Aquaretic and hormonal effects of a vasopressin V(2) receptor antagonist after acute and long-term treatment in rats.

A single oral administration of 1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethoxy)cyclohexane]indo l-2 -one SR121463 (0.3-3 mg/kg), a vasopressin non-peptide V(2) receptor antagonist, to rats induced dose-dependent aquaresis which was accompanied by Na(+), K(+), aldosterone and arginine vasopressin excretion over 6 h after dosing. However, no solute excretion was observed over 24 h. As a result of aquaresis, hemoconcentration and increases in plasma angiotensin II and adenocorticotrophin hormone were seen with 3 mg/kg at 2 h after dosing. Chronic treatment with SR121463 (3 mg/kg/dayx28 days) induced a marked aquaresis associated with aldosterone and vasopressin excretion. After a week of treatment, urine volume and aldosterone excretion were reduced ( approximately 40%) and then stabilised, while urine vasopressin excretion remained almost constant throughout the study. There were no changes in arterial pressure, plasma osmolality, plasma sodium concentration, or in number and affinity of liver vasopressin V(1A) and kidney V(2) receptors 24 h after the last treatment. These results indicate that SR121463 is a potent aquaretic agent and might be useful for the chronic management of water-retaining diseases in humans.

Study of SR 142801, a new potent non-peptide NK3 receptor antagonist on cardiovascular responses in conscious guinea-pig.

1. The cardiovascular responses to intravenous (i.v.) injection of natural tachykinins, substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and selective tachykinin (NK) receptor agonists, [Sar9, Met(O2)11]SP, [beta Ala8]NKA(4-10), [MePhe7]NKB and senktide were assessed in conscious, freely moving, guinea-pigs. 2. SP and [Sar9, Met(O2)11]SP (1-1000 pmol kg-1) induced dose-dependent decreases in mean arterial blood pressure (MAP) accompanied by increases in heart rate (HR). NKA evoked only weak hypotensive effects at high doses (3000 pmol kg-1) whereas [beta Ala8]NKA(4-10) (1-3000 pmol kg-1) had no effects. By contrast, NKB [MePhe7]NKB (1-10,000 pmol kg-1) and senktide (1-1000 pmol kg-1), produced dose-related hypertensive effects with the following rank order of potency: senktide > [MePhe7]NKB > NKB. Bradycardia occurred simultaneously with the increases in arterial pressure. 3. The pressor response to intravenous injection of senktide (300 pmol kg-1) was partially reduced by pretreatment with prazosin (0.71 mumol kg-1), or clonidine (0.38 mumol kg-1) and was completely inhibited by the combination of the two compounds. Atropine (1.5 mumol kg-1) suppressed the decrease in HR induced by senktide without altering the blood pressure response. These findings suggest that the blood pressure response to senktide is an indirect effect mediated by noradrenaline released from sympathetic nerve endings, whereas the bradycardia is of vagal reflex origin. 4. SR 142801, ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenyl-piperidin-4-yl)-N-methylacetamide), a potent and specific non-peptide NK3 receptor antagonist dose-dependently (0.46-4.6 mumol kg-1, i.v.; 4.6-46 mumol kg-1, p.o.) inhibited the cardiovascular effects of senktide and displayed a long-lasting inhibitory effect after oral administration. By contrast, SR 142806 (4.6 mumol kg-1, i.v.), the (R)-enantiomer of SR 142801 had no effect on the responses to senktide. SR 142801 at a high dose (15 mumol kg-1, i.v.) was inactive toward the [Sar9, Met(O2)11]SP-induced hypotension. 5. SR 142801 did not modify MAP in conscious guinea-pigs both after i.v. (4.6 and 15 mumol kg-1) and oral (46 and 150 mumol kg-1) administration, showing a lack of agonistic properties. However, a slight reduction in HR was observed only after i.v. injection. 6. In conclusion, these results show evident differences in the functional role of tachykinin receptors in the peripheral control of the cardiovascular system. Furthermore, a clear pressor effect of senktide, which was selectively blocked by SR 142801, was observed in conscious guinea-pigs. Hence, this antagonist appears suitable for investigating the functional role of NK3 receptors.

A pharmacodynamic study of SR 47436, a selective AT1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys.

1. Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. 2. SR 47436 at 10 mg kg-1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg-1, indicating that a maximal hypotensive effect had already been obtained. 3. A single oral dose of SR 47436 (10 mg kg-1) caused a sustained hypotension and a marked inhibition of the AII-induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug (t 1/2 approximately 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. 4. Although a fair correlation between individual plasma drug concentrations and inhibition of AII-induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. 5. Basal arterial pressure and AII-induced pressor response were not affected by blood samplings. 6. These results suggest that SR 47436 is an effective and long lasting AT1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious blocker of the RAS in man and suitable for once-a-day dosing.

Pharmacological study of SR 47436, a non-peptide angiotensin II AT1-receptor antagonist, in conscious monkeys.

OBJECTIVE: The hypotensive and hormonal responses of an AT1-subtype angiotensin II receptor antagonist, SR 47436, were investigated and compared with those of DuP 753 (losartan), the leading AT1-receptor antagonist, and captopril and enalapril, two major angiotensin converting enzyme (ACE) inhibitors, in conscious, sodium-replete and sodium-depleted non-human primates. DESIGN AND METHODS: Blood pressure and heart rate were measured in conscious, chronically instrumented sodium-replete (n = 3-5) and sodium-depleted (n = 4) cynomolgus monkeys (Macaca fascicularis). Plasma renin activity (PRA), active renin and angiotensin II plasma concentrations were determined. RESULTS: SR 47436 induced a dose- and time-related fall in blood pressure in sodium-depleted monkeys; the blood pressure-lowering effect was obtained at a range of doses from one-third to one-tenth the equihypotensive dose of DuP 753 after intravenous and oral administrations. The hypotensive effect obtained with SR 47436 was similar to that of captopril and was sustained in sodium-replete monkeys, although it was weaker and less long-lasting than that of enalaprilat. In both sodium-depleted and sodium-replete monkeys the AT1 antagonist and ACE inhibitors caused similar increases in PRA and active renin. However, although angiotensin II levels increased after SR 47436 or DuP 753 treatment, they decreased after treatment with enalaprilat. Modest decreases in the heart rate sometimes accompanied the hypotension, irrespective of the compound tested. CONCLUSION: These data demonstrate that the AT1 antagonist SR 47436 is an effective hypotensive agent in both sodium-replete and sodium-depleted monkeys, with an intrinsic potency three to 10 times that of DuP 753 and similar to that of ACE inhibitors.

Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist.

SR 47436, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, is a new potent and selective AT1 angiotensin II (AII) receptor antagonist. It competitively inhibited [125I]AII binding to AT1 subtype receptors in rat liver membranes (IC50 = 1.7 nM) and did not interact with AT2 subtypes in rat adrenal cortical membranes. In rabbit aorta, SR 47436 inhibited contractions induced by 10 nM AII (IC50 = 4.0 nM) and shifted AII contractile response curves to the right in a parallel fashion, without total recovery of the maximal response. The potency of SR 47436 was higher than that of the lead compound, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole (DuP 753) (rat liver binding: IC50 = 16 nM; rabbit aorta: IC50 = 26 nM), and equivalent to saralasin (IC50 = 1.8 and 2.7 nM, respectively). The high specificity of SR 47436 was demonstrated by its lack of activity (IC50 > 10 microM) on various other receptors, ionic channels and antiports and rabbit aorta contracted by norepinephrine and KCl, and its lack of inhibition of renin and converting enzyme. In conscious rats, SR 47436 as well as DuP 753 (0.1 to 3 mg/kg, i.v., and 0.3 to 30 mg/kg, p.o.) antagonized the AII-pressor response in a dose-related manner. In conscious dogs, SR 47436 (1-10 mg/kg, p.o.) was a more potent antagonist of the AII pressor response than DuP 753. In conscious chronically implanted cynomolgus monkeys, SR 47436 antagonized the AII-pressor response at 1 mg/kg (89% i.v. and 66% p.o.) much more strongly than DuP 753 at 10 mg/kg (83% i.v. and 20% p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a renin inhibitor, SR 43845, and of captopril on blood pressure and plasma active renin in conscious sodium-replete macaca.

The effects of the renin inhibitor, SR 43845 (IC50 = 10(-11) mol/l human and primate plasma renin) and of the angiotensin converting enzyme (ACE) inhibitor captopril on blood pressure and plasma active renin were investigated in conscious, chronically instrumented, sodium-replete macaca (cynomolgus monkeys). Perfusion of SR 43845 at 0.33, 3.3, 33, 100 and 200 micrograms/kg per min for 30 min elicited a dose-related decrease in blood pressure with a notable effect on plasma renin activity (PRA; 90% inhibition), beginning at a dose of 0.33 micrograms/kg per min. The maximal reduction in blood pressure of 22 +/- 2 mmHg (from 110 +/- 5 mmHg) was achieved at 100 micrograms/kg per min and a higher dose (200 micrograms/kg per min) induced no further reduction. Plasma levels of active renin were also significantly increased (to 104%, from 102 +/- 14 pg/ml) at the lower dose. Captopril, tested at 33 micrograms/kg per min under the same experimental conditions, lowered blood pressure in a similar manner and with the same intensity as the renin inhibitor at an equal dose (by 14 +/- 1 mmHg, from 114 +/- 4 mmHg). However, a dose six times as high only influenced the decrease of blood pressure slightly (by 16 +/- 2 mmHg, from 103 +/- 5 mmHg). For the same hypotensive effect, the plasma renin concentration was significantly higher with the renin than with the ACE inhibitor. The recovery of pre-infusion blood pressure was both time- and dose-dependent, the basal value being almost restored after 5 h with both inhibitors, although the initial plasma renin levels were not completely recovered. A comparison of the maximal hypotensive effects and the plasma active renin concentrations elicited by the renin and the ACE inhibitors suggests that there are no major differences between the two types of inhibition and that renin inhibition is slightly more efficient.