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

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.     

Inhibition of centrally-evoked pressor responses by diazepam: evidence for an exclusively supramedullary action.

Diazepam (0.1 and 0.3 $\text{mg}\text{kg}$, i.v.) caused dose-dependent reductions of pressor and tachycardie responses to stimulation of the posterior hypothalamus, periaqueductal grey, and dorsal and ventral tegmentum in anaesthetized cats. There was little or no effect on either resting blood pressure or responses to bilateral carotid artery occlusion with these doses of diazepam. Responses, either pressor or depressor to medullary paramedian reticular formation stimulation, or pressor to dorsolateral medullary stimulation were not inhibited at any current strength by either dose of diazepam. Also, pressor and tachycardie responses to fastigial nucleus stimulation in the cerebellum, which acts through the paramedian reticular formation, were not inhibited by diazepam. Hence, it appears that (1) diazepam acts to inhibit evoked sympathetic responses throughout supramedullary sympathetic centres rather than on hypothalamus exclusively and (2) it appears that resting sympathetic tone and baroreceptor responses are mediated through functionally different central structures than evoked sympathetic responses from supramedullary centres.     

The effects of captopril (SQ 14,225) on bradykinin-induced bronchoconstriction in the anesthetized guinea pig.

The effect of captopril (SQ 14,225) a potent inhibitor of angiotensin converting enzyme (ACE: kininase II) on the bronchoconstrictor response to bradykinin was studied in the anesthetized guinea pig. The i.v. administration of captopril caused a profound long lasting hypotension without affecting pulmonary resistance or dynamic compliance. Similarly, the i.v. administration of bradykinin caused small increases in pulmonary resistance and decreases in dynamic compliance which were not altered by the administration of captopril. However, after beta-receptor blockade with propranolol, bradykinin-induced changes in resistance and compliance were enhanced; additional captopril administration further potentiated the bradykinin effects. The prostaglandin synthetase inhibitor indomethacin antagonized the bradykinin-induced bronchoconstriction in beta-blocked animals and its potentiation by captopril. In the isolated perfused guinea pig lung, bradykinin caused a dose dependent release of a prostaglandin-like substance which was significantly increased by captopril and antagonized by indomethacin. These results suggest that bradykinin causes a prostaglandin-mediated bronchoconstriction. Captopril, a potent inhibitor of ACE, prevents the degradation of bradykinin thus potentiating the bradykinin-induced bronchoconstriction, an effect observed in intact animals only in the absence of pulmonary beta-receptor activation.     

Antihypertensive effects of 12 beta adrenoceptor antagonists in conscious spontaneously hypertensive rats: relationship to changes in plasma renin activity, heart rate and sympathetic nerve function

Twelve beta adrenoceptor antagonists were examined for their effects on mean blood pressure (MBP), heart rate (HR), plasma renin activity (PRA) and sympathetic nerve function in spontaneously hypertensive rats (SHR). The selected drugs included cardioselective agents (acebutolol, atenolol and metoprolol), agents with intrinsic sympathomimetic activity (oxprenolol, acebutolol, alprenolol and pindolol) and agents with local anesthetic activity (propranolol, oxprenolol, acebutolol, alprenolol and labetalol). All 12 beta adrenoceptor antagonists, administered once daily for 4 days (30 mg/kg p.o.), significantly decreased MBP of SHR. This reduction in MBP was dissociable from both reductions in HR as well as peripheral beta adrenoceptor blockade. In addition, the onset of MBP reduction was slower than the onset of beta adrenoceptor blockade and became greater with duration of treatment. PRA activity was significantly and markedly reduced by both bunolol and metoprolol shortly after dosing at a time when HR was significantly reduced but MBP was not. Conversely, at a time when MBP was significantly reduced by both bunolol and metoprolol, PRA and HR were found to be normal. The changes in HR and PRA were correlated with peripheral beta adrenoceptor blockade but changes in MBP were not. Bunolol, metoprolol and propranolol had no consistent inhibitory effect on pressor responses to nerve stimulation in pithed SHR, although positive chronotropic responses to norepinephrine, tyramine, dimethylphenylpiperazinium and angiotensin I and II were significantly and markedly reduced. It is concluded that beta adrenoceptor antagonists, as a class, reduce MBP of conscious SHR, provided that sufficient time is allowed for this observation to occur. Furthermore, the reduction in MBP caused by beta adrenoceptor antagonists is unrelated to acute beta adrenoceptor blockade, changes in HR, reductions in PRA or inhibition of sympathetic nerve function. Finally, cardioselectivity, intrinsic sympathomimetric activity and local anesthetic activity are not required for the antihypertensive activity of these agents.     

Urokinase-type plasminogen activator stimulates wound healing in the diabetic mouse

Inflammation Research -     

On the effects and mechanism of action of the antihypertensive agent TR 3369 (5-methoxytryptamine beta-methylcarboxylate) in spontaneously hypertensive rats

The effects of the serotonin (5-HT) analog TR 3369 (5-methoxytryptamine beta-methylcarboxylate) on blood pressure and heart rate of spontaneously hypertensive rats (SHR) were examined. In conscious SHR, TR 3369 caused reductions in blood pressure without importantly changing heart rate in doses ranging from 1 to 30 mg/kg p.o. TR 3369 was found to have no significant antagonistic effects on alpha-, beta-, or 5-HT receptors, nor did the drug inhibit adrenergic neuronal or ganglionic function. A slight but unimportant effect on angiotensin II pressor responses was noted. Therefore, the data are in agreement with the suggestion that TR 3369 acts through a central mechanism of action. The 5-HT antagonist cinanserin had little effect on blood pressure of SHR when administered alone, whereas it markedly reduced the duration, but not the magnitude, of the TR 3369 antihypertensive action in SHR. It is suggested that at least a portion of the antihypertensive effect of TR 3369 involves activation of central 5-HT receptors.     

The effects of L-dopa and alpha-methyldopa on reflexes and sympathetic nerve function

L-dopa (10 mg/kg, i.v.) and β-methyldopa (100 mg/kg i.v.) were compared for their relative central and peripheral effects on reflexes and symphathetic nerve function.In MAO-inhibited dogs, L-dopa alone depressed reflex responses to both bilateral carotid artery occlusion (BCO) and vertival tilting, decreased blood pressure and inhibited responses to stimulation of the lumbar sympathetic chain. Pretreatment with MK 486, an extra-cerebral decarboxylase inhibitor, prevented the effects of L-dopa on the reflex response to vertical tilting and on nerve stimulation, but not on blood pressure or responses to BCO. Pretreatment with RO 4–4602, an inhibitor of both cerebral and extra-cerebral decarboxylase, prevented all the actions of L-dopa. α-Methyldopa lowered blood pressure and reduced responses to BCO but not to vertical tilting or nerve stimulation. These results indicate that, although L-dopa impaired peripheral sympathetic nerve function in MAO-inhibited dogs, the hypotension was caused predominantly by a central mechanism. Hypotension after α-methyldopa also appeared due to a central mode of action. A central component of action was associated with an ability to selectivity depress the bilateral carotid occlusion reflex, whereas the peripheral action of L-dopa was associated with suppression of reflex responses to postural changes.