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1.
Hypertension ; 34(6): 1293-300, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10601133

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 (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). 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 (P<0.0003). 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.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Arginine Vasopressin/blood , Hormone Antagonists/therapeutic use , Hypertension/blood , Hypertension/drug therapy , Indoles/therapeutic use , Pyrrolidines/therapeutic use , Administration, Oral , Adult , Aldosterone/blood , Black People , Blood Volume/drug effects , Cross-Over Studies , Double-Blind Method , Heart Rate/drug effects , Hormone Antagonists/blood , Humans , Hypertension/ethnology , Hypertension/urine , Indoles/blood , Kidney Function Tests , Male , Platelet Aggregation/drug effects , Pyrrolidines/blood , Renin/blood , Serum Albumin/analysis , Sodium/blood , Treatment Outcome , White People
2.
Ann Neurol ; 41(6): 809-13, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9189043

ABSTRACT

The prevalence of known mutations in presenilin genes (PS1 and PS2) causing early-onset familial Alzheimer's disease (FAD) was assessed in a population of 98 singleton early-onset AD cases, 29 early-onset FAD cases, and 15 late-onset FAD cases. None of the cases tested positive for the eight mutations initially reported, and none of these mutations were observed in 60 age-matched controls. A novel mutation (R269H) in PS1 was found in a single case of early-onset AD but not in any other AD or control case. Thus, the PS mutations tested are quite rare in early-onset AD. Amyloid beta protein (A beta) deposition was investigated in the temporal cortex of the R269H mutation case using end-specific monoclonal antibodies to detect the presence of A beta x-40 and A beta x-42 subspecies. Stereologically unbiased tangle and neuropil thread counts were obtained from the same region. R269H PS1 mutation was associated with early age of dementia onset, higher amounts of total A beta and A beta x-42, and increased neuronal cytoskeletal changes. Thus, if the changes observed on this case prove to be typical of PS1 mutations, PS1 mutations may impact both amyloid deposition and neurofibrillary pathology.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Membrane Proteins/genetics , Mutation , Neurofibrils/pathology , Age of Onset , Aged , Alzheimer Disease/pathology , Brain/metabolism , Brain/pathology , Female , Humans , Male , Middle Aged , Presenilin-1
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