Conscious Normotensive Rats Research Articles

Novel synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline and analogues: potent angiotensin converting enzyme inhibitors.

A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.

Responses of blood pressure and angiotensin-converting enzyme activity to acute captopril administration in normotensive and hypertensive rats.

The purpose of these experiments ws to determine the dose of captopril which resulted in essentially complete blockade of tissue and plasma converting enzyme activity (CEA) and to correlate the effect of this dose of inhibitor on blood pressure and CEA in a number of normotensive and hypertensive rat models. Oral administration of captopril (0.3-10 mg/kg) induced a dose-related attenuation of CEA in plasma freshly drawn from normotensive conscious rats. After storage at -20 or 4 C before assay, both captopril-treated and untreated plasmas displayed markedly greater CEA. The converting enzyme inhibitor induced a parallel shift to the right of angiotensin I-induced blood pressure responses, reaching a 100-fold displacement of dose-dependent responses in the presence of 10 mg/kg captopril. Sixty minutes after oral administration of 10 mg/kg captopril, plasma CEA was blocked completely in all normo- and hypertensive models studied. This dose of the inhibitor reduced blood pressure in the sodium-deplete normotensive rat, the spontaneously hypertensive rat, and the initial phase two-kidney, one-clip Goldblatt rat but not in the sodium-replete normotensive rat, the spontaneously hypertensive rat, the mineralocorticoid hypertensive rat, or the chronic phase of two-kidney, one-clip Goldblatt rat. It is concluded that acute administration of captopril at a dose which results in complete blockade of plasma converting enzyme and severe attenuation of tissue converting enzyme reduces blood pressure in animals with high PRA but not in animals in which the PRA is low. (Endocrinology 108: 536, 1981)

Antihypertensive effects of nifedipine on conscious normotensive and hypertensive rats.

Hypotensive actions of single and repeated administrations of nifedipine were evaluated in comparison with hydralazine in normotensive, spontaneously hypertensive and renal hypertensive rats. Substantial and prolonged falls in blood pressure were observed following oral dosing with 3 mg/kg of nifedipine in renal hypertensive rats, with 10 mg/kg of nifedipine in normotensive and spontaneously hypertensive rats and with 10 mg/dg of hydralazine in all three groups of animals. The hypotensive effect of nifedipine was greater in both forms of hypertensive rats than the normotensive rats, while there was no difference in the hypotensive effect of hydralazine in normotensive and hypertensive animals. In spontaneously hypertensive rats tolerance to nifedipine and hydralazine was not observed with oral administrations for 4 weeks at a daily dose of 10 mg/kg. An increase in heart rate always accompanied the hypotension induced by both drugs, but this tachycardia was seen to a lesser extent with nifedipine than with hydralazine. The mechanism of the selective action of nifedipine in hypertensive rats in contrast to normotensive rats is discussed.

Blood pressure responses of conscious normotensive and spontaneously hypertensive rats to intracerebroventricular and peripheral administration of captopril.

In conscious spontaneously hypertensive rats, intraxerebroventricular injection of captopril (2 mg/kg) resulted in a rapid hypotensive response that lasted several hours. The same dose given by intracerebroventricular injection had no significant effect on blood pressure (BP) of normotensive Wistar-Kyoto (WK) rats over 7 hours. There was no significant change in BP of conscious spontaneously hpertensive rats (SHR) in response to intracerebroventricular injection of vehicle and only a transitory fall in BP in response to intravenous injection of captopril (2 mg/kg). There was no significant differences between plasma renin activity (PRA) of conscious normotensive WKY rats and the PRA of SHR. These results suggest biochemical differences between the brains of SHR and normotensive WKY control rats. These differences could involve the brain renin-angiotensin system or other neuropeptides.

Antihypertensive indole derivatives of phenoxypropanolamines with beta-adrenergic receptor antagonist and vasodilating activity.

A series of 25 aryloxypropanolamines containing the 3-indolyl-tert-butyl [i.e., 1,1-dimethyl-2-(1H-indol-3-yl)ethyl] or substituted 3-indolyl-tert-butyl moiety as the N substituent is reported. These compounds have been tested for antihypertensive activity in spontaneously hypertensive rats (SHR), beta-adrenergic receptor antagonist action in conscious normotensive rats, vasodilating activity in ganglion-blocked rats with blood pressure maintained by angiotensin II infusion, and for intrinsic sympathomimetic action (ISA) in reserpinized rats. Some of the compounds exhibit antihypertensive activity in combination with beta adrenergic receptor antagonist and vasodilating action. The structure--activity relationships in these tests are discussed.

On acute hypotensive effects of pindolol and propranolol in conscious rats

1. 1. An acute hypotensive effect of pindolol or propranolol have been identified in conscious normotensive and experimental hypertensive rats. 2. 2. The hypotensive effect induced with pindolol (0.1 mg/kg i.p.) was slightly inhibited by lateral ventricle injection of 6-hydroxydopamine (6-OHDA), but that induced with propranolol (5 mg/kg i.p.) was not. 3. 3. These hypotensive effects were abolished by systemic administration of 6-OHDA (50 mg/kg i.v.) or by pretreatment with indomethacin (1 mg/kg i.p.).

Observations on the effect of labetalol on pregnancy and parturition in normotensive rats

1. The effect of labetalol on blood pressure and uterine activity in conscious normotensive pregnant rats has been studied. 2. Labetalol was an effective hypotensive agent in Day 20 pregnant rats the reduction and duration of the effect being dose dependent. 3. The duration of gestation appeared to be prolonged by labetalol given daily from Day 19 to Day 22 of gestation, however, the parturient process was not significantly affected. 4. Labetalol given to parturient rats resulted in a reduction in uterine activity and a marked prolongation of the delivery process. 5. Oxytocin-induced contractions of the in vivo uterus of the Day 22 pregnant rat were significantly reduced by labetalol. 6. The mechanism of action whereby labetalol produces these effects are probably related to the ability of the drug to interfere with α- and/or β-adrenoceptors in the uterus and other organs which can indirectly alter uterine function. These are discussed.

HYPOTENSIVE ACTIONS OF SEVERAL β-ADRENOCEPTOR BLOCKING AGENTS IN CONSCIOUS NORMOTENSIVE RATS

HYPOTENSIVE ACTIONS OF SEVERAL β-ADRENOCEPTOR BLOCKING AGENTS IN CONSCIOUS NORMOTENSIVE RATS

The Effect of Angiotensin-Converting Enzyme Inhibition on Regional Blood Flow in Salt-Depleted and Salt-Loaded Normotensive Conscious Rats

The effect of angiotensin-converting enzyme inhibition on regional blood flow was studied in a total of 21 normotensive Wistar rats fed on either low or high salt diet. A new potent angiotensin-converting enzyme inhibitor (CEI), SQ 14,225 was administered intravenously in a dose of 2 mg/Kg to the conscious animals, and changes in fractional distribution of cardiac output were determined with a microsphere method. Prior to administration of CEI, there was no significant difference in mean arterial pressure (MAP) or regional blood flow between salt-depleted and salt-loaded rats. With CEI, MAP did not change significantly in either group. Fractional distribution of cardiac output increased to the kidneys (p less than 0.002), and decreased to the stomach, spleen, and skeletal muscle (p less than 0.02, p less than 0.002, and p less than 0.01, respectively) in the salt-depleted group, while a pattern of blood flow distribution was not changed in the salt-loaded group. These results suggest that angiotensin II plays an important role in regulating regional blood flow in salt-depleted conscious animals, but not in salt-loaded ones.

Synthetic phosphatidylethanolamines as renin inhibitors.

SummaryAnti-renin and hypotensive effects of synthetic PEs were examined.(i) Eighteen PEs including optical isomers were newly synthesized. Arachidonic acid, linolenic acid, and stearic acid were substituted at the positions of β, γ, or both. Natural PE was extracted from porcine kidney, and the lyso form was prepared by treatment of phospholipase A.(ii) Anti-renin activity of these compounds was determined using high-renin plasma obtained from the dog. The inhibition of renin activity was expressed as a percentage of the reduction in the production rate of angiotensin I as measured by radioimmunoassay.(iii) The inhibitory effects of PE(β-C18=3, γ-C18) series, d- and DL-PE(β-C20=4, γ-C18), and dl- and l-PE(β-C18, γ-C20=4) were greater than that of the natural PE, but did not exceed the effect of lyso-PE.(iv) Hypotensive effect was evaluated in conscious normotensive, spontaneously hypertensive, and renal hypertensive rats by daily im injection of the test compounds.(v) Following repeated administration of...

無麻酔ラット血圧における<I>dl</I>-Mandelamidine(Olmidine)と他の降圧薬との相互作用

Hypotensive effect of dl-Mandelamidine (Olmidine, MA) in combination with some established antihypertensive drugs was studied in conscious normotensive rats. The mean blood pressure and heart rate were measured by means of a pressure transducer via a polyethylene tube inserted into the abdominal aorta of rat according to the method described by Weeks. The results obtained were as follows; 1) The hypotensive effects of guanethidine and hydrochlorothiazide were enhanced in combination with MA. 2) The hypotensive effect of reserpine was reduced by MA. 3) The hypotensive effects of clonidine, C6, propranolol and hydralazine were uneffected by MA. On the other hand, changes in heart rate induced by reserpine and C6 were increased by MA, however, those induced by guanethidine, clonidine propranolol and hydralazine were decreased by MA. The slight decrease in heart rate induced by hydrochlorothiazide was uneffected by MA. In view of our data, it is considered important that investigation of the interaction of antihypertensive drugs be done using conscious animals, as these drugs will be clinically prescribed.

HYPOTENSIVE AND VASODILATOR ACTIONS OF SK&F 24260, A NEW DIHYDROPYRIDINE DERIVATIVE

1 The blood pressure of conscious normotensive, Goldblatt-hypertensive and genetic-hypertensive rats and normotensive dogs was lowered by SK&F 24260 (1,4-dihydro-2,6-dimethyl-4-(2-trifluormethylphenyl)-3,5-pyridinedicarboxylic acid diethyl ester).2 Tachycardia always accompanied the hypotension. In rats propranolol abolished the tachycardia but in dogs there was only a small reduction in the heart rate response.3 In conscious dogs there was an increase in left ventricular output and a marked fall in total peripheral resistance.4 SK&F 24260 dilated resistance vessels in rat hindquarters. Dilatation was caused by doses of SK&F 24260 some 50 times smaller than those of hydrallazine.5 In preparations of cat skeletal muscle and intestinal vascular beds SK&F 24260 selectively dilated resistance vessels in preference to capacitance vessels and resembled hydrallazine rather than papaverine which has no such selectivity.6 Pre-capillary sphincter vessels were also dilated by SK&F 24260. Changes in fluid equilibrium caused by SK&F 24260 were consistent with selective dilatation of resistance vessels.

A specific competitive antagonist of the vascular action of angiotensin. II.

The effect of 1-Asn-8-Ala-angiotensin II (Asn-Arg-Val-Tyr-Val-His-Pro-Ala) on the vascular action of angiotensin II was studied with rabbit aortic strips, pithed rats, and conscious rats. Dose-response (contraction) curves for angiotensin II on rabbit aortic strips shifted progressively to the right with increasing bath concentrations of 1-Asn-8-Ala-angiotensin II. The pA 2 value (an indication of the relative affinity of a competitive antagonist for an agonist's receptor site) was 6.84 ± 0.03. Dose-response curves for norepinephtine, serotonin, and histamine were relatively unaffected. No pA 3 values could be obtained with these agonists in the concentration range tested. Partial dose-response (pressor) curves for angiotensin II in pithed rats shifted to the right during infusions of 1-Asn-8-Ala-angiotensin II at 20 and 60 µg/kg min -1 Partial dose-response curves for vasopressin, phenylephririe, and tyramine were unaffected. Infusions of 1-Asn-8-Ala-angiotensin II counteracted the pressor effect of angiotensin II infusions in pithed and conscious rats. Infusions of 1-Asn-8-Ala-angiotensin II (200 µ/ kg min -1 ) effective in reducing the blood pressure of conscious angiotensin II-infused rats caused only small pressor effects in conscious normotensive rats but reduced the blood pressure in 75% of the conscious rats with acute unilateral renal hypertension. The data presented are consistent with the conclusion that 1-Asn-8-Ala-angiotensin II is a specific competitive antagonist of the vascular action of angiotensin II both in vitro and in vivo.

The neurogenic component in the experimental hypertensive rat.

Experiments were carried out to determine the role of the sympathetic nervous system in maintaining an elevated blood pressure in chronic renal and deoxycortico sterone/NaCl induced hypertension in the rat. Inhibition of sympathetic nerve function by pithing, mecamylamine and reserpine markedly reduced the blood pressure in both normotensive and hypertensive anaesthetised preparations. When anti-hypertensive agents were given to conscious normotensive and hypertensive rats, only frusemide lowered the blood pressure of the hypertensive rat to the level obtained after similar treatment of the normotensive rat. With the Gillespie and Mum preparation [8] the hypotensive action of some of these drugs was independent of their effects on the peripheral sympathetic nervous system.