Detection of CNS-depressant properties of antihypertensives: validity of various test methods in rodents and estimation of therapeutic margin in hypertensive rats.

Central nervous effects, sedatton m particular, are common side-effects of many drugs used for the treatment of nonpsychlatnc disorders, including antihistamines, antiemetscs and antihypertens~ves, among others. It Is therefore of considerable ~mportance to detect and quantify sedative properUes of new compounds at an early stage of pharmacological mvesUgatlon. Although there are numerous methods which are currently in use for this purpose, the evaluaUon of sedaUve potenUal m a drug remains one of the most ddticult tasks wRh which pharmacologists are faced This is largely due to the fact that m ammals sedaUon is usually defined by means of behavioral parameters such as reduced locomoUon, delayed or impmred motor responses or simply by general appearance Many types of pharmacolog|cal effects, however, can mterfere with these measures m a non-specific manner. Thus, for instance, motor mcoordination or paralysis can lead to decreased or delayed behavmrai responses, although the state of vigilance may be unchanged. Prolongatmn of barbRurate anesthesia, which ~s often used to detect sedative qualities, can be due to interference with metabohc degradation of barbRurates. Numerous other examples can be given (see Riley and Spmks, 1958). In order to estabhsh reliable criteria for measurements of sedaUon m small rodents such as mice and rats, we have studied the effects of antihypertenslve agents m various CNS tests. Drugs selected for mvesUgation included those known to produce incapacitating s~gns of depressmn m the chmc as well as those generally devoid of such effects. In addition, for purposes of comparison, several centrally-acting drugs lacking antihypertenssve properUes were also studied (Table 1) Measurement of the