The VCD Mouse Model of Menopause and Perimenopause for the Study of Sex Differences in Cardiovascular Disease and the Metabolic Syndrome.

In females, menopause, the cessation of menstrual cycling, is associated with an increase in risk for several diseases such as cardiovascular disease, osteoporosis, diabetes, the metabolic syndrome, and ovarian cancer. The majority of women enter menopause via a gradual reduction of ovarian function over several years (perimenopause) and retain residual ovarian tissue. The VCD mouse model of menopause (ovarian failure in rodents) is a follicle-deplete, ovary-intact animal that more closely approximates the natural human progression through perimenopause and into the postmenopausal stage of life. In this review, we present the physiological parameters of how to use the VCD model and explore the VCD model and its application into the study of postmenopausal disease mechanisms, focusing on recent murine studies of diabetic kidney disease, the metabolic syndrome, and hypertension.

Improving the timeliness of meticillin-resistant Staphylococcus aureus antimicrobial decolonization therapy administration: a descriptive account.

BACKGROUND: It is important to ensure that the timely administration of appropriate antimicrobial decolonization therapy occurs when patients are identified as meticillin-resistant Staphylococcus aureus (MRSA)-colonized. Computerized Provider Order Entry (CPOE) with embedded Clinical Decision Support (CDS) may help to facilitate this. AIM: To investigate changes in the average time from patient admission to administration of MRSA decolonization antimicrobial therapy in the context of various national and local infection control interventions, including the use of CPOE. METHODS: Data concerning the time of admission and of administration of patients' first MRSA decolonization antimicrobials were extracted from a locally developed CPOE system (Prescribing Investigation and Communications System: PICS) which was introduced at a large university teaching hospital in the UK in 1998. Data were extracted retrospectively from January 2006 to March 2012. FINDINGS: A variety of relevant local and national interventions occurred from 2006 to 2012. Notably, the automatic charting of MRSA decolonization antimicrobial therapy was introduced in December 2007. There was a significant decline of 15.0% per year (95% confidence interval: 11.1-18.7%; P < 0.001) in the time taken from admission to administration of MRSA decolonization antimicrobial therapy during the study period. CONCLUSIONS: Numerous factors may have contributed to the observed reductions in the time from admission to administration of MRSA decolonization antimicrobials, including the implementation of specific features within a CPOE system. By rapidly attending to positive MRSA colonizations there is decreased potential for MRSA to spread, which may help to reduce the prevalence of MRSA colonizations within hospitals and improve patient outcomes.

Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases.

AIMS/HYPOTHESIS: Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. MATERIALS AND METHODS: Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. RESULTS: In streptozotocin-treated animals, permeability to [(14)C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [(14)C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [(14)C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. CONCLUSIONS/INTERPRETATION: These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.

Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney.

The regulation of sodium transport in the kidney is important for maintenance of extracellular fluid volume and arterial blood-pressure regulation. The major sodium transporters and channels in individual renal tubule segments have been identified via physiological techniques, and complementary DNAs for all of the key sodium transporters and channels expressed along the renal tubule have been cloned. Complementary DNA probes and antibodies are now being used to investigate the molecular basis of renal tubule sodium-transport regulation. This review summarizes some of the major observations made in the past year that are relevant to the regulation of the major sodium transporters in the proximal tubule (the type 3 sodium-hydrogen exchanger, NHE3), the thick ascending limb of Henle (the bumetanide-sensitive sodium-potassium-chloride cotransporter, NKCC2), and the distal convoluted tubule (the thiazide-sensitive sodium-chloride cotransporter, NCC).

The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon.

The kidneys "escape" from the Na-retaining effects of aldosterone when circulating levels of aldosterone are inappropriately elevated in the setting of normal or expanded extracellular fluid volume, e.g., in primary aldosteronism. Using a targeted proteomics approach, we screened renal protein extracts with rabbit polyclonal antibodies directed to each of the major Na transporters expressed along the nephron to determine whether escape from aldosterone-mediated Na retention is associated with decreased abundance of one or more of renal Na transporters. The analysis revealed that the renal abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) was profoundly and selectively decreased. None of the other apical solute-coupled Na transporters displayed decreases in abundance, nor were the total abundances of the three ENaC subunits significantly altered. Immunocytochemistry showed a strong decrease in NCC labeling in distal convoluted tubules of aldosterone-escape rats with no change in the cellular distribution of NCC. Ribonuclease protection assays (RPAs) revealed that the decrease in NCC protein abundance was not associated with altered NCC mRNA abundance. Thus, the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule appears to be the chief molecular target for regulatory processes responsible for mineralocorticoid escape, decreasing in abundance via a posttranscriptional mechanism.

Distribution and abundance of insecticide resistant greenbugs (Homoptera: Aphididae) and validation of a bioassay to assess resistance.

Laboratory bioassays were conducted to determine the toxicity of four insecticides (ethyl parathion, chlorpyrifos, malathion, and carbofuran) to insecticide-susceptible and resistant populations of greenbug, Schizaphis graminum (Rondani). These bioassays were used to develop and validate a discriminating concentration for assessing insecticide resistance in greenbug populations in the field. Samples from wheat and sorghum in two states, Oklahoma and Kansas, indicated that insecticide resistance persists in greenbug populations over a large area at a low level.

Immunocytochemical and immunoelectron microscopic localization of alpha-, beta-, and gamma-ENaC in rat kidney.

Epithelial sodium channel (ENaC) subunit (alpha, beta, and gamma) mRNA and protein have been localized to the principal cells of the connecting tubule (CNT), cortical collecting duct (CCD), and outer medullary collecting duct (OMCD) in rat kidney. However, the subcellular localization of ENaC subunits in the principal cells of these cells is undefined. The cellular and subcellular localization of ENaC subunits in rat kidney was therefore examined. Immunocytochemistry demonstrated the presence of all three subunits in principal cells of the CNT, CCD, OMCD, and IMCD. In cortex and outer medulla, confocal microscopy demonstrated a difference in the subcellular localization of subunits. alpha-ENaC was localized mainly in a zone in the apical domains, whereas beta- and gamma-ENaC were found throughout the cytoplasm. Immunoelectron microscopy confirmed the presence of ENaC subunits in both the apical plasma membrane and intracellular vesicles. In contrast to the labeling pattern seen in cortex, alpha-ENaC labeling in IMCD cells was distributed throughout the cytoplasm. In the urothelium covering pelvis, ureters, and bladder, immunoperoxidase and confocal microscopy revealed differences the presence of all ENaC subunits. As seen in CCD, alpha-ENaC was present in a narrow zone near the apical plasma membrane, whereas beta- and gamma-ENaC were dispersed throughout the cytoplasm. In conclusion, all three subunits of ENaC are expressed throughout the collecting duct (CD), including the IMCD as well as in the urothelium. The intracellular vesicular pool in CD principal cells suggests ENaC trafficking as a potential mechanism for the regulation of Na(+) reabsorption.

Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics.

The Na+-H+ exchanger NHE3 and the thiazide-sensitive Na+-Cl- cotransporter NCC are the major apical sodium transporters in the proximal convoluted tubule and the distal convoluted tubule of the kidney, respectively. We investigated the mechanism of compensation that allows maintenance of sodium balance in NHE3 knockout mice and in NCC knockout mice. We used a so-called 'targeted proteomics' approach, which profiles the entire renal tubule with regard to changes in Na+ transporter and aquaporin abundance in response to the gene deletions. Specific antibodies to the Na+ transporters and aquaporins expressed along the nephron were utilized to determine the relative abundance of each transporter. Semiquantitative immunoblotting was used which gives an estimate of the percentage change in abundance of each transporter in knockout compared with wild-type mice. In NHE3 knockout mice three changes were identified which could compensate for the loss of NHE3-mediated sodium absorption. (a) The proximal sodium-phosphate cotransporter NaPi-2 was markedly upregulated. (b) In the collecting duct, the 70 kDa form of the y-subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. This is thought to be an aldosterone-stimulated form of y-ENaC. (c) Glomerular filtration was significantly reduced. In the NCC knockout mice, amongst all the sodium transporters expressed along the renal tubule, only the 70 kDa form of the y-subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. In conclusion, both mouse knockout models demonstrated successful compensation for loss of the deleted transporter. More extensive adaptation occurred in the case of the NHE3 knockout, presumably because NHE3 is responsible for much more sodium absorption in normal mice than in NCC knockout mice.

Macular hole surgery with and without internal limiting membrane peeling.

OBJECTIVE: To compare results of surgery for idiopathic macular hole with and without internal limiting membrane (ILM) peeling in a series of consecutive patients over a 5-year period. DESIGN: A retrospective, nonrandomized, comparative trial with concurrent control group. PARTICIPANTS: Forty-four eyes with macular holes of less than or equal to 6 months duration without ILM peeling were compared to 116 eyes with ILM peeling and the same hole duration. A third group of 65 eyes with ILM peeling and duration greater than 6 months was also evaluated. INTERVENTION: All eyes underwent pars plana vitrectomy with or without ILM peeling, intravitreous gas, and positioning face down. No adjunctive therapies were used in any group. MAIN OUTCOME MEASURES: Comparing the closure and/or reopening rate, prognosis, visual acuity, and complications for macular holes with and without ILM peeling. RESULTS: All patients had postsurgical follow-up of 18 months or greater. Primary closure was significantly improved with ILM peeling with 116 of 116 eyes (100%) showing no reopenings versus 36 of 44 holes (82%) primarily closed, 9 of which (25%) reopened without ILM peeling (P: < 0.00001) in holes less than or equal to 6 months. The 27 eyes without ILM peeling that had successful surgery displayed a mean postoperative vision of 20/40, which is the same as the successful eyes with ILM peeling (P: = 0.6). The 52 stage II eyes with ILM peeling had a mean postoperative vision of 20/30, and 48 of the 52 eyes (92%) were 20/40 or better. Stage III eyes (greater than 400-microm holes) without ILM peeling had a poor prognosis, with 6 of the 25 eyes (24%) having initial surgery fail and an additional 4 of 25 eyes (16%) reopening. Without ILM peeling, holes less than 300 microm had only one reopen, whereas holes greater than or equal to 300 microm had 16 of the 17 (94%) primary failures and/or reopenings (P: < 0.001). All 12 holes that reopened and/or primarily failed were repaired with ILM peeling with excellent visual recovery. Macular holes with a duration greater than 6 months were treated with ILM peeling, and 63 of 65 holes (97%) were closed primarily and 65% had an increase in vision by two or more Snellen lines. CONCLUSIONS: ILM peeling significantly improves visual and anatomic success in all stages of recent and chronic macular holes and reopened and failed holes, while eliminating reopening for holes greater than 300 microm.

Aldose reductase-deficient mice develop nephrogenic diabetes insipidus.

Aldose reductase (ALR2) is thought to be involved in the pathogenesis of various diseases associated with diabetes mellitus, such as cataract, retinopathy, neuropathy, and nephropathy. However, its physiological functions are not well understood. We developed mice deficient in this enzyme and found that they had no apparent developmental or reproductive abnormality except that they drank and urinated significantly more than their wild-type littermates. These ALR2-deficient mice exhibited a partially defective urine-concentrating ability, having a phenotype resembling that of nephrogenic diabetes insipidus.

Localization of glucokinase gene expression in the rat brain.

The brain contains a subpopulation of glucosensing neurons that alter their firing rate in response to elevated glucose concentrations. In pancreatic beta-cells, glucokinase (GK), the rate-limiting enzyme in glycolysis, mediates glucose-induced insulin release by regulating intracellular ATP production. A similar role for GK is proposed to underlie neuronal glucosensing. Via in situ hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large populations of glucosensing neurons (the arcuate, ventromedial, dorsomedial, and paraventricular nuclei and the lateral area). GK also was found in brain areas without known glucosensing neurons (the lateral habenula, the bed nucleus stria terminalis, the inferior olive, the retrochiasmatic and medial preoptic areas, and the thalamic posterior paraventricular, interpeduncular, oculomotor, and anterior olfactory nuclei). Conversely, GK message was not found in the nucleus tractus solitarius, which contains glucosensing neurons, or in ependymal cells lining the third ventricle, where others have described its presence. In the arcuate nucleus, >75% of neuropeptide Y-positive neurons also expressed GK, and most GK+ neurons also expressed KIR6.2 (the pore-forming subunit of the ATP-sensitive K+ channel). The anatomic distribution of GK mRNA was confirmed in micropunch samples of hypothalamus via reverse transcription-polymerase chain reaction (RT-PCR). Nucleotide sequencing of the recovered PCR product indicated identity with nucleotides 1092-1411 (within exon 9 and 10) of hepatic and beta-cell GK. The specific anatomic localization of GK mRNA in hypothalamic areas known to contain glucosensing neurons and the coexpression of KIR6.2 and NPY in GK+ neurons support a role for GK as a primary determinant of glucosensing in neuropeptide neurons that integrate multiple signals relating to peripheral energy metabolism.

Inhibition of aquaporin-1 water permeability by tetraethylammonium: involvement of the loop E pore region.

Previously, the only known blockers of water permeability through aquaporin-1 (AQP1) water channels were mercurial reagents such as HgCl(2). For AQP1, inhibition by mercury has been attributed to the formation of a mercaptide bond with cysteine residue 189 found in the putative pore-forming region loop E. Here we show that the nonmercurial compound, tetraethylammonium (TEA) chloride, reduces the water permeability of human AQP1 channels expressed in Xenopus oocytes. After preincubation of the oocytes for 15 min with 100 microM TEA, AQP1 water permeability was reduced by 20 to 40%, a degree of partial block similar to that obtained with 15 min of incubation in 100 microM HgCl(2). The reduction of water permeability was dose-dependent for tested concentrations up to 10 mM TEA. TEA blocks the Shaker potassium channel by interacting with a tyrosine residue in the outer pore region. We tested whether an analogous tyrosine residue in loop E of AQP1 could be involved in the binding of TEA. Using polymerase chain reaction, tyrosine 186 in AQP1, selected for its proximity to the mercury-binding site, was mutated to phenylalanine (Y186F), alanine (Y186A), or asparagine (Y186N). Oocyte expression of the mutant AQP1 channels showed that the water permeability of Y186F was equivalent to that of wild-type AQP1; the other mutant channels did not conduct water. However, in contrast to wild-type AQP1, the water permeability of Y186F was not reduced with 100 microM TEA. These results suggest that TEA reduces AQP1 water permeability by interacting with loop E.

Cloned human aquaporin-1 is a cyclic GMP-gated ion channel.

Aquaporin-1 (AQP1) is a member of the membrane intrinsic protein (MIP) gene family and is known to provide pathways for water flux across cell membranes. We show here that cloned human AQP1 not only mediates water flux but also serves as a cGMP-gated ion channel. Two-electrode voltage-clamp analyses showed consistent activation of an ionic conductance in wild-type AQP1-expressing oocytes after the direct injection of cGMP (50 nl of 100 mM). Current activation was not observed in control (water-injected) oocytes or in AQP5-expressing oocytes with osmotic water permeabilities equivalent to those seen with AQP1. Patch-clamp recordings revealed large conductance channels (150 pS in K(+) saline) in excised patches from AQP1-expressing oocytes after the application of cGMP to the internal side. Amino acid sequence alignments between AQP1 and sensory cyclic-nucleotide-gated channels showed similarities between the cyclic-nucleotide-gated binding domain and the AQP1 carboxyl terminus that were not present in AQP5. Competitive radioligand-binding assays with [(3)H]cGMP demonstrated specific binding (K(D) = 0.2 microM) in AQP1-expressing Sf9 cells but not in controls. These results indicate that AQP1 channels have the capacity to participate in ionic signaling after the activation of cGMP second-messenger pathways.

Inflammatory breast carcinoma: a community hospital experience.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare form of rapidly progressive breast cancer. We reviewed the diagnosis, treatment, and outcome of IBC in our inner city community-based hospital and compared results with previous published reports. STUDY DESIGN: Twenty-five patients were diagnosed and treated for IBC at the Catholic Medical Center of Brooklyn and Queens during the 6-year period of January 1989 through December 1995. Criteria for inclusion in this study were clinical or histopathologic evidence, or both, of inflammatory carcinoma. RESULTS: IBC comprised 2.0% (25 of 1,257) of all breast cancer patients initially diagnosed during this study. All presented with clinical signs of IBC. Invasion of dermal lymphatics by neoplastic cells was demonstrated in 68% (17 of 25) of biopsy specimens. Sixty-eight percent (17 of 25) of patients presented with metastatic (ie, stage IV) disease and 28% (7 of 25) with stage IIIb; one patient (4%) died before staging. Estrogen and progesterone receptor studies were done on 72% (18 of 25) of all specimens. Of those patients who died, 85% were estrogen and progesterone receptor negative; of those surviving, 60% were estrogen receptor positive. Twenty (80%) of the 25 patients died, after a mean survival of 11.8 months and 5 (20%) remain alive, with a mean survival of 44.8 months. Of those who died, 85% were stage IV at presentation. All five survivors were stage IIIb at presentation. Patients underwent a variety of multimodal therapies. Survival was significantly associated with earlier stage at diagnosis and estrogen receptor positivity. CONCLUSIONS: IBC is characterized by rapid progression and dismal outcome. Earlier stage at diagnosis and positive estrogen receptor status suggest a more favorable prognosis. Neoadjuvant chemotherapy, as part of a multimodal approach, has significantly improved the outcome for IBC, but this is limited to patients with stage IIIb disease. Most of our patients presented with stage IV disease. If improvement is to be realized at the community level, limited health care resources must be directed toward aggressive physician and public education.

Ultrastructural features of tissue removed during idiopathic macular hole surgery.

PURPOSE: To compare the ultrastructural features of excised tissue removed during surgery for idiopathic macular holes with the preoperative stage of the macular hole. METHODS: Twelve consecutive patients with a unilateral idiopathic macular hole underwent vitrectomy with surgical removal of the internal limiting membrane of the retina and epiretinal tissue overlying and surrounding the hole. The excised specimens were evaluated with transmission electron microscopy, and findings were compared with the preoperative stage of the macular hole according to the classification of Gass. RESULTS: Surgery was performed on 12 eyes of 12 patients with stage 2, 3, or 4 macular holes. Internal limiting membrane was present in 11 of 12 specimens. Tissue from one of two eyes with stage 2 holes showed cellular elements enmeshed in cortical vitreous. Tissue from four of seven eyes with stage 3 holes and three of three eyes with stage 4 holes had cellular proliferation on the internal limiting membrane. Cells with myofibroblastic differentiation were present in five of the eight cellular proliferations. CONCLUSION: Our results support the clinical stages of idiopathic macular holes described by Gass. Idiopathic macular holes appear to form from contraction of the prefoveal vitreous, and the hole enlarges because of contraction of myofibroblasts on the inner surface of the internal limiting membrane. On the basis of the mechanical mechanisms of idiopathic macular hole formation, removal of the internal limiting membrane and adherent epiretinal tissue surrounding and overlying the macular hole is a reasonable surgical approach to close idiopathic macular holes.

Evolution and overview of classical transmitter molecules and their receptors.

All the classical transmitter ligand molecules evolved at least 1000 million years ago. With the possible exception of the Porifera and coelenterates (Cnidaria), they occur in all the remaining phyla. All transmitters have evolved the ability to activate a range of ion channels, resulting in excitation, inhibition and biphasic or multiphasic responses. All transmitters can be synthesised in all three basic types of neurones, i.e. sensory, interneurone and motoneurone. However their relative importance as sensory, interneurone or motor transmitters varies widely between the phyla. It is likely that all neurones contain more than one type of releasable molecule, often a combination of a classical transmitter and a neuroactive peptide. Second messengers, i.e. G proteins and phospholipase C systems, appeared early in evolution and occur in all phyla that have been investigated. Although the evidence is incomplete, it is likely that all the classical transmitter receptor subtypes identified in mammals, also occur throughout the phyla. The invertebrate receptors so far cloned show some interesting homologies both between those from different invertebrate phyla and with mammalian receptors. This indicates that many of the basic receptor subtypes, including benzodiazepine subunits, evolved at an early period, probably at least 800 million years ago. Overall, the evidence stresses the similarity between the major phyla rather than their differences, supporting a common origin from primitive helminth stock.

Regional redistribution of myocardial perfusion by UL-FS 49, a selective bradycardic agent.

The effects of UL-FS 49, a specific bradycardic agent, on systemic hemodynamics, regional myocardial function (sonomicrometry, percentage of segment shortening), and regional coronary blood flow (radioactive microspheres) were studied in open-chest, anesthetized dogs with severe left circumflex coronary artery (LCX) stenosis. UL-FS 49 was administered as two sequential bolus injections of 0.25 mg/kg. Heart rate decreased from 149 +/- 13 beats/min to 102 +/- 6 and 77 +/- 4 beats/min after 0.25 and 0.5 mg/kg cumulative doses of UL-FS 49, respectively. The reduction in heart rate was not associated with any significant change in left ventricular pressure or mean arterial pressure, left ventricular dp/dt, or coronary vascular resistance. Similarly no hemodynamic changes occurred with atrial pacing to the initial heart rate. Application of an LCX stenosis of sufficient severity to produce a 50% reduction in mean LCX blood flow (44 +/- 4 to 22 +/- 2 ml/min) resulted in a significant reduction in the percentage of segment shortening in the ischemic zone (9.8 +/- 1.6% to 6.5 +/- 1.1%). The percentage of segment shortening in the ischemic zone progressively improved to 8.4 +/- 1.2% and 9.4 +/- 0.5% after 0.25 and 0.5 mg/kg UL-FS 49, respectively. Subepicardial perfusion in the ischemic zone was decreased and subendocardial perfusion was increased after administration of UL-FS 49. Consequently the ischemic zone endocardial/epicardial ratio increased from 0.43 +/- 0.08 to 1.12 +/- 0.22 and 1.48 +/- 0.32 with low and high doses of UL-FS 49.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma of the ciliary epithelium in a 12-year-old black child.

Histopathologic examination of a blind eye from a 12-year-old black girl revealed an unsuspected adenocarcinoma of the nonpigmented ciliary epithelium and evidence of previous penetrating trauma. The association between adenocarcinoma of the ciliary epithelium and ocular trauma has been well documented in elderly patients but not in children. The histopathologic distinction between a pleomorphic adenocarcinoma of the ciliary epithelium and a uveal melanoma may be difficult. Signs of previous penetrating trauma should heighten suspicion of an adenocarcinoma, even in young children.

Regional myocardial function after repetitive brief episodes of ischemia: effect of altering the duration of the reperfusion period.

How recovery of regional contractile function in myocardium is influenced by alterations in the duration of reperfusion after repetitive brief coronary artery occlusions was investigated in chronically instrumented, conscious dogs. All animals underwent five 5 minute left anterior descending coronary artery occlusions with a final 5-hour reperfusion period. Dogs were randomly assigned to one of three groups determined by the duration of reperfusion (5, 10, or 15 minutes) between successive 5-minute occlusion periods. A shortening of the duration of the reperfusion period between occlusions led to reduced recovery and progressive deterioration in systolic shortening after multiple occlusion-reperfusion sequences. With 15-minute reperfusion periods, the percentage of segment shortening (%SS) during the first through fourth reperfusion periods ranged from 17.1 +/- 2.6% to 18.2 +/- 1.8% and did not differ from the preocclusion control value (18.8 +/- 1.7%) by the end of the final reperfusion period. In contrast, in those dogs with 5-minute reperfusion periods, %SS was significantly reduced from the preocclusion control value (20.2 +/- 2.2%) at the completion of the final 5-hour reperfusion period (11.4 +/- 1.5%). Results of the present study indicate that after only a few brief periods of coronary artery occlusion, rapid and cumulative deterioration in regional contractile function can occur when the duration of intermittent reperfusion is sufficiently brief.

Dipyridamole-induced decrement of functional recovery of postischemic reperfused myocardium in conscious dogs with well-developed coronary collateral circulation.

The effects of dipyridamole (20 and 40 micrograms/kg/min intravenously) on the time course of functional recovery of myocardium after five 5-minute coronary artery occlusions and four 5-minute reperfusions and a subsequent 5-hour reperfusion period were studied in chronically instrumented, conscious dogs with well-developed coronary collateral circulation. In comparison with vehicle-treated control dogs, those given dipyridamole (20 and 40 micrograms/kg/min, respectively) 15 minutes before and during coronary occlusion had a greater depression of regional segment shortening (38 +/- 7% and 19 +/- 4%, respectively, vs control levels of 69 +/- 10% of preocclusion values) during acute coronary artery occlusion. After a 5-hour reperfusion period, segment shortening returned to preocclusion values in the control group but remained decreased in the dipyridamole groups (87 +/- 4% and 75%, respectively). These results suggest that dipyridamole in a dose-dependent manner exacerbates recovery of contractility of postischemic reperfused myocardium in dogs with well-developed coronary collateral circulation.