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The alpha, beta-adrenergic blocking, antihypertensive and vasodilating properties of N-1518 were compared with those of labetalol. N-1518 blocked alpha- and beta-adrenoceptors competitively as indicated by parallel rightward displacement of the dose-response curve of each agonist in isolated organs and in anesthetized dogs. As judged by pA2 values and DR10 values, N-1518 was as potent as labetalol in blocking alpha- and beta-adrenoceptors. The beta 1/alpha 1 ratio of N-1518 was 8.3 for pA2 values in isolated organs and 13.6 for DR10 values in anesthetized dogs, respectively. N-1518 inhibited dose-dependently the pressor response to intravenous administration of noradrenaline, but labetalol did not depress the response to noradrenaline in anesthetized dogs. N-1518 is composed of four optical isomers. The SR-isomer was the most potent in blocking beta-receptors, and the RR-isomer was the most potent in blocking alpha-receptors. N-1518 has no intrinsic sympathomimetic activity in reserpinized rats and has no local anesthetic activity in guinea pigs. Single oral administration of N-1518 produced a fall in blood pressure in conscious SHR and renal hypertensive dogs without causing tachycardia. Intra-arterially administered N-1518 in the dog hindlimb resulted in vasodilation as indicated by the increase in blood flow. The magnitude of the responses was approximately 3 times more potent than that of labetalol.

The effect of labetalol (alpha- and beta- adrenoceptor blocking agent) on the respiratory organs of guinea pig was investigated in vivo and in vitro. The asthmatic symptoms which were induced by inhalation of histamine were relieved by pretreatment with labetalol (1-5 mg/kg, i.p.) in most cases. Propranolol, on the contrary, aggravated distinctly the histamine-induced asthma, although phentolamine and diphenhydramine relieved the asthma. Experiments carried out in vitro showed that labetalol relaxed the tonus of isolated tracheal preparation, shifting the histamine dose-response curve to the right and downward. The down shifting by labetalol was dose-dependent and much more sensitive than that by papaverine, and it disappeared after pretreatment of propranolol. Thus, it was considered that labetalol exerted a relaxing action on the tracheal preparation by a beta 2-adrenoceptor partial agonist action (intrinsic sympathomimetic activity, ISA). Since labetalol in high concentration also shifted the histamine dose-response curve parallel to the right as seen with phentolamine or diphenhydramine, it was considered that labetalol exerted not only an alpha-blocking action but also an antihistaminic action.

Effects of labetalol on the cardiovascular system were studied in dogs, guinea pigs, rats, rabbits, and bullfrogs. In dogs anesthetized with pentobarbital, labetalol decreased heart rate, arterial blood pressure, and myocardial contractile force, and inhibited carotid sinus reflex, without affecting pO2 and pH of circulating blood, urine volume, and urinary excretion of sodium and potassium. Alpha- and beta-adrenergic blocking action of labetalol was demonstrated in dog hearts, arterial preparations of guinea pigs and rats, isolated rabbit hearts, and bullfrog hind limb and rabbit ear preparations. In bullfrog hind limb and rabbit ear preparations, labetalol dilated blood vessels in concentrations larger than those which produced alpha- and beta-adrenergic blockade. The dilatation of blood vessels was observed only when labetalol was added to the perfusate, whereas alpha- and beta-adrenergic blockade continued even after removal of labetalol from the perfusate. It is concluded that labetalol blocks alpha- and beta-adrenergic receptors in the heart and blood vessels of the species used herein, and that this compound inhibits carotid sinus reflex in dogs. In addition, the dilatation of the blood vessels of the bullfrog hind limb and rabbit ear as evoked by labetalol probably involves a mechanism different from that of adrenergic blockade.

Beta-adrenoceptor blockade (beta-blocker) has recently been introduced for use in treating hypertension of pregnancy. The aim of this investigation is to determine the effects of beta-blocker (alprenolol and labetalol) on parturition and on the fetal cardiovascular and metabolic system in normotensive pregnant rats. The continuous administration of alprenolol to pregnant Wistar rats revealed the following: a small placenta intrauterine growth retardation delayed parturition intrauterine death (21.8%) morbidity (30.3%) and, hypoglycemia of neonates. In the cases which received the administration of both labetalol and alprenolol, the growth of fetuses was retarded. However, there was twice as much growth retardation of the fetuses treated with alprenolol. No other abnormalities were observed. The administration of alprenolol in pregnant rat uteri (in vitro) resulted in stimulation of myometrial contractility (oxytocic reaction) and lowered the c-AMP levels in the bath medium. However, when labetalol was administered, uterine activity was reduced in a dose-dependent manner (tocolytic reaction) with a concurrent rise in c-AMP levels in the bath medium. The effect of alprenolol on rat uterine blood flow using the thermocouple method resulted in a decrease of 18-30 percent but with labetalol there was only a slight decrease (0-5%).

In the isolated atria, trachea and aorta of the guinea pig and in the heart-lung preparation (HLP) of the dog, labetalol was 3.6 approximately 5.9 times less potent than phentolamine in blocking alpha-adrenoceptors, 1.4 approximately 3.6 times less potent as beta 1-blocker and 6 times less potent as beta 2-blocker than propranolol. Beta 1 and beta 2-blocking actions were 12 approximately 28 and 7 times more potent than alpha-blocking action, respectively. As regards beta 1-blockade, attenuation of the heart rate increase was more prominent than that of the augmentation of the contractile force. Both in the isolated atrial preparation of the guinea pig and in canine HLP, labetalol produced a positive inotropic and chronotropic effect and a slight increase in the coronary flow associated with a slight increase in the myocardial O2 consumption and improvement of the myocardial redox potential. Myocardial extraction and usage of lactate, pyruvate and glucose tended to be decreased and those of FFA decreased significantly. The positive inotropic and chrontropic effect was observed in HLP of 6-hydroxydopamine-pretreated dogs and was abolished with propranolol. Labetalol produced a relaxation of the isolated trachea of the guinea pig, which was inhibited with propranolol. In doses higher than those required for alpha- and beta-adrenoceptor blockade, labetalol produced calcium-antagonistic action.

Effects on blood pressure and heart rate of labetalol, a new beta-adrenoceptor blocking agent with alpha-blocking action were studied in conscious hypertensive rats (SHR, DOCA-hypertensive rats and renal hypertensive rats (RHR)). Labetalol with two asymmetric carbon atoms consists of an equal proportion of two racemates. In SHR, prevention of the development of hypertension was noted after 1.5 weeks of chronic oral administration of labetalol 25, 50 and 100 mg/kg/day, while bradycardia occurred beginning with the day of administration. Thus, the prevention of the development of hypertension appeared much earlier than in the case of the other beta-blockers. Antihypertensive effects and bradycardia were also noted in DOCA hypertensive rats and RHR after oral administration of labetalol 10, 30 and 100 mg/kg/day for six days. In DOCA hypertensive rats, the antihypertensive effect was more pronounced that in the RHR. These findings are in contrast to those with other beta-blockers. Other beta-blockers produced antihypertensive effects only in SHR. It is concluded that not only the beta-blocking action, but also the alpha-blocking action of labetalol plays an important role in the antihypertensive effects of labetalol.