Safety, Tolerability, and Pharmacokinetics of SR 49059, a V1A Vasopressin Receptor Antagonist, After Repeated Oral Administration in Healthy Volunteers

Brouard, R; Laporte, Vincent; Gal, C. Serradeil Le; Pignol, Régis; Jang, Haejong; Donat, François; Lockwood, G.; Fournie, D.; Dreux, F.

doi:10.1007/978-1-4615-4871-3_59

Cited by 15 publications

(12 citation statements)

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“…This 300-mg dose has been shown to effectively block AVP-induced platelet aggregation in normal volunteers and to prevent uterine contractions induced by lysine AVP in 12 healthy women. 15,31 In this group of 12 normotensive women, injection of lysine AVP produced a transient increase in supine systolic blood pressure on placebo treatment (ϩ5 mm Hg), whereas a 4 mm Hg decrease was noted after the administration of 300 mg of SR49059, with the difference between the treatments being significant at 1 and 2 hours after the dose. No significant differences in supine diastolic blood pressure or HR were observed.…”

Section: Discussionmentioning

confidence: 99%

“…In healthy human volunteers, SR49059 inhibits exogenous AVP-induced platelet aggregation, skin blanching, and vasoconstriction. 15,16 In the present article, we report the results of the first administration of the nonpeptide V 1 R antagonist SR49059 to untreated hypertensive patients before and during an hypertonic saline infusion that produces a significant osmotic release of AVP in the circulation.…”

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confidence: 99%

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Effects of the Nonpeptide V ₁ Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

et al. 1999

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Abstract-We assessed the clinical and pharmacological profile of the orally active V 1 vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (Pϭ0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (Pϭ0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (PϽ0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V 1 vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V 1 vascular receptor antagonist that is devoid of V 2 renal receptor actions. (Hypertension. 1999;34:1293-1300.)Key Words: vasopressins Ⅲ nonpeptide antagonist Ⅲ vasopressins Ⅲ hypertension, essential Ⅲ osmoregulation T he neurohypophysial hormone arginine vasopressin (AVP) is involved in the regulation of body fluid osmolality, blood volume, blood pressure, cell contraction, cell proliferation, and adrenocorticotropic hormone secretion via the stimulation of specific receptors currently classified into V 1 vascular (V 1 R), V 2 renal (V 2 R), and V 3 pituitary (V 3 R) subtypes with distinct pharmacological profiles and intracellular second messengers. 1 AVP has been shown to be one of the most powerful in vitro vasoconstrictor substances, 2 and its vasoconstrictor and mitogenic actions may contribute to the pathogenesis of arterial hypertension, heart failure, and atherosclerosis. 3,4 AVP plays a role in the maintenance of blood pressure in several conditions, including upright posture, dehydration, hemorrhage, adrenal insufficiency, and cardiac failure, and during surgery. 5,6 An...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Effects of the Nonpeptide V ₁ Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

et al. 1999

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“…SR 49059 is a potent and selective orally effective nonpeptidic antagonist of both rat and human V 1a receptors. SR 49059 has an apparent half-life of 24 -30 h in human and is rapidly and widely distributed in the body after a single oral dose administration (23). SR 49059 and placebo tablets were identical in appearance.…”

Section: In Vivo Studiesmentioning

confidence: 97%

Evidence for a Role of Vasopressin in the Control of Aldosterone Secretion in Primary Aldosteronism:in Vitroandin VivoStudies

Perraudin

Delarue

Lefebvre

et al. 2006

The Journal of Clinical Endocrinology & Metabolism

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“…The orally and intravenously active non- (402) and in women receiving tocolytic treatment (113,465). Although SR49059 was useful in proving the beneficial effects of V1a receptor antagonists and it has a good safety profile (72), the phase II study of SR49059 has been discontinued (323,453). SRX251 is a new V1a receptor antagonist (153) and is under clinical evaluation in a recently completed phase I study (ClinicalTrials.gov; identifiers: NCT00461370 and NCT00532467).…”

Section: B V1a and V1b Receptor Antagonistsmentioning

confidence: 99%

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

Koshimizu

Nakamura

Egashira

et al. 2012

Physiological Reviews

334

297

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The neurohypophysial hormone arginine vasopressin (AVP) is essential for a wide range of physiological functions, including water reabsorption, cardiovascular homeostasis, hormone secretion, and social behavior. These and other actions of AVP are mediated by at least three distinct receptor subtypes: V1a, V1b, and V2. Although the antidiuretic action of AVP and V2 receptor in renal distal tubules and collecting ducts is relatively well understood, recent years have seen an increasing understanding of the physiological roles of V1a and V1b receptors. The V1a receptor is originally found in the vascular smooth muscle and the V1b receptor in the anterior pituitary. Deletion of V1a or V1b receptor genes in mice revealed that the contributions of these receptors extend far beyond cardiovascular or hormone-secreting functions. Together with extensively developed pharmacological tools, genetically altered rodent models have advanced the understanding of a variety of AVP systems. Our report reviews the findings in this important field by covering a wide range of research, from the molecular physiology of V1a and V1b receptors to studies on whole animals, including gene knockout/knockdown studies.

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Safety, Tolerability, and Pharmacokinetics of SR 49059, a V1A Vasopressin Receptor Antagonist, After Repeated Oral Administration in Healthy Volunteers

Cited by 15 publications

References 15 publications

Effects of the Nonpeptide V ₁ Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

Effects of the Nonpeptide V ₁ Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

Evidence for a Role of Vasopressin in the Control of Aldosterone Secretion in Primary Aldosteronism:in Vitroandin VivoStudies

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

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Safety, Tolerability, and Pharmacokinetics of SR 49059, a V1A Vasopressin Receptor Antagonist, After Repeated Oral Administration in Healthy Volunteers

Cited by 15 publications

References 15 publications

Effects of the Nonpeptide V 1 Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

Effects of the Nonpeptide V 1 Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

Evidence for a Role of Vasopressin in the Control of Aldosterone Secretion in Primary Aldosteronism:in Vitroandin VivoStudies

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

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Effects of the Nonpeptide V ₁ Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

Effects of the Nonpeptide V ₁ Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients