Angiotensin II-induced drinking and pressor responses to central or systemic irbesartan and losartan.

Angiotensin II (ANG II) is a peptide hormone that is important for maintaining blood pressure and body fluid homeostasis. Two nonpeptide angiotensin type 1 (AT(1)) receptor antagonists, irbesartan and losartan, were compared for their antidipsogenic and antihypertensive efficacy in both normotensive and hypertensive rats. ANG II-induced drinking and pressor responses were examined following central or systemic administration of irbesartan and losartan. Both agents inhibited the drinking response to ANG II in normotensive rats. Irbesartan was more effective than losartan at inhibiting pressor responses to ANG II in normotensive and hypertensive rats. These data indicate that centrally administered irbesartan may be somewhat more effective as an AT(1) receptor antagonist than losartan. However, evaluating the antihypertensive efficacy of these drugs when administered systemically is complex due to several pharmacokinetic factors (e.g., metabolism and lipophilicity).     

Antihypertensive action of indapamide. Comparative studies in several experimental models.

1-(4-Chloro-3-sulfamylbenzamido)-2-methyl-indoline (indapamide), after single oral dose administration, showed antihypertensive activity in genetically hypertensive rats, DOCA/saline hypertensive rats, unilaterally-nephrectomised DOCA/saline hypertensive rats and dogs made hypertensive by renal encapsulation. The activity was observed at doses as low as 1-3 mg/kg and lasted at least 48 h. Increasing the dose level considerably prolonged the duration of action but did not substantially enhance the maximum antihypertensive effect. In genetically hypertensive rats indapamide was 30-300 times more potent than furosemide, spironolactone and chlorthalidone. Indapamide had no effect on blood pressure in normotensive rats. In concentrations of 1 X 10(-5) to 1 X 10(-3) g/ml, indapamide antagonised contractions of arterial and venous strips to angiotensin, epinephrine and norepinephrine revealing a direct vascular action. Indapamide has a prolonged saluretic action which in combination with the direct vascular effects may well account for its antihypertensive activity.     

CONTRIBUTION OF THE SYMPATHETIC NERVOUS SYSTEM TO THE CENTRALLY-INDUCED PRESSOR ACTION OF ANGIOTENSIN II IN RATS

Angiotensin II (ANG II) may increase blood pressure by central nervous system mechanisms. The involvement of the sympathetic nervous system in the centrally-induced pressor effect of ANG II in the rat was investigated. 2 Plasma noradrenaline concentrations, measured as an index of sympathetic nervous system activity, increased after intracerebroventricular (i.e.v.) injection of pressor doses of ANG II, both in normotensive and in spontaneously hypertensive rats. 3 To assess the functional significance of this, the sympathetic nervous system was inhibited by phentolamine, reserpine, and guanethidine. In phentolamine-infused rats, low doses of i.c.v. ANG II elicited a blood pressure decrease, but at maximal pressor doses, no difference between phentolamine-treated and control rats was observed. In reserpinized rats, the central pressor effect of ANG II was greater than in controls. Guanethidine pretreatment did not affect the blood pressure response to i.c.v. injected ANG II. 4 It is concluded that the central pressor effects o f ANG II are accompanied by a stimulation of the sympathetic nervous system. In the rat, this stimulation may be functionally important for the initial phase of the central pressor action. This could not be established for the maximal pressor responses.     

An increased reactivity in hypertensive rats unaffected by prolonged antihypertensive therapy.

1. Isolated perfused mesenteric arteries obtained from chronic experimental hypertensive rats (deoxycorticosterone/NaCl) exhibited an increased reactivity to noradrenaline, 5-hydroxytryptamine and adenosine 5'-triphosphate (ATP) when compared with similar preparations from age-matched normotensive animals. 2. The dose-response curves to all three vasoconstrictor agents obtained from hypertensive animals exhibited a steeper slope, and higher maximum without any significant change in the threshold dose suggesting that adaptive/structural changes in the blood vessels had taken place. 3. Ten week treatments with antihypertensive combinations of hydrallazine, hydrochlorothiazide and reserpine or hydrallazine and mecamylamine lowered the systolic blood pressures of the hypertensive rats to those of normotensive animals and also reversed secondary changes such as periarteritis nodosa of the mesentery and cardiac hypertrophy. 4. The reactivity of these blood vessels to all these vasoconstrictor agents from the hypertensive rats with a normalized blood pressure was similar to those obtained with untreated hypertensive animals. 5. The persistent increased reactivity in the hypertensive rats after long-term anti-hypertensive treatment suggests that the hyperresponsiveness is secondary to the elevated blood pressures and that the adaptive/structural changes of the blood vessels in chronic hypertensive rats cannot be reversed by prolonged antihypertensive therapy.     

Differences in the response to periarterial nerve stimulation or exogenous noradrenaline infusion in the mesenteric vascular bed with the intestinal tract harvested from commonly used rat models of hypertension

Many hypertensive animal models have been developed and used to elucidate the pathophysiology of hypertension and to develop antihypertensive drugs. Among them, the spontaneous hypertensive rat (SHR), deoxycorticosterone acetate (DOCA)‐treated and high salt intake rat (DOCA‐salt), and high sodium‐fed Dahl salt‐sensitive rat (HS) models are commonly used. Multiple studies have been conducted, however, elevation in blood pressure in these models due to the reactivity of adrenergic vasoconstriction has not been well characterized in a centralized experiment. In this study, the pressor responses to periarterial nerve stimulation (PNS) or exogenous noradrenaline (NA) infusion were measured in the isolated mesenteric vascular bed with the intestinal tract to investigate the reactivity of mesenteric adrenergic vasoconstriction. The systemic arterial blood pressure of the hypertensive rat models was uniformly elevated compared with their respective controls. However, the changes in perfusion pressure in the mesenteric vascular bed in response to PNS and exogenous NA infusion were quite different depending on the model. The pressor responses to PNS in SHRs and Dahl S HS rats were significantly higher, and those in DOCA‐salt rats were significantly lower than those in the controls. The pressor responses to exogenous NA infusion in SHRs were significantly higher, and those in Dahl S HS rats were significantly lower than those in their respective controls. No difference was observed in the pressor responses to the exogenous NA between the DOCA‐salt and sham groups. These results demonstrate that the reactivity of adrenergic vasoconstriction is different for each type of experimental hypertensive model rat.     

Effects of beta-adrenergic receptor blocking agents on blood pressure in conscious hypertensive rats.

The effects of beta-adrenergic receptor blocking agents administered i.v. on the blood pressure in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and normotensive Wistar strain rats (NR) were studied. dl-Propranolol and dl-YB-2, 1 mg/kg i.v., caused a sustained rise in blood pressure in SHR and RHR. The maximum response of each beta-blocking agent after phentolamine, 10 mg/kg i.v., in SHR and RHR was significantly larger than that in NR. The potency ratio for the hypertensive activities of the 1- and d-isomers of propranolol and YB-2 was similar to the ratio of their beta-blocking activities. The pressor effects of the beta-blocking agents after phentolamine were significantly inhibited by adrenalectomy, reserpinization and pretreatment with hexamethonium. The results suggest that the pressor effect of the beta-blocking agents may be due to their beta-blocking activities and the unmasking of alpha-receptor activities of the blood vessels. Furthermore, the greater pressor effect of the agents observed in hypertensive rats is attributed to a greater activity of the sympathetic nervous system in these rats as compared to normotensive rats.     

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.     

Vascular reactivity of perfused vascular bed in spontaneously hypertensive and normotensive rats.

1 Hypertensive and normotensive rats of the same age group were isolated from an inbred colony of spontaneously hypertensive rats. 2 The perfused hindquarter and mesenteric artery preparations obtained from hypertensive and normotensive rats exhibited an increased reactivity to noradrenaline (NA) and angiotensin II. 3 Dose-response curves to NA obtained from hypertensive and normotensive rats exhibited a steeper slope and higher maximum than those from control rats. 4 These findings suggest that increased vascular reactivity of blood vessels is independent of the development or maintenance of elevated blood pressure.     

Further study of possible direct vascular actions of indapamide in the conduit and renal arteriolar vessels of spontaneously hypertensive rats

The effect of indapamide on vascular reactivity and its properties as a calcium antagonist were studied in both isolated aorta and perfused renal vasculature of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. Indapamide was given orally to SHR and WKY rats for 2 weeks at a dose of 5 mg/kg per day. During this period indapamide did not lower blood-pressure in SHR and WKY rats although there was an adequate concentration of indapamide in the blood. There were no differences observed in the vascular reactivity towards noradrenaline and high-K+ in both the above mentioned vessels in either indapamide- or vehicle-pretreated SHR and WKY rats. Verapamil (10(-9)-10(-5) M) caused a concentration-dependent relaxation of high-K+-depolarized aortas and a decrease in the renal-arteriolar perfusion pressure elevated by high-K+ in both strains of rat. However, indapamide (10(-7)-10(-4) M) did not affect the K+-induced effect on either vessel type. Preloading of the vessels in vivo with indapamide for 2 weeks did not influence the results. In conclusion, further evidence has been presented to show that indapamide does not have calcium-antagonist properties in conduit (aorta) or resistance (renal) vessels under hypertensive conditions. Preloading of the vessels with indapamide was not a prerequisite for the demonstration of a pharmacological action of indapamide.     

Influence of anti-hypertensive drug treatment on vascular reactivity in spontaneously hypertensive rats.

1. The effect of prolonged anti-hypertensive drug treatment on the blood pressure of conscious spontaneously hypertensive rats (SH-rats), and of age-matched normotensive Sprague-Dawley rats was determined during the development of hypertension in SH-rats and in the early stages of established hypertension. A comparison of the vascular reactivity to noradrenaline (NA) and 5-hydroxytryptamine (5-HT) was also made in isolated perfused mesenteric artery preparations from treated and control SH- and Sprague-Dawley rats. 2. Chronic treatment from age 4 to 16 weeks with hydrallazine alone, or a combination of hydrallazine/hydrochlorothiazide/reserpine, ad libitum in the drinking water, prevented the development of hypertension in SH-rats and also reduced the vascular reactivity to NA and 5-HT in isolated vessel preparations from treated compared to control rats. 3. Similar drug treatments started in early established hypertension reduced blood pressure in SH-rats over the 12 week treatment period (from age 8 to 20 weeks) without affecting vascular reactivity to NA and 5-HT in the isolated vessel preparation. 4. Drug treatments had little effect on blood pressure of age-matched Sprague-Dawley rats and no effect on vascular reactivity to NA and 5-HT in the isolated perfused mesenteric artery preparation from treated compared to control rats. 5. These results indicate that the development of increased vascular reactivity and of hypertension in SH-rats occurs simultaneously and, therefore, the vascular changes may be a consequence of the structural changes induced by the raised blood pressure. 6. In established hypertension, no regression of vascular changes was observed despite prolonged reduction of blood pressure. The role of an increased vascular reactivity in the maintenance of hypertension is therefore questionable.     

The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats.

1. The effects on blood pressure and on pressor responses to noradrenaline (NA), of NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), inhibitors of the L-arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS). 2. Infusion of LPS (10 mg kg-1 h-1) for 50 min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng-1 micrograms kg-1). L-NMMA (30 mg kg-1), but not D-NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by L- but not D-arginine (100 mg kg-1). 3. In LPS-treated rats, blood pressure responses to NA were only marginally increased by the cyclooxygenase inhibitor, indomethacin (5 mg kg-1). L-NAME (1 mg kg-1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin. 4. Co-infusion of vasopressin (100 ng kg-1, for 10 min) with LPS (10 mg kg-1 h-1) in order to reproduce the hypertensive effect of L-NMMA and L-NAME increased pressor responsiveness to 100 and 300 ng kg-1 NA but not to 1 microgram kg-1 NA. 5. Infusion of sodium nitroprusside (30 micrograms kg-1 min-1) decreased responsiveness to NA even when the hypotension was corrected by co-infusion of vasopressin (50 ng kg-1 min-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of potassium adaptation on blood pressure and pressor responses in normotensive and renal hypertensive Wistar rats

Potassium adaptation reduces blood pressure (BP) in hypertensive humans and animals but its effects on normotensive BP and the nature of pressor responses to vasoactive drugs are not known. We measured directly, the mean arterial pressure (MAP) of normotensive control, normotensive potassium-adapted (given 0.75% potassium chloride solution for 5 weeks), renal hypertensive (RHP), and renal hypertensive Wistar rats later adapted to potassium. The maximum percentage change, the ED25, and recovery times after bolus injections of noradrenaline (NA), angiotensin II (Ang. II), sodium nitroprusside (SNP), and acetylcholine (ACh) were compared. The MAP of normotensive potassium-adapted rats was significantly lower than that of the normotensive controls (95.6+/-5.0 vs. 110.8+/-2.8 mmHg, p<0.05). The potassium-adapted hypertensive rats (RHP-A) also had significantly lower MAP values than the non-adapted hypertensive ones (116.0+/-4.4 vs. 138.2+/-4.1 mmHg, p<0.01). Potassium adaptation significantly blunted responses to NA and augmented responses to SNP but while the duration of action of Ang. II was significantly shortened, that of SNP was significantly increased. We conclude that potassium adaptation reduces BP in the normotensive and hypertensive rats and may influence both the degree and duration of action of vasoactive drugs given as bolus injections.     

Reactivity of normotensive and spontaneously hypertensive rats (SHR) to some antihypertensive agents after acute and chronic treatment.

Hypotensive action of some antihypertensive agents was studied on normotensive and spontaneously hypertensive rats in acute and chronic treatment. The reactivity of normotensive rats was much more weaker than in rats with spontaneous hypertension (SHR). Results of the experiments indicate also that the selection of new antihypertensive agents should be based on tests carried out with at least two models of hypertension.     

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension

Indapamide is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity. Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.     

Vascular reactivity to 5-hydroxytryptamine and hypertension in the rat

Summary Isolated perfused mesenteric artery preparations of genetic (Japanese strain), renal and DOCA/saline hypertensive rats showed a marked increase in reactivity to the vasoconstrictor effect of 5-hydroxytryptamine (5-HT) as compared with normotensive controls. In the arteries of the hypertensive animals, the threshold vasoconstrictor doses of 5-HT were lower, the 5-HT dose-response curves were steeper and their maxima were increased by a factor of 2.5–4.2. These observation only partially fit into the concept that increased vascular reactivity in hypertension is due to an increased wall/lumen ratio of the arterial blood vessels. Pressor responses to 5-HT were also higher in isolated perfused hindquarter and in pithed preparations from renal and DOCA/saline hypertensive rats but not in those from genetic hypertensive rats. In isolated perfused renal artery preparations, the reactivity to 5-HT was equal for normotensive and hypertensive (genetic and DOCA/saline) animals, indicating that not all arteries of hypertensive rats share the increased reactivity to 5-HT. Pretreatment with reserpine slightly reduced the reactivity to 5-HT in arteries from both hypertensive and normotensive rats. Non-vascular smooth muscle of DOCA/saline hypertensive rats, for which isolated gastric strips were used as an example, responded to 5-HT in the same way as that of normotensive rats. Methysergide blocked the pressor responses to 5-HT but did not influence the blood pressure of the hypertensive animals, thus questioning a causal relationship between the increased vascular reactivity to 5-HT and the maintenance of high blood pressure in these three types of experimental hypertension.Preliminary results have been presented at the 3rd Meeting of the Union of the Swiss Societies for Experimental Biology in Zurich (Haeusler and Finch, 1971).     

Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats

1. Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hypertension and to interfere with the effectiveness of some anti-hypertensive therapies. In this study, we tested the effects of a gastric-sparing, nitric oxide-releasing derivative of aspirin (NCX-4016) on hypertension in rats. 2. Hypertension was induced by administering L-NAME in the drinking water (400 mg l(-1)). Groups of rats were treated daily with aspirin, NCX-4016 or vehicle. 3. NCX-4016 significantly reduced blood pressure relative to the aspirin-treated group over the 2-week period of treatment. Aspirin and, to a lesser extent, NCX-4016 suppressed whole blood thromboxane synthesis. 4. In anaesthetized rats, acute intravenous administration of NCX-4016 caused a significant fall in mean arterial pressure in hypertensive rats, but was devoid of such effects in normotensive controls. 5. In vitro, NCX-4016 relaxed phenylephrine-pre-contracted aortic rings obtained from both normotensive and hypertensive rats, and significantly reduced their responsiveness to the contractile effects of phenylephrine. 6. These results suggest that NCX-4016 reduces blood pressure in hypertensive rats, not simply through the direct vasodilatory actions of the nitric oxide released by this compound, but also through possible interference with the effects of endogenous pressor agents. These properties, added to its anti-thrombotic effects, suggest that NCX-4016 may be a safer alternative to aspirin for use by hypertensive patients.     

Influence of enalapril on the endothelial function of DOCA-salt hypertensive rats

In the present study, we investigated whether the correction of endothelial dysfunction can be independent of the normalization of high blood pressure levels by enalapril in deoxycorticosterone (DOCA-salt) hypertensive rats. Aorta morphology and the response of aortas with (E+) and without (E-) endothelium to noradrenaline, acetylcholine, and sodium nitroprusside were studied. DOCA-salt hypertensive and normotensive (control) rats were or were not treated with enalapril (5 mg/day/rat in the drinking fluid) for 1, 7, or 15 days. Blood pressure was measured before and after 1, 3, 7, and 15 days of enalapril treatment. Enalapril normalized the high blood pressure levels in 50% (responders) of the hypertensive rats after 3 to as many as 15 days but not after 1 day of treatment. Initial blood pressure levels were not different between responders and nonresponders. Blood pressure levels of normotensive control rats were not altered by enalapril treatment. The tunica media of aortas of DOCA-salt hypertensive rats treated or not treated with enalapril for 15 days was thicker than aortas from normotensive rats. Enalapril corrected the reduced response to acetylcholine observed in aorta from hypertensive rats from the first day of treatment. This treatment rendered aortas from normotensive control rats more sensitive (lower EC(50)) to acetylcholine without a change in the maximal responses. The responses to sodium nitroprusside, a nitric oxide donor, were unaltered in aorta E+ or E- from control and hypertensive rats before and after enalapril treatment. Enalapril did not correct the increased responses to noradrenaline observed in aorta E+ of hypertensive rats. These results suggest that the high blood pressure in DOCA-salt hypertension is not correlated with the altered response to endothelium-dependent agents (either dilator or constrictors). The endothelium-dependent vasodilation by antihypertensive agents can be corrected independently of normalization of blood pressure levels or the vascular morphology.     

Haemodynamic changes in peripheral arterial circulation during antihypertensive treatment with captopril, methyldopa and indapamide

Structural changes in resistance vessels of the lower limbs have been detected in early stages of arterial hypertension. In these patients it might be important to reduce blood pressure by drugs which do not impair peripheral blood flow. Twenty-four patients with arterial hypertension, without target organ damage were randomly given a placebo, 50 mg captopril, 500 mg methyldopa or 2.5 mg indapamide and their blood pressure, arterial blood flow and peripheral resistance were measured at baseline and at the peak action of the antihypertensive treatment. Significant decreases in blood pressure and peripheral resistance have been induced by a single oral dose of captopril and methyldopa: a concomitant significant increase in peripheral blood flow to the lower limbs was also observed during methyldopa treatment. No acute effect was observed on the placebo or on indapamide: the latter induced a decrease in blood pressure and in peripheral resistance along with an increase in arterial blood flow during long-term treatment after four weeks of therapy. Our observations seem to support the usefulness in hypertensive patients with concomitant lesions in the peripheral arterial tree of antihypertensive agents such as methyldopa and indapamide which increase blood flow and reduce peripheral resistance while lowering high blood pressure.     

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.     

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.