Atrial natriuretic factor inhibits hypertonic saline-mediated decreases in renal hemodynamics

The present study in the anesthetized dogs was designed to test the hypothesis that atrial natriuretic factor (ANF) attenuates whole kidney tubuloglomerular feedback (TGF) mediated decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) produced by hypertonic saline (HS). Secondly, as adenosine (AD) has been implicated as a metabolic mediator of TGF, we also hypothesized that ANF would antagonize the renal actions of AD. To test this hypothesis, RBF and GFR were assessed in response to hypertonic saline (HS, 16%, i.r.) or adenosine (AD, 0.1 mumol/min, i.r.) in the presence and absence of exogenous ANF (100 ng/kg/min, i.r.). ANF attenuated HS-mediated reductions in GFR (HS, -39.6 +/- 9.8 ml/min vs. HS + ANF, -14.3 +/- 4.5 ml/min, P less than 0.05) and in RBF (HS, -143 +/- 35 ml/min vs. HS + ANF, -5 +/- 22 ml/min, P less than 0.05). GFR was reduced by AD (-9.2 +/- 3.0 ml/min, P less than 0.05), but maintained by AD + ANF (-0.4 +/- 2.0 ml/min, NS). A transient adenosine-mediated vasoconstriction was attenuated by ANF (AD, -54.5 +/- 3.6 ml/min vs. AD + ANF, -3.7 +/- 3.1 ml/min, P less than 0.005). We conclude that ANF at pharmacologic concentrations attenuates at the whole kidney level hypertonic saline and adenosine-mediated reductions in RBF and GFR.     

Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage

A dose-escalation study of the calcium ion entry blocking drug nicardipine was performed using large dose infusions in 67 patients with recent aneurysmal subarachnoid hemorrhage (SAH). A safe, potentially therapeutic dose of the drug was determined. Patients admitted within 7 days of SAH from a documented cerebral aneurysm were entered into the study if no spasm was present on the initial angiogram. Nicardipine was administered as a continuous intravenous infusion throughout the 14-day period after SAH, regardless of the timing of surgery. To determine the safest possible dose, nicardipine was administered at seven dose levels from 0.01 to 0.15 mg/kg/hr. The total daily doses ranged from 27.7 mg to 375.0 mg. A follow-up angiogram was carried out on all 67 patients 7 to 10 days after SAH. Computerized tomography and neurological examinations were used to determine the presence of cerebral infarction. No major adverse effects, unexpected reactions, or permanent sequelae could be attributed to nicardipine. A decline in blood pressure was noted following administration of the drug. This occurred more frequently among patients given the largest dose but did not produce clinical problems or require discontinuation of the drug. Favorable outcomes were noted in 52 patients (78%). Vasospasm was found by arteriography in 31 patients (46%). A dose-related trend was noted: only eight (24%) of 33 patients treated at the highest dose level (approximately 10 mg/hr) developed arteriographic evidence of vasospasm. Symptomatic vasospasm was diagnosed in only two (6%) of 33 patients treated with this dose. Of the 34 patients receiving the lower dose levels, angiographic spasm was observed in 68% and symptomatic vasospasm in 27%. No deaths due to vasospasm occurred. Nicardipine appears to prevent both vasospasm and cerebral ischemia after SAH. A multicenter randomized double-blind trial to test this hypothesis is planned.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.