiac output and left ventricular work but did not affect heart rate. These actions were not affected by atropinization or by bilateral vagotomy. However, the positive inotropic effects of thyronamine were completely abolished in dogs and almost completely abolished in isolated guinea-pig atria by prior administration of reserpine or by β-adrenergic blockade. These results suggest that thyronamine acts mainly by releasing endogenous catecholamines acting on β-adrenergic inotropic receptors. The differential inotropic-chronotropic effects of thyronamine, which resemble those of dopamine, suggest that the β 1 -type adrenoceptors are not homogeneous and that inotropic and chronotropic receptors may differ from each other.

Effects of verapamil on regional myocardial blood flow and ST segment. Role of the induced bradycardia.

The effects of verapamil on regional myocardial blood flow and on the ST segment were studied in both normal and ischemic regions in dogs with and without cardiac pacing. In the absence of cardiac pacing, verapamil (0.05 mg/kg/min/10 min) induced marked bradycardia, a drop in blood pressure and an increase in epicardial and endocardial flows both in normal and ischemic regions of the heart. However, in ischemic regions, redistribution was favorable since the endo/epi ratio increased from 0.46 to 0.61 (p less than 0.01) whereas this ratio did not vary in normal regions (0.94 vs. 0.92). This increase is accompanied by less marked ST segment elevation during coronary occlusion in dogs treated with verapamil. In dogs with cardiac pacing, administration of verapamil under the same conditions again induced a drop in blood pressure and, in normal regions only, a homogeneous but less marked increase in epicardial and endocardial flows, the endo/epi ratio varying from 0.94 to 0.98. In contrast, in ischemic regions, blood flow was not modified by verapamil, but the endo/epi ratio dropped from 0.46 to 0.31 (p less than 0.01), while the ST segment elevation observed did not differ from that recorded during the control occlusion. These results demonstrate the major role of verapamil-induced bradycardia in the anti-anginal affects of this drug.

Studies on 1-(o-cyclopropylphenoxy)-3-isopropylamino-2-propanol, a new β-adrenergic blocking drug

Abstract The beta-adrenergic blocking action, the effects on resting cardiovascular parameters and the anti-arrhythmic properties of 1-(o-cyclopropylphenoxy)-3-isopropylamino-2-propanol hydrochloride (SD 2124-01) were investigated. SD 2124-01 was 6 to 43 times more potent than propranolol in antagonizing the effects of isoproterenol on heart rate, myocardial contractile force, dLVP/dt and diastolic blood pressure. In isolated preparations (guinea pig atria and tracheal chains), it was 7 to 10 times more potent than propranolol. LD 50 s of SD 2124-01 and propranolol in mice were not significantly different. At beta-adrenergic blocking doses, SD 2124-01 was devoid of any intrinsic beta sympathomimetic activity and did not depress the resting cardiovascular parameters of chloralose-anesthetized dogs. Simultaneously, SD 2124-01 facilitated ‘auriculoventricular conduction’. At high doses, it reversed ouabain-induced ventricular tachycardia but reversio was then associated with moderate cardiac depression. Thus, SD 2124-01 appears to be, like prinodolol, one of the most potent and least cardiodepressive beta-adrenergic blocking drugs.

β-Adrenoceptor Blockade and Genetic Hypertension Development in Rats

The effects of propranolol (100 mg/kg), atenolol (200 mg/kg) and acebutolol (1000 mg/kg) administered daily by gavage to spontaneously hypertensive rats (SHRs) from their 6th to 20th weeks of age were investigated on genetic hypertension development (GHD) and at regular intervals on heart rate (HR), cardiac output (CO), stroke volume (SV), peripheral resistance (PR), plasma renin concentration (PRC) and heart weight/body weight ratio (HW/BW). Treatment with propranolol and especially atenolol markedly inhibited GHD while acebutolol was ineffective. No correlation was found between GHD prevention and (1) the degree of β-adrenergic blockade (2) the reductions in HR and CO and (3) the decrease in PRC induced by the three treatments. Although none of the three drugs prevented the progressive increase in PR which develops in SHRs during their growth, propranolol and atenolol opposed GHD mainly by reducing CO, this effect being however partly counterbalanced for atenolol by a secondary potentiation of PR increa...