Hypotensive and hemodynamic effects of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline

The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.     

Evidence that the hypotensive action of methyldopa is mediated by central actions of methylnoradrenaline

Mean arterial blood pressure was recorded in conscious normotensive rats through indwelling arterial catheters. The effect of l -α-methyldopa (α-MD) (400 mg/kg, i.p.) was studied in animals pretreated with α-methyl-m-tyrosine (400 mg/kg i.p.) 27 and 15 h before α-MD, α-methyl-p-tyrosine methylester (H 44/68) (250 mg/kg, i.p.) 1 h before α-MD, and dl -α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485, 100 mg/kg, i.p.) 30 min before α-MD. This pretreatment, which resulted in a severe depletion of endogenous catecholamines, did not alter the hypotensive effect of α-MD. The effect of α-MD (200 mg/kg, i.p.) was studied 30 min after pretreatment with the dopamine β-hydroxylase inhibitor, bis (4-methyl-l-homopiperazinyl-thiocarbonyl) disulphide (FLA-63) (25 mg/kg, i.p.). The hypotensive response to α-MD was completely abolished in these experiments. The formation of α-methylnoradrenaline from α-MD was prevented after FLA-63 but there was a significant increase in the amounts of α-methyldopamine formed.     

Role of opioidergic component in the antihypertensive effect of clonidine

The role of opioidergic system in the antihypertensive effect of clonidine was investigated in albino normotensive and renal-DOCA-salt hypertensive models of rats. Clonidine (2.5, 5 and 10.0 micrograms/kg, iv) produced a dose-related depressor response. Yohimbine (2 mg/kg, ip) blocked the clonidine-induced responses in both normotensive and hypertensive rats. Naloxone (2 mg/kg, iv) blocked the clonidine-induced depressor responses in hypertensive rats, but not in normotensive animals. Morphine (0.11 mg/kg, iv) produced a depressor response in both normotensive and hypertensive rats. Yohimbine (1 mg/kg, iv) did not affect the hypotensive effect of morphine in normotensive or hypertensive rats, whereas pretreatment with naloxone significantly blocked the hypotensive effect of morphine in both groups of animals. It is concluded that the hypotensive effect of clonidine in hypotensive rats could be due to an opioidergic mechanism since it is blocked by both naloxone and yohimbine.     

Antihypertensive effect of naftopidil (KT-611), a novel alpha 1-adrenoceptor antagonist, in freely moving experimental hypertensive rats and dogs

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.     

Effect of Korea red ginseng on the blood pressure in conscious hypertensive rats.

The change of blood pressure and heart rate after intravenous injection of Korea red ginseng (KRG) were studied in the conscious normotensive and one-kidney, one-clip Goldblatt hypertensive (1K, 1C-GBH) rats. Crude saponin (CS) of KRG (50, 100 mg/kg i.v.) induced a hypotensive effect and bradycardia in a dose-dependent manner in the anesthetized rats. On the other hand, CS of KRG (100 mg/kg) induced a hypotensive effect and reflex tachycardia in the conscious rats. Saponin-free fraction (SFF) of KRG did not affect them in the anesthetized normotensive rats (P>.05). The maximal hypotensive effect by CS of KRG in the conscious 1K, 1C-GBH hypertensive rats and L-nitroarginine methyl ester (L-NAME, 40 mg/kg)-treated conscious hypertensive rats was not different from that of conscious normotensive rats (Delta 31.6+/-6.3, Delta 27.5+/-5.8 vs. Delta 26.7+/-4.3 mmHg, P>.05). However, pretreatment of L-NAME significantly inhibited the reflex tachycardia by CS of KRG (70.8+/-7.0 vs. 30.6+/-15.0 bpm, P<.05). Hemolysate-sensitive nitric oxide (NO) current by the CS of KRG was greater than that of the SFF of KRG (651.9+/-128.2 pA for CS and 164.9+/-92.5 pA for SFF, P<.001). These findings suggest that KRG has a hypotensive effect and its effect may be due to saponin fraction of KRG in the conscious rats. The releasing effect of NO of KRG, like NO donor, may be partly contributed to the hypotensive effect of KRG.     

Hypotensive effect of SA446, an angiotensin converting enzyme inhibitor, in 2-kidney, 1-clip renal hypertensive and normotensive dogs

Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1-clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.     

Antihypertensive action of a non-sulfhydryl angiotensin converting enzyme inhibitor (CV-3317) in various hypertensive models

The antihypertensive action of N-[N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-N-(indan-2-yl) glycine hydrochloride (CV-3317), a nonsulfhydryl compound characterized as an angiotensin converting enzyme inhibitor in our previous work, was examined in hypertensive animal models. In 2-kidney, 1 clip hypertensive rats and dogs, CV-3317 (3 and/or 10 mg/kg, p.o.) produced a sustained antihypertensive action of about 15 to 25 mmHg. Daily oral administrations of CV-3317 (1 to 10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 5 weeks produced a sustained antihypertensive action of 20 to 40 mmHg. When CV-3317 (3 mg/kg) was combined with hydrochlorothiazide (10 mg/kg), its antihypertensive action was intensified in potency and duration. CV-3317 (30 mg/kg) induced a slight hypotension (5 to 10 mmHg) in normotensive rats, but had no effect on the blood pressure of 1-kidney, 1 clip hypertensive rats and on that of a low renin type of DOCA/salt hypertensive rat. The antihypertensive activity of CV-3317 was more potent than that of captopril. In pithed SHR, the pressor response induced by an electrical stimulation of the preganglionic sympathetic nerve, but not the pressor response to norepinephrine, was attenuated by both agents (0.3 mg/kg, i.v.). Both agents may exert their antihypertensive action not only primarily by inhibiting the renin-angiotensin system, but also by inhibiting norepinephrine release from the sympathetic nerve terminals indirectly by reducing the formation of vascular angiotensin II.     

Cardiovascular and renal effects of buspirone in several animal models

Intravenous administration (0.3 or 3 mg/kg) of buspirone to anesthetized rats elicited a transient pressor response (14 +/- 2 mmHg) and sustained bradycardia. However, oral administration (30 mg/kg) reduced the blood pressure and heart rate of conscious normotensive (-14 +/- 4 mmHg) and DOCA-salt hypertensive rats (-22 +/- 5 mmHg). Buspirone (3-100 mg/kg, p.o.) elicited increases in urinary volume and electrolyte excretion of conscious normotensive rats and decreased these parameters in conscious mice. Buspirone was observed to possess alpha 1-adrenoceptor agonist activity in ganglion-blocked anesthetized rats. Buspirone (0.3-3 mg/kg, i.v.) elicited transient elevations in the blood pressure of open-chest anesthetized dogs. There was a sustained increase in total peripheral resistance and a decrease in aortic blood flow, heart rate, right ventricular contractile force and left ventricular dp/dt max. Intravenous and oral administration to anesthetized and conscious dogs elevated urinary volume and electrolyte excretion. However, the doses used to elicit the observed alterations in hemodynamic/renal function are considerably greater than those which produce anxiolytic effects. Thus, it is doubtful that anxiolytic doses of buspirone will produce cardiovascular alterations in patients.     

Pharmacological analysis of the mode of action of mandelamidine with sustained antihypertensive effect. (II). Mechanism of transient hypotensive action of mandelamidine]

The mode of a transient hypotensive action of dl-Mandelamidine (MA) was studied in both anesthetized and unanesthetized animals. In the blood pressure of unanesthetized rats, a transient hypotensive action of MA (1 approximately 30 mg/kg i.v.) like papaverine (1 approximately 10 mg/kg i.v.) was much less predominant than in rats anesthetized with urethane (1.5 g/kg s.c.). The transient hypotensive action of MA (10 mg/kg i.v.) in rats anesthetized with urethane (1.5 g/kg s.c.) was not reduced when MA was injected continuously. Moreover C6 (5 mg/kg i.v.), propranolol (1 mg/kg i.v.), diphenhydramine (10 mg/kg i.v.) and atropine (2 mg/kg i.v.) did not block this transient hypotensive action. MA blocked the pressor action of epinephrine (3 mug/kg i.v.) in three minutes, but then potentiated it. MA (10 mug/kg i.a. approximately 1 mg/kg i.a.) caused a temporary vasodilation on the perfused leg artery and vertebral artery in dogs anesthetized with sodium pentobarbital (30 mg/kg i.v.). In the perfused leg artery, atropine (2 mg/kg i.v.) and propranolol (1 mg/kg i.v.) did not block the vasodilation of MA, and MA showed no marked blocking effect of the vasoconstriction of norepinephrine (0.2 mug/kg i.a.). In the dog heart-lung preparation and the guinea-pig heart, MA showed inhibiting effects. On the contraction of the cat nictitating membrane elicited by the stimulation of the postganglionic cervical sympathetic nerve, the blocking action of MA (1 mug/kg i.a. approximately 1 mg/kg i.a.) was much less predominant than that of phentolamine (10 mug/kg i.a.). In the rabbit descending aorta, MA (3 X 10(-4) g/ml) antagonized non-competitively the contraction elicited by norepinephrine. These findings suggest that a transient hypotensive action of MA depends upon the inhibiting effects on the cardiovascular system, and the adrenergic alpha-blocking effect of MA may be very weak.     

Antihypertensive effect of CV-4093.2HCl, a new calcium antagonist, in three rat models of hypertension

The hypotensive action of CV-4093.2HCl (CV-4093), a new calcium antagonist, was studied in spontaneously hypertensive, renal hypertensive, DOCA-salt hypertensive and normotensive rats. CV-4093 (3 and 10 mg/kg, p.o.) dose-dependently decreased systolic blood pressure in the three types of hypertensive rats. At the dose of 10 mg/kg, the compound decreased the blood pressure to the normotensive level between 1 and 3 hr after it was administered; the antihypertensive effect lasted for at least 8 hr. The systolic blood pressure in normotensive rats was also decreased at 3 and 10 mg/kg, p.o., but less evidently than in the hypertensive rats. When the antihypertensive effect of CV-4093 was compared with that of seven known calcium antagonists in spontaneously hypertensive rats, it was the most potent and the most long-lasting.     

Antihypertensive effect of betaxolol, a cardioselective beta-adrenoceptor antagonist, in experimental hypertensive rats

Betaxolol is a highly selective beta 1-adrenoceptor antagonist without intrinsic sympathomimetic activity. In this study, the antihypertensive effect of betaxolol was investigated in experimental hypertensive rats; and the antihypertensive mechanism was also studied. Betaxolol (1 and 10 mg/kg, p.o.) produced acute hypotensive effects in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats, deoxycorticosterone/saline hypertensive rats and normotensive rats. The effect was particularly marked in SHR. Furthermore, daily oral administration of betaxolol to SHR for 3 weeks showed sustained antihypertensive effects without producing tolerance. In pithed rats, the pressor response induced by an electrical stimulation of the spinal cord was inhibited by both betaxolol and atenolol. However, only betaxolol reduced the pressor response to norepinephrine. These findings suggest that a certain relaxing effect on peripheral vascular beds in addition to inhibition of presynaptic beta-adrenoceptors may contribute to the antihypertensive mechanism of betaxolol.     

Effects of phospholipases A2 from Vipera russelli snake venom on blood pressure, plasma prostacyclin level and renin activity in rats

Vipera russelli venom contains several isoenzymes of phospholipase A2 (PLA2) which were isolated by column chromatography. The effects of PLA2 fractions on blood pressure, plasma prostacyclin level and renin activity were studied in normotensive and renal hypertensive rats. PLA2 fractions II-5, II-7, III-3 and III-6 (0.1 mg/kg) injected i.v. into rats decreased the arterial blood pressure. The hypotensive action of PLA2 fractions was not affected by heat treatment (70-80 degrees C, 30 min, pH 6.8). After indomethacin (30 mg/kg, i.v.), the hypotensive response to PLA2 was markedly reduced. Plasma prostacyclin (PGI2) and thromboxane A2 (TXA2) levels were measured by radioimmunoassays of their degradation products, 6-keto-PGF1 alpha and TXB2, respectively. PLA2 fractions (0.1 mg/kg) induced an increase in plasma PGI2 and TXA2 levels. There was a positive linear correlation between the PLA2-induced hypotensive effect and the ratio of increased 6-keto-PGF1 alpha to TXB2 (r = 0.83) in normotensive rats. In renal hypertensive rats, the increase in PGI2 level was larger than in normotensive rats. Plasma renin activity was also measured by the radioimmunoassay. Plasma renin activity was reduced by PLA2 fractions in renal hypertensive rats, but not in normotensive rats. These results suggest that the hypotensive effect of PLA2 fractions in normotensive rats may be partly due to the increase in plasma prostacyclin and thromboxane A2 levels. In addition to the larger increase in plasma PGI2 level, the reduction in plasma renin activity may also contribute to the greater hypotensive effect of PLA2 fractions in renal hypertensive rats.     

The effect of prostaglandin E2 on the arterial blood pressure of normotensive and spontaneously hypertensive rats

1 In anaesthetized rats, injection of prostaglandin E(2) (0.5-5.0 mug/kg i.v.) caused a dose-dependent vasodepressor response. The magnitude of response was significantly greater in spontaneously hypertensive rats than in normotensive rats.2 In spontaneously hypertensive rats, the magnitude of the prostaglandin-induced depressor response was closely correlated with blood pressure. The higher the blood pressure, the greater was the response evoked by prostaglandin.3 In spontaneously hypertensive rats, a combination of guanethidine plus hydralazine reduced both blood pressure and prostaglandin-induced depressor responses.4 Spontaneously hypertensive rats and normotensive rats did not differ in the magnitude of their vasodepressor responses to intravenously administered acetylcholine or isoprenaline.     

SOME CARDIOVASCULAR EFFECTS OF MONOAMINE OXIDASE INHIBITORS IN UNANAESTHETIZED RATS

The effects of four monoamine oxidase (MAO) inhibitors on the blood pressure of conscious normotensive and DOC-salt hypertensive rats were measured. Harmaline (20 mg/kg p.o.), pargyline (100 mg/kg p.o.) and tranylcypromine (10 mg/kg p.o.) all lowered blood pressure significantly in both normotensive and hypertensive rats whereas methylaplysinopsin (10 mg/kg p.o.) had no effect on blood pressure. The effects of these MAO inhibitors on blood pressure responses to serotonin, tyramine and beta-phenylethylamine were determined in conscious normotensive rats. Pargyline and tranylcypromine shifted the dose-response curves for tyramine and beta-phenylethylamine, but not serotonin, to the left, indicating inhibition of type B MAO. Harmaline and methylaplysinopsin shifted the dose-response curves for tyramine and serotonin but not beta-phenylethylamine, to the left, indicating inhibition of type A MAO. Since the four antagonists tested inhibited at least one form of MAO, and yet not all of these MAO inhibitors lowered blood pressure, we suggest that our results are consistent with the view that the hypotensive action of MAO inhibitors is not necessarily related to inhibition of MAO.     

Effects of intracerebroventricular administration of magnesium sulphate on blood pressure and heart rate in anesthetized normotensive and hypertensive rats

Intracerebroventricular (i.c.v.) injection of magnesium sulphate (MgSO4:2.5, 5 and 10 mumol in 5 microliters) decreased blood pressure and heart rate in both anesthetized normotensive (WKY) and hypertensive rats (SHR). The effects were greater in WKY than in SHR. Moreover, a pretreatment with hexamethonium (2 mg/kg, i.v.) significantly blunted the hypotensive and bradycardic effects induced by i.c.v. injection of 10 mumol of MgSO4 in both WKY and SHR. Our data suggest that MgSO4 produces hypotensive and bradycardic effects when injected i.c.v. in both WKY and SHR.     

Comparison of acute cardiovascular effects of cadmium and captopril in relation to oxidant and angiotensin converting enzyme activity in rats

Cadmium (0.1, 0.32, 1.0 mg/kg i.v.) produced dose dependent hypertensive response in pentobarbitone anesthetized Sprague-Dawley (S-D) rats. The peak hypertensive effect was observed within 15 min of cadmium administration. This response gradually decreased over 1-h observation period. Heart rate did not change significantly. Serum malondialdehyde (MDA) levels increased with cadmium administration. The lower dose of cadmium (0.1 mg/kg i.v.) increased serum MDA to 0.14 +/- 0.02 nmol/mL as compared to 0.12 +/- 0.01 nmol/mL in the control group and was not statistically significant. However, mid (0.32 mg/kg i.v.) and high doses (1.0 mg/kg i.v.) raised serum MDA levels significantly (P < 0.01). Cadmium inhibited serum angiotensin converting enzyme (ACE) levels at all the three tested doses and was statistically significant (P < 0.01). Captopril (1.0, 3.2 mg/kg i.v.) produced a dose dependent mild hypotensive response. The peak effect was observed within 5 min. Cadmium produced inhibition of serum ACE levels, however, a dose response effect was not observed. Captopril (3.2 mg/kg i.v.) decreased serum ACE levels to 5.4 +/- 1.1 U/mL (control levels 10.7 +/- 1.4 U/mL). Serum MDA levels were decreased by captopril treatment. A correlation between serum ACE and MDA following higher dose of cadmium was found. These results indicate that acute administration of cadmium, an inorganic blocker of ACE and calcium channels cadmium produced hypertensive response while captopril produced mild hypotensive response in rats.     

Effects of 6-hydroxydopamine on spontaneously hypertensive rats

Summary In order to evaluate the role of the sympathetic nervous system in the development and maintenance of spontaneous hypertension, spontaneously hypertensive and normotensive rats were give 6-hydroxydopamine (6-OH-dopamine).A single i.v. dose of 6-OH-dopamine (100 mg/kg) caused a biphasic rise in blood pressure in both hypertensive and normotensive rats.During long-term treatment the first dose of 6-OH-dopamine (25 or 50 mg/kg i.v.) lowered the blood pressure, measured 24 h after injection, two or three times more in hypertensive than in normotensive rats. As a result, the blood pressure reached the same level in both groups, i.e. 90–100 mm Hg. Within three days this hypotension subsided. After repeated weekly administration of 6-OH-dopamine the depressor effect declined gradually and after 4 weeks it was no longer significant. When this stage was reached, adrenal demedullation as such neither lowered the basal blood pressure, nor prevented the development of tolerance to 6-OH-dopamine. Accordingly, the adrenal medulla is not decisive in maintaining the blood pressure and in the development of tolerance to the depressor effect of 6-OH-dopamine in spontaneously hypertensive and normotensive animals.After treatment with 8 weekly doses of 6-OH-dopamine, the pressor response to noradrenaline increased in both hypertensive and normotensive rats, while the response to tyramine decreased.When, on the second day after birth, new-born rats of the hypertensive strain were given a single dose of 6-OH-dopamine (50 mg/kg i.p.) the development of hypertension was inhibited to some degree. This inhibition was more marked when the animals were given weekly doses of 6-OH-dopamine (50 mg/kg i.p.) during 5 weeks. On the other hand, when pregnant rats of the same strain received 6-OH-dopamine (50 mg/kg i.v.) twice during the last week before delivery, the offsprings did develop hypertension.It is evident that the adrenergic nervous system plays an important part in the development of hypertension in rats of a spontaneously hypertensive strain, but it is no longer of essential importance once the hypertension is established.Partly presented at the Fifth International Congress on Pharmacology, San Francisco, July 23–28, 1972 (Neuvonen et al., 1972).     

A new potent inhibitor of converting enzyme: (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid(SA446)

(2R, 4R)-2-(2-Hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid (SA446) is a novel potent converting enzyme inhibitor having a sulfhydryl group in the molecule. SA446 inhibited the activity of semi-purified rabbit lung converting enzyme (IC50 = 6 nM). The contractile response of isolated guinea pig ileum to angiotensin I (AI) was markedly inhibited by SA446 (IC50 = 28 nM). On the other hand, SA446 augmented the contraction to bradykinin (BK) (AC50 = 0.7 nM), but did not affect the contraction caused by angiotensin II (AII), acetylcholine and histamine. These in vitro potencies of SA446 were 4 to 5 times larger than those of captopril. SA446 inhibited the pressor response to AI in rats (ID50 = 0.06 mg/kg, i.v., 0.48 mg/kg, p.o.) and dogs (ID50 = 0.01 mg/kg, i.v.). SA446 augmented the depressor response to BK (AD50 = 0.009 mg/kg, i.v.), but did not affect the pressor responses to AII and norepinephrine in rats. These in vivo activities of SA446 in dogs were more potent than those of captopril, but the reverse was seen in rats. Oral administration of SA446 had a hypotensive effect on two-kidney, one-clip renal hypertensive rats and spontaneously hypertensive rats, at doses over 3 and 10 mg/kg, respectively. However, the blood pressure of normotensive and DOCA-salt hypertensive rats was not affected by SA446, in doses up to 100 mg/kg. These results indicate that oral SA446 is a potent active inhibitor of converting enzyme and may be classed as an antihypertensive agent.     

The interaction between prazosin and clonidine at alpha-adrenoceptors in rats and cats.

In pithed rats prazosin (10μg/kg, i.v.) caused a prolonged antagonism of the hypertensive response to clonidine and (?)-noradrenaline, probably due to inhibition of vascular, postsynaptic α-adrenoceptors. The clonidine-induced reduction of the tachycardia evoked in pithed rats by electrical stimulation of cardiac sympathetic nerve fibres was antagonized by piperoxan and less effectively by prazosin, thus suggesting that prazosin displays a modest degree of cardiac presynaptic α-adrenoceptor blocking activity apart from its predominantly postsynaptic affinity. Prazosin (1 mg/kg, i.p.) significantly affected the hypotensive effect of clinidine (2 and 6 μg/kg, i.v.), but not the bradycardia induced by clonidine in pentobarbitone-anaesthetized, normotensive rats. Prazosin proved to be an effective hypotensive drug in anaesthetized cats. This action was peripheral as no central nervous origin could be demonstrated. Prazosin in low doses significantly reduced the central hypotensive effect of clonidine (1 μg/kg), injected into the left vertebral artery of chloralose-anaesthethized cats. Since the intravenous pretreatment with low doses of prazosin did not alter the central hypotensive response to clonidine, the interaction was likely to have occured within the brain-stem. Presumably, postsynaptic α-adrenoceptors in the brain, similarly to those in the periphery are inhibited by prazpsin, thereby preventing the central hypotensive effect of clonidine. It is submitted that clonidine and prazosin should not be combined in antihypertensive therapy in patients.     

Cardiovascular responses to central clonidine, alpha-methyldopa, and 6-hydroxydopamine in conscious normotensive and spontaneously hypertensive rats following naloxone

The possible involvement of endogenous opioid peptides in the cardiovascular responses observed following central alpha-adrenoceptor stimulation with clonidine, alpha-methyldopa (alpha-MD), and 6-hydroxydopamine (6-OHDA) was examined in conscious normotensive Wistar and spontaneously hypertensive (SHR) rats. Clonidine [2.5 micrograms intracisternally (i.c.)] produced rapid hypotension (-36 +/- 2 mm Hg) and bradycardia (-53 +/- 5 beats/min) in SHR that were similar to observations in animals given either naloxone (50 micrograms i.c. or 10 mg/kg i.p.) or appropriate saline control injections. Peripheral doses of naloxone (1-2 mg/kg) or saline did not further change arterial pressure or heart rate in either Wistar rats or SHR given alpha-MD (1.0 mg i.c.) 3 h earlier. In addition, central doses of naloxone (3 X 50 micrograms i.c.) given at hourly intervals did not affect the responses to alpha-MD. Central administration of 6-OHDA acutely releases noradrenaline which produces an initial fall in arterial blood pressure and heart rate. Intracisternal 6-OHDA (400 micrograms) produced similar time course and maximum circulatory effects in rats given naloxone (50 micrograms i.c. before and at each subsequent hour) as in saline-treated animals. Naloxone (1 mg/kg s.c.) significantly attenuated morphine-induced analgesia. These findings do not support a critical role of endogenous opioids in mediating the acute antihypertensive actions of clonidine and alpha-MD or in the cardiovascular responses produced by noradrenaline release following central 6-OHDA.