Physical restraint in the ICU: does it prevent device removal?

BACKGROUND: Physical restraint is frequently used in the intensive care setting but little is known regarding its clinical scenario and effectiveness in preventing adverse events (AEs), defined as device removal. METHODS: We carried out a prospective observational study in three Intensive Care Units on 120 adult high-risk patients. The effectiveness of physical restraint was evaluated using the propensity score methodology in order to obtain comparable groups. RESULTS: Physical restraint was applied in 1371 of 3256 (43%) nurse shifts accounting for 120 patients. Substantial agitation, the nurse's judgement of insufficient sedation and sedative drug reduction were positively associated with physical restraint, whereas the presence of analgesics at admission, increased disease gravity and the treating hospital as the most substantial variable showed a negative association. Eighty-six AEs were observed in 44 patients. Quiet (SAS=1-4), unrestrained patients accounted for 40 cases, and agitated (SAS≥5) but physically restrained patients for 17 cases. The presence of any type of physical restraint had a protective effect against any type of AE (OR=0.28; CI 0.16-0.51). The observed AEs showed a limited impact on the patients' course of illness. No physical harm related to physical restraint was reported. CONCLUSION: Physical restraint efficiently averts AEs. Its application is mainly driven by local habits. Typically, the almost recovered, apparently calm and hence unrestrained patient is at greatest risk for undesirable device removal. The control/interpretation of the patient's analgo-sedation might be inappropriate.

Fine mapping of Lvm1: a quantitative trait locus controlling heart size independently of blood pressure.

We have previously reported a quantitative trait locus (QTL) on rat chromosome 2 that influences heart size independently of blood pressure (Left Ventricular Mass Locus 1; Lvm1). The recent release of the rat genome sequence allowed us to retest and refine this relatively broad QTL with a view to identifying within it candidate genes worthy of structural investigation. We sought to achieve this 'fine mapping' by increasing the marker density within the interval and undertaking a linkage analysis in a previously defined population of F2 hybrids generated from inbred spontaneously hypertensive rats (SHR) of the Okamoto strain and Fischer rat (F344) progenitors. We were able to reconfirm and resolve Lvm1 from its original width of approximately 45 to 15 cM. By reference to the ENSEBL rat genome data bank, we identified within Lvm1 27 known genes, 109 predicted genes and 7 pseudogenes. Of the known genes, candidates include potential regulators of cardiac growth, a sodium channel and calcium channel as well as the fibroblast growth factor 2 gene. Located nearby the Lvm1 locus was the gene for the angiotensin Type 1B receptor. Given the evidence that the ligand for the angiotensin Type 1B receptor-angiotensin II-is a potent cardiotroph, we also consider this gene a potential candidate. The identification of the precise allelic variant(s) within Lvm1 involved in the control of pressure-independent cardiac growth awaits further molecular studies.

Development of colorectal sensitization is associated with increased eosinophils and mast cells in dextran sulfate sodium-treated rats.

We used conscious restrained rats, in which balloon distension of the colorectum was used as a repeated visceral stimulus over a 21-day period, either alone or in conjunction with a luminal irritant, dextran sodium sulfate (DSS), in order to elicit sensitization as evidenced by amplified blood pressure responses. Female Sprague Dawley rats received 5% DSS in the drinking water for 3 days. A water-filled balloon was used to distend the colorectum. Set volumes (1, 1.5, and 2 mL) were applied for 3 min, at 10-min intervals, weekly for 3 weeks, with colorectal and tail-cuff blood pressures measured. Tissue for mast cell localization and histology were taken from proximal and distal colon at sacrifice. Mean colorectal balloon pressures and blood pressures in the DSS-treated rats compared to controls were 12% (P < 0.01) and 64% (P < 0.03) higher, respectively. At sacrifice the DSS-treated rats had twice the number of mast cell numbers in the mucosa of the proximal colon compared to controls, suggesting that the sensitization effect may be linked to inflammatory mediators (P < 0.05).

PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP: PTH/PTHrP receptor antagonism increases SHR fetal weight.

Parathyroid hormone-related protein (PTHrP) has important roles in fetal growth and development through stimulation of placental calcium transport, vasodilatation of the uteroplacental vasculature and regulation of cellular growth and differentiation. The growth restricted spontaneously hypertensive rat (SHR) has reduced fetal plasma, placental and amniotic fluid PTHrP concentrations compared to its progenitor, the Wistar Kyoto (WKY) rat. The aim of this study was to determine whether intrauterine PTHrP infusions can restore PTHrP levels and promote SHR fetal growth. PTHrP(1-34), midmolecule PTHrP(67-94), the PTH/PTHrP receptor antagonist [Asn(10), Leu(11)]-PTHrP(7-34) or vehicle were infused via a mini-osmotic pump between 10 and 20 days of gestation into the uterine lumen of SHR and WKY rats. Uterine, placental, amniotic fluid and plasma (fetal and maternal) PTHrP were measured via N-terminal radioimmunoassay. PTH/PTHrP receptor antagonism and mid-molecule PTHrP(67-94) induced endogenous intrauterine PTHrP production with receptor antagonism eliciting a greater and more wide spread effect. The PTH/PTHrP receptor antagonist [Asn(10), Leu(11)]-PTHrP(7-34) acting through a receptor other than the PTH/PTHrP receptor increased SHR fetal and placental weights above vehicle (P<0.05) to that of the WKY and restored SHR amniotic fluid volume (P<0.05). This was associated with a highly significant up regulation of placental, uterine and plasma (fetal and maternal) PTHrP (P<0.05). Modest increases in placental and uterine PTHrP (P<0.05) following intrauterine infusions of PTHrP(1-34) and PTHrP(67-94) had no effect on WKY and SHR fetal weight. Effective growth promoting actions of increased endogenous PTHrP were observed following PTH/PTHrP receptor antagonism rather than exogenous PTHrP administration. A novel finding was that mid-molecule PTHrP also up regulates endogenous intrauterine N-terminal PTHrP production supporting the existence of a mid-molecule receptor. This study highlights that an increase in endogenous uterine, placental and fetal plasma PTHrP following PTH/PTHrP receptor antagonism was associated with increased SHR fetal growth presumably by improving placental growth and function.

The spontaneously hypertensive rat fetus, not the mother, is responsible for the reduced amniotic fluid PTHrP concentrations and growth restriction.

Intrauterine parathyroid hormone-related protein (PTHrP) concentrations are reduced in association with growth restriction in the spontaneously hypertensive rat (SHR) compared to those of its normotensive control, the Wistar Kyoto (WKY) rat, implicating PTHrP as a pivotal fetal growth factor. The aim of this study was to examine, by embryo cross-transplanation between SHR and WKY, whether the mother, fetus, or both, are responsible for the suppressed SHR amniotic fluid PTHrP. One-day-old SHR embryos were gestated in either an SHR (SHR-in-SHR) or WKY (SHR-in-WKY) surrogate, similarly one-day-old WKY embryos were gestated in either an SHR (WKY-in-SHR) or WKY (WKY-in-WKY) mother. At 20 days gestation, maternal plasma and amniotic fluid samples were collected and assayed for PTHrP concentrations. Data were analysed by two-way ANOVA (mean+/-sem, n=5-9 mothers/group). There were no differences in litter number or maternal plasma PTHrP concentrations. Fetal weight (P< 0.009), fetal/placental weight ratio (P< 0.004) and amniotic fluid PTHrP concentrations (P< 0.001) were lower and amniotic fluid volume (P< 0.0001) was higher with an SHR fetus compared to the WKY fetus irrespective of maternal strain. Thus, the SHR fetus is growth restricted and has suppressed amniotic fluid PTHrP, which are largely determined by the fetus or gestational tissues and are independent of maternal hypertension or maternal PTHrP. We suggest that the low SHR amniotic fluid PTHrP may play a role in the development of SHR growth restriction.

First report of active renin in rat amniotic fluid.

1. Epidemiological studies indicate that a reduced birthweight increases the likelihood of human cardiovascular disease later in life. The role of hormonal factors in this finding is not known. Given that angiotensin II is believed to be a fetal regulator of growth, we have examined in the hypertensive Ren-2 transgenic rat whether it has active renin in its amniotic fluid and whether this is associated with fetal underdevelopment. 2. We found that while the Sprague-Dawley rat contained no active renin in its amniotic fluid near term (20 days), Ren-2 amniotic fluid contains high levels of active renin and is associated with a reduced fetal weight. 3. This is the first report of active renin in the rat and allows the possibility that renin overproduction plays a role in reduced fetal growth and the prenatal 'programming' of essential hypertension that has been proposed to occur in humans.

Reduced fetal, placental, and amniotic fluid PTHrP in the growth-restricted spontaneously hypertensive rat.

Evidence implicates pivotal roles for parathyroid hormone-related protein (PTHrP) in stimulating cell growth and differentiation, placental calcium transport, and placental vasodilatation. As spontaneously hypertensive rat (SHR) fetuses are growth restricted compared with those of its normotensive control, the Wistar Kyoto (WKY) rat, we examined intrauterine PTHrP and total and ionic calcium concentrations in these rats. Fetal plasma PTHrP concentrations, but not total calcium concentrations, were lower in the SHR compared with WKY (P < 0.05). SHR placental concentrations of PTHrP were lower than in WKY (P < 0.03) and failed to show the increase observed in WKY near term (P < 0.05). PTHrP concentrations in amniotic fluid from SHR were not raised near term and were lower compared with WKY (P < 0.0005). The increased ionic calcium concentrations in amniotic fluid in the WKY near term (P < 0.05) were not detected in the SHR. Thus SHR fetal plasma, placental, and amniotic fluid PTHrP concentrations were reduced and associated with fetal growth restriction. We suggest that PTHrP may play a role in the etiology of both growth restriction during pregnancy and hypertension later in life.

Fetal versus maternal determinants of the reduced fetal and placental growth in spontaneously hypertensive rats.

OBJECTIVE: Epidemiological studies indicate that a reduced birth weight and enlarged placenta increase the likelihood of human cardiovascular disease later in life. The relative importance of fetal versus maternal factors in these phenomena is not known. To assess the relative role of genotypic versus environmental factors in this effect, we examined whether the altered fetal and placental growth rates and amniotic fluid volume of spontaneously hypertensive rat (SHR) fetuses of the Okamoto strain, are modified by gestation in normotensive Wistar- Kyoto (WKY) rat mothers and vice versa. DESIGN: One-day-old SHR embryos were gestated for 16 days in either SHR or WKY recipients. Similarly, 1-day-old WKY rat embryos were gestated for 16 days in either SHR or WKY surrogates. At 16 days, fetal and placental weights were recorded. Paternal and maternal donor and recipient blood pressures, maternal body weight and average litter size within the four groups were also studied. METHODS: One cell SHR and WKY embryos were harvested from timed matings and transferred to psuedopregnant mothers of the same or opposite strain. Timed matings required routine vaginal smears for the detection of proestrus and the presence of sperm following overnight matings. Harvested embryos were temporarily maintained in culture medium in a 37 degrees C incubator until injection into the oviduct of recipients. Blood pressures were meaured using indirect tail-cuff plethysmography and a computerized data acquisition system. RESULTS: SHR fetal and placental weights at 16 days gestation were significantly lower than WKY fetal and placental weights, irrespective of maternal strain. At 16 days of gestation, the fetal and placental weights of SHR fetuses gestated in WKY rat surrogate mothers (0.21 +/- 0.01 g and 0.19 +/- 0.01 g, respectively) were not significantly different from those of SHR gestated in a surrogate SHR mother (0.21 +/- 0.01 g and 0.18 +/- 0.01 g, respectively). Similarly, the fetal and placental weights of WKY fetuses gestated in a WKY rat (0.27 +/- 0.01 g and 0.25 +/- 0.01 g, respectively) were unaltered by gestation in a SHR recipient (0.25 +/- 0.01 g and 0.23 +/- 0.01 g, respectively). The amniotic fluid volumes of SHR gestated in WKY rats and those of WKY fetuses gestated in SHR were not significantly different to each other (0.37 +/- 0.01 ml versus 0.38 +/- 0.01 ml, respectively) and were intermediate between the values for SHR and WKY fetuses gestated in a mother of the same strain (0.34 +/- 0.01 ml versus 0.44 +/- 0.02 ml, respectively). CONCLUSION: The SHR fetus exhibited reduced growth rate and placental size irrespective of maternal surrogate strain, suggesting that these measures are likely to be determined by the fetus or the placenta and, presumably, are independent of maternal blood pressure or altered electrolyte and hormonal milieu.

Altered nuclear protein binding to the first intron of the renin gene of the spontaneously hypertensive rat.

We and others have reported elevated levels of renin mRNA in extrarenal tissues of the spontaneously hypertensive rat (SHR) of the Okamoto strain. We hypothesise that this is due to mutations we have found in putative, cis-regulatory regions in the first intron of its renin gene. Here we report two G-A mutations at position +502 and +934 of the first intron of the SHR renin gene, when compared to normotensive Wistar Kyoto (WKY) and Sprague Dawley (SD) rats. These mutations fall within consensus sequences for the well described E2A and peroxisome proliferator-activated receptor (PPAR) transcription factors. We used electrophoretic mobility shift assays to determine if these mutations alter the pattern or affinity of nuclear protein binding to oligonucleotides homologous to these regions of the renin gene. Both mutations significantly altered the intensity and pattern of nuclear protein binding to oligonucleotides homologous with the renin gene regions bearing these putative transcription factor binding sites. Thus these mutations have the potential to alter the type and/or affinity of transcriptional factors for the SHR renin gene in vivo, and result in renin overproduction at an extra-renal tissue site subserving blood pressure control.

Cosegregation of spontaneously hypertensive rat renin gene with elevated blood pressure in an F2 generation.

OBJECTIVE: To investigate the role of the renin gene in the hypertension of the spontaneously hypertensive rat (SHR) of the Okamoto strain. METHODS: We determined whether the SHR renin allele was cosegregated with high blood pressure in 137 F2 rats derived from inbred SHR and Wistar-Kyoto rats. Systolic blood pressure in conscious rats was measured by the tail-cuff method, whereas mean arterial pressure was determined from an indwelling catheter in the left carotid artery. Renin genotypes of F2 rats were determined using a SHR-specific Bg/II restriction fragment length polymorphism that we have previously described. RESULTS: The SHR renin allele was cosegregated significantly with higher systolic blood pressure in male F2 rats aged 8-24 weeks and in females aged 12-24 weeks. The greatest differences in blood pressure between SHR renin allele homozygotes and Wistar-Kyoto rat renin allele homozygotes were 35 mmHg for males and 17 mmHg for females aged 24 weeks. The SHR renin allele was also associated with a higher mean arterial pressure in rats aged 24 weeks and cosegregated with higher body weight of male F2 rats aged 12-24 weeks but not with that of the females. In contrast to the relationship with blood pressure, the SHR renin allele was segregated with lower plasma renin concentrations in rats aged 24 weeks. CONCLUSION: These results are consistent with the SHR renin gene being one of the loci determining high blood pressure in rats of this strain, possibly through action at some extra-renal site subserving control of blood pressure.

Nucleotide variations in intron 1 of the renin gene of the spontaneously hypertensive rat.

The renin gene is known to be overexpressed in the spontaneously hypertensive rat (SHR) of the Okamoto strain. As the first intron of many genes controls transcription rate, we examined whether the first 1,100 base pairs of the SHR first intron possessed mutations in putative transcriptional factor binding sites. Such mutations might then form the basis for overexpression of the renin gene in the SHR. A BglII restriction fragment length polymorphism (RFLP) was identified in the first 1,100 base pairs of the first intron of the renin gene of the SHR when compared to Wistar Kyoto (WKY) and Sprague Dawley (SD) normotensive rats. Sequence analysis of this region located the BglII RFLP between positions 501-505 of the rat renin gene. The new BglII cut site was produced by a single base mutation from G to A at position 502. While a number of other insertional and deletional events were found in the SHR, WKY and SD sequences over this region, only two were unique to the SHR. These mutations occurred at positions 191, 502, 934 and 1070. The latter three fell within sequence motifs known to bind the transcriptional factors PPAR, E2A and AP2 respectively. Thus we propose that these mutations alter the DNA binding characteristics of one or more transcriptional factors to the SHR renin gene first intron resulting in its overexpression which, in turn, might form the basis for a tissue renin-angiotensin dependent hypertension in this strain.

Altered age-dependent modulation of tissue renin messenger RNA levels in the spontaneously hypertensive rat.

OBJECTIVE: To evaluate the possible role of tissue renin overproduction in the pathogenesis and time course of hypertension development in the spontaneously hypertensive rat (SHR) of the Okamoto strain by measuring tissue renin gene expression at different stages of hypertension development. DESIGN: Measurements of kidney, adrenal gland and brain stem renin messenger RNA (mRNA) levels were performed in SHR aged 4, 12, 20 and 36 weeks and in age-matched normotensive Wistar-Kyoto (WKY) rats. METHODS: A fully quantitative, competitive reverse transcriptase polymerase chain reaction method was used to measure tissue renin mRNA levels. Plasma renin concentrations were measured by radioimmunoassay. RESULTS: Compared with age-matched WKY rats, renin mRNA levels in the adrenal gland of SHR were significantly higher at ages 4, 12 and 36 weeks. Brain stem renin mRNA levels were significantly higher in SHR than in WKY rats at ages 4, 12 and 20 weeks. In contrast, renal renin mRNA levels were consistently lower in SHR at all ages, as were plasma renin concentrations. CONCLUSIONS: The present study indicates an important role for renin gene expression both in adrenal and in brain stem tissues in the pathogenesis of hypertension in SHR. Adrenal and brain renin-angiotensin systems may interact with each other synergistically in the development and maintenance of hypertension in SHR. Suppressed renal renin gene expression could then be an indirect consequence of the amplified renin-angiotensin system in the adrenal gland and in the brain or a baroreceptor-mediated consequence of its hypertension.

Full expression of the exaggerated salt appetite of the spontaneously hypertensive rat requires a prenatal factor.

1. The spontaneously hypertensive rat (SHR) exhibits a lower bodyweight in utero and an exaggerated salt appetite post partum. To determine whether salt appetite is affected by the perinatal environment, we measured the salt appetite of embryo-cross-transferred SHR and Wistar Kyoto (WKY) rats at maturity. 2. One-cell embryos were collected from the oviducts of donor rats and transferred into the oviducts of recipients through the infundibulum. The salt appetite of the resultant female offspring for 0.10 and 0.15 mol/L saline was measured at 20-30 weeks of age. 3. Salt intake of SHR gestated in WKY rats was significantly lower than that of SHR gestated in SHR, while that of WKY rats gestated in SHR was higher than that of WKY rats gestated in WKY rats. 4. Therefore, some maternal factor plays a role in the development of the exaggerated salt appetite of the SHR. This factor is also able to affect the later salt appetite of WKY rat offspring born to SHR surrogates.

Mutations in the first intron of the SHR renin gene disrupt putative regulatory elements.

1. Four single base mutations unique to the spontaneously hypertensive rat (SHR) were identified in the first 1100 base pairs of its renin gene first intron when compared to that of Wistar-Kyoto and Sprague-Dawley normotensive rats. 2. These mutations were found to fall within the consensus sequences for a number of transcription factors and thus may alter the affinity of these putative transcription factor binding sites. 3. The reported overexpression of the renin gene in the SHR may therefore result from these structural abnormalities and, in turn, result in a tissue angiotensin-dependent hypertension in this strain.

Novel mutation in the first intron of the spontaneously hypertensive rat renin gene upstream of the tandem repeat element.

1. The first 1100 base pairs of the first intron of the renin gene was amplified from the spontaneously hypertensive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. A Bgl II restriction fragment length polymorphism (RFLP) was identified in this region of the SHR renin gene. 2. Sequence analysis located the Bgl II RFLP between positions 500 and 505 of the reported rat renin gene. The new Bgl II cut site was produced by a single base mutation from G to A. 3. Whether this mutation in the first intron of the SHR renin gene plays a role in the reported overexpression of the renin gene in this strain remains to be elucidated.

Amniotic fluid composition and fetal and placental growth rates in genetically hypertensive and normotensive rats.

Reduced birth weight has been observed in offspring of the spontaneously hypertensive rat (SHR) and in human hypertension. To determine which uterine factors might contribute to this fetal underdevelopment, fetal and placental growth rates and the volume and composition of amniotic fluid were measured in SHR and normotensive control Wistar Kyoto (WKY) rats during the final trimester of intra-uterine development. SHR and WKY fetuses were collected on Days 15-22 of pregnancy, and fetal and placental weight and amniotic fluid volume were recorded. The sodium and potassium concentrations of amniotic fluid were also measured. Placental weight was significantly lower in SHR than in WKY between Days 15 and 20 of gestation, but significantly higher on Days 21 and 22. Fetal weight was significantly lower in SHR between Days 17 and 22. These differences were reduced or abolished when fetal and placental weights were corrected for differences in maternal weight between strains. Amniotic fluid volume was significantly lower in SHR between Days 15 and 18, but significantly higher at Days 20, 21 and 22. Amniotic fluid sodium concentration was relatively constant over the period of observation and not different between strains. SHR amniotic fluid potassium concentration was significantly lower than that of WKY near term. Thus, the altered fetal and placental weight of SHR may be due to the overall reduced growth rate of this strain. However, the rate of fluid and electrolyte resorption close to term is markedly different between strains. The mechanism for this altered fluid and electrolyte handling by the SHR feto-placental unit remains to be determined.

Vascular endothelial growth factor: tissue distribution and size of multiple mRNA splice forms in SHR and WKY.

1. We have determined the optimal polymerase chain reaction (PCR) conditions for the amplification and detection of mRNA for a new vascular growth factor-vascular endothelial growth factor (VEGF)-and determined its size and tissue distribution in genetically normotensive and hypertensive rats. 2. Multiple VEGF mRNA subtypes were obtained which were 625, 520 and 480 base pairs in length. 3. All three species of VEGF mRNA were found in heart, kidney, aorta, adrenal and brainstem and the size and tissue distribution of VEGF mRNA subtypes were not different between spontaneously hypertensive rats (SHR) of the Okamoto strain and normotensive Wistar-Kyoto (WKY) controls. 4. Thus multiple forms of VEGF mRNA can be readily detected by PCR in a variety of tissues. While these preliminary results suggest no difference in size and tissue distribution between SHR and WKY, sequencing and quantitative studies will be required to confirm this.

Altered uterine environment in the spontaneously hypertensive rat.

1. In order to determine the role of the uterine environment in the development of hypertension in the spontaneously hypertensive rat (SHR) we examined the patterns of fetal and placental growth and the composition of amniotic fluid of SHR and normotensive Wistar-Kyoto (WKY) rats during the final trimester of pregnancy. 2. SHR and WKY embryos and amniotic fluid were collected at days 15 and 20 of pregnancy, and fetal and placental weight and amniotic fluid volume were recorded. The sodium and potassium concentration of amniotic fluid was also measured. 3. Fetal and placental weights were significantly lower in SHR compared to WKY at 15 and 20 days of gestation. Amniotic fluid volume was significantly lower in SHR at 15 days, but significantly higher at 20 days. Amniotic fluid sodium concentration was significantly lower in SHR at 15 days but not different at 20 days when compared to WKY. Potassium concentration was lower in SHR at both ages. 4. Thus the reduced placental weight early in the gestational period of the SHR may play a role in its underdevelopment in utero and hence its reduced birthweight. The SHR foetus is also bathed in a hypokalaemic amniotic fluid of increased volume. How this might influence fetal development and later blood pressure is unclear. Also whether these changes are of maternal or fetal origin remain to be determined.

Brief treatment of SHR with an ace inhibitor fails to cause long-term normotension but markedly increases mortality.

1. We examined the effect of three doses (0.03, 0.3 and 3 mg/kg per day) of the angiotensin converting enzyme (ACE) inhibitor, perindopril, on the long-term blood pressure of spontaneously hypertensive rats (SHR) of the Okamoto strain after treatment during the developmental stage of hypertension development. 2. While the 0.03 mg/kg per day dose, given between the ages of 4-10 weeks of age, failed to lower blood pressure, the two higher doses resulted in normotension over this treatment period as did the highest dose given between the ages of 4-20 weeks of age. 3. Only the 0.3 mg/kg per day dose resulted in a moderate (17%) long-term fall in blood pressure upon cessation of treatment when compared to untreated SHR controls. The highest dose, given over the 4-20 week period resulted in a significant rebound hypertension above the blood pressure level of untreated, control SHR. 4. The 3 mg/kg per day dose, whether given over the 4-10 or 4-20 week treatment period, resulted in 100% mortality in these groups by 52 weeks of age. There were no deaths in the groups receiving the two lower doses. 5. We conclude that treatment of SHR with perindopril during the developmental phase of hypertension development results in only a modest fall in long-term blood pressure upon cessation of treatment and that the relationship between the dose of this ACE inhibitor and long-term blood pressure is not linear. The 100% mortality in the two groups receiving the highest dose of perindopril may be due to either a toxic action of this drug or vascular rupture due to insufficient hypertrophy for the rapid rise in blood pressure upon cessation of treatment.

A new restriction fragment length polymorphism in the first intron of the spontaneously hypertensive rat renin gene.

1. Amplification of the entire first intron of the renin gene of spontaneously hypertensive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley rats (SD) followed by Bgl II digestion uncovered a new deletion (approximately 50 bp) which exists upstream of the SHR renin gene first intron tandem repeat element. 2. The SHR tandem repeat element was 600 bp shorter than that in the WKY while the WKY tandem repeat element was 280 bp shorter than that in the SD. 3. Since elements regulating gene expression are known to exist in the first intron of other genes, this new restriction fragment length polymorphism (RFLP) might play a role in the reported overexpression of the SHR renin gene independent of changes in the length of the tandem repeat element.