Zola P. Horovitz

Cyclic Adenosine Monophosphate Phosphodiesterase in Brain: Effect on Anxiety

Drugs that reduce anxiety may be mediated by cyclic adenosine monophosphate in the brain because (i) potent anxiety-reducing drugs are also potent inhibitors of brain phosphodiesterase activity; (ii) dibutyryl cyclic adenosine monophosphate has the ability to reduce anxiety; (iii) the methylxanthines show significant anxiety-reducing effects; (iv) theophylline and chlordiazepoxide produce additive anxiety-reducing activity; and (v) there is a significant correlation between the anxiety-reducing property of drugs and their ability to inhibit phosphodiesterase activity in the brain.

Captopril (SQ 14,225) (d-3-mercapto-2-methylpropanoyl-l-proline): A novel orally active inhibitor of angiotensin-converting enzyme and antihypertensive agent

Abstract Relatively potent and specific in vitro and in vivo (oral or intravenous) inhibition of angiotensin-converting enzyme by a nonpeptidic compound, captopril (SQ 14,225; d -3-mercapto-2-methylpropanoyl- l -poline), was demonstrated in excised guinea pig ileum and in rats, rabbits, cats, dogs, and monkeys. The design of captopril was based on a hypothetical model of the active site of the enzyme. Captopril, in vitro or in vivo, was about ten times as potent as teprotide. Inhibition of angiotensin-converting enzyme was evaluated in vitro and in vivo by inhibition of the contractile or vasopressor activity of angiotensin I or by augmentation of the contractile or vasodepressor activity of bradykinin. Acute of subacute dosage with captopril moderately to markedly lowered the blood pressure of the renin-dependent aorticligated and the conscious two-kidney Goldblatt hypertensive rat; in the latter, the effect was intensified by concomitant dosage with a thiazide diuretic. Furthermore, the life-prolonging effects of captopril in renal hypertensive rats were augmented by a thiazide diuretic. In the two-kidney Goldblatt rat, acute captopril (p.o.) was about ten times as potent as teprotide (s.c.) in lowering blood pressure. Acute or subacute oral doses of captopril moderately reduced the blood pressure of the spontaneously hypertensive Wistar-Kyoto rat; chronic dosage almost normalized blood pressure. Captopril produced little or no hypotension in the saltreplete normotensive Wistar-Kyoto rat. Bilateral nephrectomy virtually abolished the hypotensive activity of captopril in the spontaneous hypertensive rat. The results suggest that captopril acts in large part by inhibiting the renin-angiotensin-aldosterone system to reduce elevated blood pressure, especially in renindependent models of hypertension; the roles of the kallikrein-kinin-prostaglandin systems and sodium balance remain to be elucidated. Captopril also lowers blood pressure in apparently non-renin-dependent types of hypertension by mechanisms that are as yet undefined.

Chronic antihypertensive effects of captopril (SQ 14,225), an orally active angiotensin I-converting enzyme inhibitor, in conscious 2-kidney renal hypertensive rats

Indirect systolic blood pressure (SBP) was monitored in 9 groups of 15 male conscious 2-kidney renal hypertensive rats (RHR) for over 6 months. Daily oral dosing with captopril (SQ 14,225, D-3-mercapto-2-methylpropanoyl-L-proline, 30 mg/kg), an orally active angiotensin I-converting enzyme inhibitor, lowered SBP 30--50 MM Hg during this period. Withdrawal of captopril for 5 days at 1, 3 and 6 months resulted in gradual return of SBP to control levels without overshoot. Resumption of dosage with captopril again decreased SBP. Daily oral dosing with hydrochlorothiazide (HCTZ, 6 mg/kg/day) alone for 6 months had little or no effect on SBP, but increased the antihypertensive effect of captopril. Daily oral dosing with hydralazine (6 mg/kg) caused an initial marked antihypertensive effect greater than that of captopril but almost complete tolerance developed within 4 weeks of dosing. Highest survival rates occurred in RHR treated with captopril plus HCTZ. In four other similarly treated groups of RHR and normotensive rats (NR), least cardiac hypertrophy and highest plasma renin activity occurred in captopril-treated animals compared with vehicle-treated controls. Plasma renin activity was about 2 to 4 fold higher in the rats dosed with captopril compared with vehicle-treated rats. Heart weight/body weight ratios, initially higher in the two RHR groups compared to NR, decreased only in the captopril treated group to or near those of the NR groups. These results indicate that chronic treatment with captopril decreased SBP and cardiac weights of RHR, and that HCTZ, or possibly other diuretics, can augment the antihypertensive effect of captopril while having little or no effect by themselves.

LONG-TERM EFFICACY OF CAPTOPRIL (SQ 14,225) IN 2-KIDNEY RENAL HYPERTENSIVE RATS

The effects of daily captopril therapy (30 mg/kg p.o.) given for one year on systolic blood pressure, heart rate and survival of 2-kidney renal hypertensive rats (2K-RHR) were examined. Captopril caused significant and sustained reductions in systolic blood pressure of 2K-RHR throughout the 1-year period with no important changes in heart rate. Simultaneous administration of the diuretic hydrochlorothiazide (HCTZ) enhanced the antihypertensive effect of captopril but did not normalize blood pressure, this despite no effect on blood pressure by HCTZ given alone. On the other hand, co-administration of guanethidine with captopril normalized blood pressure. Survival rates of 2K-RHR were highest in the rats receiving captopril plus HCTZ, next highest in rats receiving captopril alone and lowest in rats receiving water or HCTZ. The results demonstrate the long-term efficacy of captopril and suggest a sympathetic component in the maintenance of chronic 2-kidney renal hypertension.

Effects of Captopril on Sympathetic Control of the Heart and Vasculature in Dogs

Experiments were conducted in pentobarbital anesthetized dogs to investigate the effects of captopril on sympathetic neuronal control of the heart and hindlimb vasculature. Captopril, 3.1 mg/kg, i.v. produced marked reductions in blood pressure and hindlimb perfusion pressure, an observation consistent with the high plasma renin activity in the test animals. Increments in hindlimb perfusion pressure elicited by electrical stimulation of the lumbar sympathetic chain were also significantly reduced following captopril administration (p less than .002). The subsequent administration of a ten fold higher dose of captopril, 31.0 mg/kg, produced no further attenuation of the neurally mediated responses. In contrast to the decreased vascular responses to nerve stimulation after captopril, the tachycardia produced by stimulation of pre- or post-ganglionic neurons to the stellate ganglion were not altered. The results of the present study suggest that captopril acts by inhibiting vascular sympathetic neuronal function when the activity of the renin-angiotensin system is elevated. The attenuation of neurally mediated vasoconstriction may be due to the interruption of angiotensin II formation, thereby, preventing the facilitatory effects of angiotensin on sympathetic neurons.

Captopril (Capoten®; SQ 14,225) (d-3-Mercapto-2-methylpropanoyl-l-proline)

The enzymatic conversion of angiotensin I (AI) to angiotensin II (AII) and the inhibition of such conversion have been recently reviewed.1–3 Angiotensin-converting enzyme (ACE) [E.C. 3.4.15.1] has also been designated as converting enzyme (CE), peptidyldipeptide carboxy hydrolase, kininase II, or “bradykininase.” Hence, in vivo inhibition of ACE will reduce the pressor activity of AI, but not that of AII, and augment the vasodepressor activity of bradykinin (BK).