K. O. Ellis

Effects of subacute oral administration of captopril (SQ 14,225) on the renin-angiotensin system in spontaneously hypertensive rats

Captopril (SQ-14,225) is an orally active inhibitor of angiotensin I (Ang I ) converting enzyme (ACE) (Rubin et al 1978). It has been reported to be an effective antihypertensive agent in the spontaneously hypertensive rat (SHR) (Laffan et al 1978) and in essential, malignant and renovascular hypertensive patients (Case et a1 1978: Gavras et a1 1978). It is generally assumed that the mechanism by which captopril reduces blood pressure is closely related to its inhibiting ACE thereby blocking the production of angiotensin I1 (Ang 11) (Gavras et al 1978). The results of acute studies appear to be unequivocal in that the serum ACE activity was lowered following acute captopril administration (Kokubu et a1 1980; Waeber et a1 1980). However, the effects of chronic treatment with captopril on serum ACE activity in hypertensive patients are equivocal: serum ACE levels have been reported to be decreased (Gavras et al 1978), increased (Larochelle et a1 1979) or unchanged (Waeber et a1 1980) during captopril therapy. Recently it has been reported that while the administration of a single dose of captopril lowered serum ACE activity in normotensive rats, a significant elevation of serum ACE activity was found during 30 days of captopril administration (Kokubu et a1 1980). We have investigated the effects of captopril on several parameters of the renin-angiotensin system during subacute treatment in the SHRs to determine the relationship between the antihypertensive activity and its effects on the renin-angiotensin system. We have confirmed the antihypertensive efficacy of captopril in the SHRs and extended the finding of captopril-induced increase in serum ACE in normotensive rats to the SHRs. Male Okamoto-Aoki SHRs (Taconic Farms, Germantown, N.Y.), 250-300 g, were surgically prepared for the direct measurement of arterial blood pressure (BP) and heart rate (HR) with an indwelling catheter according to the method of Weeks & Jones (1960). At least 4 days elapsed between the installation of aortic catheters and the start of drug administration. Rats were given 0.5% methylcellulose or captopril (E. R. Squibb & Sons, Princeton, N.J.) (100 mg k g l ) orally in the morning, daily for 15 days,

5-PHENYL-2-FURAMIDINES: A NEW CHEMICAL CLASS OF POTENTIAL ANTIDEPRESSANTS

A series of 5-phenyl-2-furamidines has been synthesized and evaluated for antidepressant activities. Substitution in the phenyl ring with a nitro (4) or an amino (12) group in the ortho-position resulted in an increase in antidepressant activity. Both 4 and 12 antagonized tetrabenazine-induced ptosis in rodents and inhibited norepinephrine (noradrenaline) uptake into crude synaptosomes of whole mouse brain at doses or concentrations comparable to those of the tricyclic antidepressants. However, these compounds did not possess the anticholinergic and antihistaminic activities common to tricyclic antidepressants. In addition, they lacked monoamine oxidase inhibitory activity. The 5-phenyl-2-furamidines represent a new chemical class of antidepressants and may be useful for depressive patients who cannot tolerate the compromising side effects of the tricyclic antidepressants and monoamine oxidase inhibitors.