Animal experiments on the cardiovascular effects of lofexidine.

The cardiovascular effects of 2-[1-(2,6-dichlorphenoxy)-ethyl-2-imidazoline hydrochloride (lofexidine, Lofetensin and Loxacor), a hypotensive imidazoline derivative, have been studied in anaesthetized and conscious rats and in anaesthetized cats and dogs. In all three species intravenous administration of lofexidine caused a marked and long-lasting reduction of the systolic and diastolic pressure. The experiments in conscious and anaesthetized rats showed that lofexidine is also effective by the oral route both in normotensive and in hypertensive animals (spontaneously hypertensive rats and rats with renal hypertension). Based on the effective doses (1 microgram/kg i.v. and higher), lofexidine is a potent compound comparable in this respect to clonidine. In experiments in conscious rats, following intracerebroventricular administration and in anaesthetized cats, following intravertebral administration, the substance was even more potent than by the intravenous route, so it can be assumed to have a central mechanism of action. This was confirmed by other investigations. The hypotensive effect was accompanied in all species by a more or less pronounced fall in heart rate. The reduction of myocardial contractility and cardiac output observed in cats and dogs occurred in parallel with and may have caused, the lowering of blood pressure. Following intravenous administration, there was an initial, short-lived rise in blood pressure in the three species. This was interpreted as a direct, alpha-sympathomimetic effect on the vessels. Pretreatment with atropine, diphenhydramine and amitriptyline reduced the hypotensive and bradycardiac effects of lofexidine to some extent; this is also the case with clonidine. There were no adverse interactions in tests in which lofexidine was combined with a diuretic drug (hydrochlorothiazide). There was a slight tendency for the blood pressure effect to be enhanced in anaesthetized rats and dogs. The results of these tests indicate that lofexidine has the typical pharmacodynamic profile of a centrally acting, hypotensive compound. This justifies further experimental work to develop this drug as an antihypertensive agent.