Antihypertensive effect of arotinolol (S-596), a new adrenergic beta blocking agent, on experimental hypertension

Effects of a new adrenergic beta-blocking agent, arotinolol (S-596), on the blood pressure and heart rate were assessed in comparison with those of other beta-blocking agents in deoxycorticosterone acetate (DOCA)-saline induced and spontaneously hypertensive rats (SHR). The relationship between the antihypertensive effect and the beta- or alpha-adrenoceptor blocking action of S-596 was also investigated in normotensive conscious rats. In the rat, a cannula was implanted chronically in a femoral artery, from which blood pressure was recorded. The test drugs were administered orally once a day for 14 days at several dose levels. The development of hypertension in DOCA-saline treated rats was clearly retarded with the consecutive oral administration of propranolol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day), but not with S-596 (20, 50 and 100 mg/kg/day) or pindolol (10 mg/kg/day). On the other hand, in SHR, S-596 (more than 10 mg/kg/day) propranolol (50 mg/kg/day), pindolol (10 mg/kg/day), labetalol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day) produced definite antihypertensive effects after the chronic administration. In normotensive conscious rats, the vasodepressor responses induced by isoproterenol were reduced by the beta-blocking agents at lower dose levels than those required for development of antihypertensive effects. The acute effects on blood pressure were determined in hypertensive rats during the chronic treatment with the test drugs. In either type of hypertension, S-596, (10-50 mg/kg/day) showed a depressor effect at 4 and/or 8 hr after administration. In normotensive conscious rats, S-596 antagonized the pressor responses to phenylephrine at doses more than 30 mg/kg. It is therefore suggested that an adrenergic alpha-blocking property is at least partly involved in the hypotensive effect of S-596 as labetalol. In the experiment of acute effect in SHR, pindolol and labetalol showed prominent hypotensive effect after the 1st administration, but lesser effect after the 10th administration. Propranolol showed a marked rise in blood pressure in this experiment.     

Antihypertensive activity of the aqueous extract of Retama raetam Forssk. leaves in spontaneously hypertensive rats

The antihypertensive and diuretic effects of the aqueous extract of Retama raetam Forssk. (RR) leaves were studied in both normotensive (WKY) and spontaneously hypertensive rats (SHR). In SHR rats, daily oral administration of RR (20 mg/kg) for three weeks exhibited a significant reduction in blood pressure. The systolic blood pressure decreased significantly from the seventh day (P < 0.01) and persisted through the end of treatment (P < 0.001) in SHR rats. The RR significantly enhanced the diuresis in WKY rats (P < 0.001). Furthermore, oral administration of RR at a dose of 20 mg/kg produced a significant increase on urinary excretion of sodium (P < 0.05), potassium (P < 0.01) and chlorides (P < 0.01) in SHR rats. In WKY rats, RR treatment induced a significant increase on urinary potassium elimination (P < 0.05) without affecting sodium and chloride excretion. Irbesartan (Avapro) 20 mg/kg (body weight), an angiotensin II receptor antagonist, was used as reference drug. No significant changes were noted in heart rate after RR treatment in SHR as well as in WKY rats. Glomerular filtration rate showed a significant increase after RR administration in WKY rats (P < 0.01) and a no significant increase in SHR rats. These results suggest that oral administration of aqueous RR extract exhibited antihypertensive and diuretic effects in SHR rats and diuretic action in WKY rats.     

The hemorheological effects of Lychnis chalcedonica L. extracts

The hemorrheological effects of extracts from Maltese cross campion (Lychnis chalcedonica L.) prepared using 40% (I) and 70% (II) aqueous ethanol solutions were studied in vitro in comparison with tanakan on the model of high blood viscosity syndrome. Under the hyperthermia conditions, extracts I and II at a concentration of 1 x 10(-5) g/ml limited the growth of blood viscosity and thrombocyte aggregation and the drop in thrombocyte deformability. The effects of both extracts were comparable to those of tanakan. Prolonged (5 days) administration of extract I (daily dose, 150 mg/kg p.o) in rats with arterial hypertension (SHR) decreased the viscosity of whole blood and plasma, reduced the concentration of fibrinogen, and increased the deformability of erythrocytes. No reliable effects of the extracts in vivo upon the erythrocyte aggregation and hematocrit were observed.     

Pharmacological studies on pinacidil, a new anti-hypertensive agent. 1. Antihypertensive effects in SHR and DOC/saline hypertensive rats

Antihypertensive effects of pinacidil (PND) were compared with those of hydralazine (HDL) and nifedipine (NFD) by determining the systolic blood pressure of the caudal arteries of conscious SHR and desoxycorticosterone (DOC)/saline hypertensive rats at temperatures between 29 degrees C to 30 degrees C using a newly developed tail cuff method. 1) A dose-dependent antihypertensive effect of PND in male SHR was observed in a dose exceeding 1 mg/kg, p.o. Comparison of antihypertensive effects during 6 hr after oral administration of antihypertensive agents showed that relative potencies of HDL and NFD to PND (1.0) were approximately 0.8 and 0.3, respectively. 2) Although no difference was observed in the antihypertensive effect of HDL between male and female SHR, these effects by PND and NFD were more potent in female SHR. 3) No tolerance was observed in the antihypertensive effect of PND by the once a day oral administration for 5 weeks in male SHR and DOC/saline hypertensive rats. Dose-dependent antihypertensive effects of PND in doses above 1 mg/kg were always observed during experimental periods. 4) In spite of the potent antihypertensive effects, pathological changes such as hyperplasia and hyalinization of arterial walls in kidneys in DOC/saline hypertensive rats were not improved by continuous administration of PND or HDL.     

Effects of indomethacin on hormonal and blood pressure responses to captopril in spontaneously hypertensive rats

The possible role of vasodilatory prostanoids in the antihypertensive action of captopril was investigated in spontaneously hypertensive rats (SHR). Captopril (100 mg/kg/day for 5 days) decreased systolic blood pressure and increased water consumption, urine excretion and plasma renin activity (PRA). It also enhanced the urinary excretion of the prostacyclin metabolite 6-keto-PGF1 alpha, but did not change the excretion of PGE2. Indomethacin (3 mg/kg/day), given both alone and in combination with captopril, reduced markedly the urinary excretions of 6-keto-PGF1 alpha and PGE2 but did not alter PRA, compared with corresponding groups without indomethacin. The suppression of prostanoid synthesis caused by indomethacin did not affect the antihypertensive effect of captopril or the basal blood pressure in SHR. Neither did indomethacin influence drinking or urine excretion in SHR not receiving captopril, but it reduced the dipsogenic and diuretic effects of captopril. The results suggest that captopril augments the production of vasodilatory prostacyclin. Yet prostanoids have no significant role in the antihypertensive mechanism of captopril in SHR.     

Anti-inflammatory activity of propolis

Propolis (bee-glue), known as a folk medicine, is a lipophilic material found in honeybee hives. In the present study on the anti-inflammatory effect of Korean propolis, it was extracted with ethanol, and used as a test material. The LD₅₀ value with the oral administration of ethanolic extract of Korean propolis (EEKP) was higher than 2 g/kg in mice. The oral administration of the propolis extract (100 mg/kg) significantly inhibited the development of hind paw edema induced by carrageenin in rats. The oral pretreatment of the propolis extract markedly inhibited the increase in vascular permeability and the number of writhing induced by acetic acid in mice. Propolis extract, 50 and 100 mg/kg p.o. per day for 7 days, produced a significant inhibitory effect on granuloma and exudate formation in rats. This inhibitory effect was enhanced with the concomitant use of prednisolone (2.5 mg/kg). These results suggest that Korean propolis apparently has a strong anti-inflammatory activity.     

Effects of single and repeated oral administration of MK-421 and captopril on blood pressures in normotensive and experimental hypertensive rats

In the single dose study, the aortic blood pressure in conscious normotensive rats, 2-kidney, 1-clip renal hypertensive rats (2K-RHR), 1-kidney, 1-clip renal hypertensive rats (1K-RHR) or DOCA hypertensive rats was measured for 24 hr after the oral administration of angiotensin converting enzyme (ACE) inhibitors such as MK-421 or captopril. MK-421 at 3 mg/kg and captopril at 10 mg/kg markedly lowered the blood pressure of 2K-RHR. MK-421 at 10 mg/kg and captopril at 30 mg/kg only modestly lowered the blood pressure of 1K-RHR. In contrast, both ACE inhibitors failed to reduce blood pressure in DOCA and normotensive rats. In the repeated dose study, the systolic blood pressures in normotensive rats, 2K-RHR or spontaneously hypertensive rats (SHR) were measured twice a week for 3 weeks treatment of either MK-421 at 3 mg/kg or captopril at 10 mg/kg. Both ACE inhibitors produced significant antihypertensive effects in these model rats, and the effects were sustained throughout the treatment period. The antihypertensive effects in 2K-RHR were greater than those in SHR and normotensive rats. These results indicate that MK-421 and captopril cause the most significant antihypertensive effect in 2K-RHR in which the renin-angiotensin system played a dominant role in blood pressure regulation. The antihypertensive effect of MK-421 was approximately 3 times as potent as that of captopril in these hypertensive models.     

Effects of African Mistletoe Extract on Blood Pressure in Spontaneously Hypertensive Rats

African Mistletoe, Loranthus bengwensis L. (Loranthaceae) is known in folk medicine for its therapeutic values. To explore the possible antihypertensive effect of this plant, normotensive (NWR) and spontaneous hypertensive (SHR) rats were orally dosed with the aqueous extract (1.32 g/kg per day) or an equal volume of saline for 8 days. A significant reduction in the Mean Arterial Pressure (MAP) in both NWR (P&lt;0.01) and SHR (P&lt;0.001) was obtained. This does not affect the respiratory rate or the urinary flow rate but a significant reduction of the serum total cholesterol (P&lt;0.05) was obtained on days 6, 7, and 8. This result confirms that African Mistletoe has a reducing effect on the blood pressure and thus could be a useful antihypertensive agent. This study provides the first indication that the plant may have activity which lowers blood pressure suggesting the need for further investigation of African Mistletoe as an antihypertensive agent.     

CALCIUM ANTAGONISTS AND HYPERTENSION

1. Calcium antagonists, including verapamil, are now used widely in the management of patients with hypertension. 2. Six weeks of chronic therapy with verapamil (50 mg/kg per day, orally) to produce a plasma level of 80-100 ng/ml in Sprague-Dawley rats depletes cardiac noradrenaline (NA) without apparently causing beta 1 adrenoceptor 'up' regulation. 3. The effect of verapamil on cardiac NA is rapidly reversed upon verapamil withdrawal. 4. Chronic therapy with nisoldipine (100 mg/kg per day, orally) had no effect on cardiac NA. 5. Verapamil (50 mg/kg per day, orally) and nisoldipine (100 mg/kg per day, orally) therapy for 6 weeks prevented the time-dependent increase in systolic blood pressure in SHR rats. 6. Binding studies with (-)[3H]-D888 (desmethoxyverapamil) indicated that the affinity of the phenylalkylamine binding sites is higher in hearts of SHR relative to hearts from age-matched (25 weeks) WKY and SD, without any change in density.     

The effects of chronic treatment with Morus bombycis KOIDZUMI in spontaneously hypertensive rats

The present study was performed to evaluate the antihypertensive effects of Morus bombycis KOIDZUMI (MK) in spontaneously hypertensive rats (SHRs). In addition, the effects on vascular responses and cardiac functions were also investigated. In isolated rat aortic preparations, the 100% ethanol extract of MK exhibited a potent vascular relaxant effect with IC(50) value of 3.9 microg/ml, and this vasorelaxant effect was completely abolished by pretreatment of the aortic tissues with N(G)-nitro-L-arginine methyl ester or the denudation of endothelial layer. In isolated rat hearts, the MK extract significantly reduced cardiac functions such as left ventricular developed pressure and heart rate. In an antihypertensive study in SHRs, long-term administration with MK extracts (10, 30, 100 mg/kg) for 42 d dose-dependently decreased systolic blood pressure (approximately 20 mmHg). In SHRs, MK extract enhanced the aortic relaxation to acetylcholine and sodium nitroprusside after 42 d of treatment. In addition, lipid peroxidation and DNA damage in liver of SHRs were also attenuated by long-term treatment with MK extract. These results suggest that chronic treatment with MK extract exerts an antihypertensive effect in SHRs, and its direct vasorelaxant, negative inotropic actions, and anti-oxidant properties may contribute to reduce the elevated blood pressure.     

Anti-hypertensive effect of the dongchunghacho,isaria sinclairii,in the spontaneously hypertensive rats

The present study examined the effect of the methanol extract of Isaria sinclairii, a kind of Donchunghacho (Tochukaso), on blood pressure in spontaneously hypertensive rats (SHR). Blood pressure and heart rate were measured after treatment with the methanol extract of I. sinclairii by the indirect tail-cuff method and the direct in vivo model. Starting at 12 weeks of age, male SHR were treated with the extracts for 2 or 4 weeks. We found that, when compared to untreated control SHR, oral treatment with I. sinclairii methanol extract (30 mg/kg/day) remarkably decreased systolic blood pressure from 200 to 112 mmHg and decreased diastolic blood pressure from 114 to 88 mmHg. Furthermore, efficacy of methanol extract of I. sinclairii was superior to captopril (30 mg/kg/mL, positive control), an angiotensin-converting enzyme inhibitor, with a lowering effect that dropped systolic blood pressure from 201 to 130 mmHg and diastolic blood pressure from 102 to 92 mmHg. However, in normal Wistar Kyoto rats, I. sinclairii methanol extract did not significantly change the normal blood pressure, suggesting that this type of Dongchunghacho has a selective effect against hypertension. Therefore, methanol extract of I. sinclairii may be used as an anti-hypertensive food/agent. Furthermore, this extract also has multiple actions such as No production in endothelial cells, inhibiting thrombin-induced blood coagulation by thrombin and mildly decreasing in prostaglandin E2 levels in cultured macrophage cells, all of which might contribute to protection against atherogenesis and thrombus formation. HPLC and MS analysis of methanol extract of I. sinclairii revealed the presence of adenosine.     

Antihypertensive effects of CS-905, a novel dihydropyridine Ca++ channel blocker

CS-905 is a novel dihydropyridine calcium blocker. A single oral administration of CS-905 or nicardipine at doses of 0.3-3.0 mg/kg produced a dose-dependent reduction of blood pressure in conscious SHR. CS-905, when administered orally in conscious SHR, was more than 3 times as potent as nicardipine. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in heart rate. An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration. This difference may be attributed to the first pass effect, which was associated with nicardipine but not with CS-905. The blood pressure lowering effects of CS-905 was most potent in DOCA-salt hypertensive rats, followed by SHR, RHR and normotensive rats, in this order. CS-905 is expected to be an antihypertensive agent that is effective on a once a day regimen in clinical settings.     

Antihypertensive activity of alacepril in spontaneously hypertensive rats and deoxycorticosterone acetate-salt hypertensive rats and dogs

Antihypertensive activity of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219), an orally active angiotensin converting enzyme (ACE) inhibitor, was investigated in hypertensive models with normal or low plasma renin activity (PRA). After single oral administration in spontaneously hypertensive rats (SHR), alacepril (1-30 mg/kg) showed a dose related antihypertensive effect with a gradual onset and long lasting action. The maximum hypotensive effect was about 3 times more potent than that of captopril (3-100 mg/kg) on a weight basis. When comparing the AOC (area over the antihypertensive curve) values, the overall antihypertensive activity of alacepril was 8 times stronger than that of captopril. In deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, alacepril (10-100 mg/kg) produced a significant and sustained hypotensive effect. The maximum hypotensive potency and the overall antihypertensive activity of alacepril were remarkably stronger than those of captopril (30, 100 mg/kg). During once daily successive oral administration for 10 days in SHR, alacepril (3-10 mg/kg/d) reduced dose relatedly the daily starting blood pressure. In DOCA-salt hypertensive rats and dogs, alacepril (30 mg/kg/d) produced a significant antihypertensive effect, while captopril (30 mg/kg/d) did not reduce daily starting blood pressure. Therefore, it may be expected that alacepril is a more effective antihypertensive agent than captopril in various hypertensions of different etiology.     

Antihypertensive effects of a new dihydropyridine calcium antagonist

Methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2 -yl)-1,4-dihydropyridine-3-carboxylate (DHP-218) is a new vasodilatory calcium antagonist with pronounced and long-lasting antihypertensive effects. It produced a significant decrease in blood pressure at doses more than 1 mg/kg in normotensive rats, 0.1 mg/kg in spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)-salt hypertensive rats and 0.3 mg/kg in renal hypertensive rats. In SHR, the antihypertensive effect of DHP-218 was approximately 7 times more potent than nifedipine. The antihypertensive effect of DHP-218 appeared very slowly and persisted even after it was injected i.v. No tolerance to the antihypertensive effects of DHP-218 was observed for 5 weeks at daily doses of 0.3 and 1 mg/kg. The antihypertensive effects of DHP-218 in cats and dogs with normal blood pressure was more than 10 and 30 times more potent than those of nifedipine, respectively. At an equivalent antihypertensive dose, the effect of DHP-218 persisted longer than that of nifedipine in all the animal species used.     

Lacidipine: a calcium antagonist with potent and long-lasting antihypertensive effects in animal studies.

Lacidipine, currently being evaluated as a once-daily antihypertensive agent, acted as a calcium entry blocker on rabbit ear artery (pA2 = 9.4) with a markedly slower onset of action than that of nitrendipine; this effect was not reversed after 9 h of drug washout. Calcium entry blocker activity was also evaluated on nonvascular smooth muscles: Lacidipine showed a more pronounced vascular selectivity than nitrendipine; for both drugs, concentrations required to induce negative inotropic effects in guinea pig ventricular strip were approximately 100 times higher than concentrations needed to antagonize calcium contraction in vascular smooth muscle. In spontaneously hypertensive rats (SHR), by the tail-cuff method, lacidipine (ED25 = 0.35 mg/kg orally, p.o.) proved approximately 30 times more potent, slower in onset, and longer-acting than nitrendipine in reducing blood pressure. These features were confirmed in chronically implanted SHR after oral and intravenous (i.v.) administration (ED25 = 0.19 mg/kg p.o. and 0.006 mg/kg i.v.). A short-lasting tachycardia was detected with both drugs. No evidence of acquired tolerance emerged after repeated oral administrations over a 3-week period. Lacidipine induced a natriuretic effect in saline-loaded SHR at antihypertensive doses. In renal hypertensive dogs, lacidipine proved more potent (three to seven times), slower in onset, and longer-lasting than nitrendipine after p.o. (ED25 = 0.22 mg/kg) and i.v. (ED25 = 0.004 mg/kg) administrations.     

Pharmacological studies of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new long-acting antihypertensive vasodilator

N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899) is a new long-acting antihypertensive vasodilator which reduces the blood pressure of conscious hypertensive rats and dogs to normal levels. The oral doses that reduce blood pressure by 50 mmHg are: 4.4 mg/kg in conscious spontaneously hypertensive rats (SHR), 18 mg/kg in conscious Milan hypertensive strain (MHS) and 1.7 mg/kg in conscious renal hypertensive dog (RHD). The i.v. doses are 1.26, 3.2 and 0.9 mg/kg. The reduction in blood pressure is slow (peak effect at 3 h) and long-lasting (more than 7 h) after p.o. or i.v. administration. Tolerance to MDL-899 is seen to develop in hypertensive dogs, whereas in hypertensive rats this phenomenon never occurs. The compound antagonizes the development of hypertension when given to SHR between days 25 and 88. The haemodynamic study in conscious normotensive rats (labelled microspheres) demonstrated that the fall in blood pressure is accompanied by increases in heart rate and cardiac output and a decrease in total peripheral resistance. The lack of alpha-blocking activity, in the rat caudal artery "in vitro"; beta 2-stimulating activity, in SHR pretreated with propranolol, and prostaglandin (PG) release activity, in SHR pretreated with indomethacin, excludes the possibility that the hypotension is due to one of these mechanisms. MDL-899 given orally to rats has no important depressant effects on the CNS at hypotensive or higher doses and induces no adrenergic system stimulation symptoms (midriasis, exophthalmus). In comparison with hydralazine, it is slower in onset and longer lasting, devoid of adrenergic system stimulation, less toxic and nonmutagenic. They are equipotent after p.o. treatment.     

Effects of terazosin on the blood pressure responses to tilting in conscious animals: comparison with prazosin

Inhibitory effects of terazosin on the compensatory blood pressure responses to tilting were studied in conscious rabbits and spontaneously hypertensive rats (SHR). In rabbits, doses which reduced the mean blood pressure by 15 mmHg were 330 micrograms/kg, i.v., for terazosin and 42 micrograms/kg, i.v., for prazosin, while those which depressed the blood pressure responses to tilting by 30 mmHg were 180 micrograms/kg, i.v., for terazosin and 54 micrograms/kg, i.v., for prazosin. In SHR, almost equal decreases in the mean blood pressure (about 30%) were observed by 1 mg/kg prazosin, p.o., 20 mg/kg hexamethonium, i.p., 3 mg/kg hydralazine, p.o., or 3 mg/kg nicardipine, p.o. In these conditions, prazosin and hexamethonium markedly depressed the blood pressure responses to tilting, whereas hydralazine and nicardipine showed little effect. The results with these antihypertensive drugs closely paralleled the established orthostatic profiles seen clinically. In this SHR tilting model, when the mean blood pressure was reduced by 15%, prazosin significantly depressed the tilting reflexes; however, terazosin produced no depression. Considering the dose ratio of terazosin to prazosin for antihypertensive effects and inhibitory effects on the tilting reflexes, the orthostatic liability of terazosin was about 3 times as low as that of prazosin. On the basis of these results, it is expected that terazosin causes less orthostatic hypotension than prazosin in clinical use.     

Antihypertensive properties of the novel calcium antagonist (1S,2S)-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino] ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride in rat models of hypertension. Comparison with verapamil

(1S,2S)-2-[2-[[3-(2-Benzimidazolyl)propyl]methylamino]ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride (Ro 40-5967) is a novel calcium antagonist. Its effect on systolic arterial blood pressure and heart rate was investigated in comparison with verapamil in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats (2K1C), deoxycorticosterone acetate (DOCA)-NaCl hypertensive rats and normotensive Wistar rats. After single oral doses, Ro 40-5967 (3-30 mg/kg) and verapamil (10-100 mg/kg) produced a dose-related decrease in blood pressure in all three types of hypertensive rats. Ro 40-5967 was 3-5 times more potent than verapamil. DOCA-NaCl hypertensive rats were more sensitive to the antihypertensive action of Ro 40-5967 than renal hypertensive rats and SHR. Both compounds lowered blood pressure of normotensive rats to a lesser degree than that of hypertensive rats. The antihypertensive effects of Ro 40-5967 and verapamil occurred fast, with similar efficacies and reached maximal values 3 and 6 h postdrug (SHR). While the significant antihypertensive effect of Ro 40-5967 (30 mg/kg) persisted for 24 h, that of verapamil (100 mg/kg) recovered completely 16 h postdrug. The experimental data suggest that Ro 40-5967 might be suitable for clinical use as a once-a-day antihypertensive agent.     

The antihypertensive effect of a selective central muscarinic cholinergic antagonist: N-(4-diethylamino-2-butynyl)-succinimide

N-(4-Diethylamino-2-butynyl)-succinimide (DKJ-21), a cholinergic antagonist selective for muscarinic receptors in the central nervous system, has an antihypertensive effect in conscious spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto (WKY) control rats. Intravenous doses over a range of 3.1 to 25.0 mg/kg produced a dose-dependent decrease in systolic blood pressure. This effect was still apparent 24 hr after drug administration, but blood pressure returned to predrug levels by 48 hr after injection of DKJ-21. In a dose–response study, the maximum antihypertensive response in a group receiving 25.0 mg/kg was 43 ± 8 mm Hg. Marked variability of the maximum response was observed in all age groups and with all doses. Decreases in blood pressure up to 75 mm Hg were obtained in individual animals. The magnitude of the antihypertensive effect is not age related since 10-, 15-, 22-, and 36-week-old SHR responded to the same degree after injection of 25 mg/kg DKJ-21. Smaller doses (50 μg) of DKJ-21 decreased blood pressure when administered into the lateral cerebral ventricle of SHR. Vascular responses to norepinephrine, acetylcholine, dimethylphenylpiperazinium, angiotensin I, and tyramine were not inhibited by i.v. injection of DKJ-21; however, the centrally mediated pressor response to physostigmine was reduced by 60%.