Growth of capillaries in the heart occurs under physiological circumstances during endurance exercise training, exposure to high altitude and/or cold, and changes in cardiac metabolism or heart rate elicited by modification of thyroid hormone levels. Capillary growth in all these conditions can be linked with increased coronary blood flow, decreased heart rate, or both. This paper brings evidence that, although increased blood flow due to long-term administration of coronary vasodilators results in capillary growth, a long-term decrease in heart rate induced by electrical bradycardial pacing in rabbits and pigs, or by chronic administration of a bradycardic drug, alinidine, in rats, stimulates capillary growth with little or no change in coronary blood flow. Decreased heart rate results in increased capillary wall tension, increased end-diastolic volume and increased force of contraction, and thus stretch of the capillary wall. This could lead to release of various growth factors possibly stored in the capillary basement membrane. Correlation was found between capillary density (CD) and the levels of low molecular endothelial cell stimulating angiogenic factor (ESAF) both in rabbit and pig hearts with CD increased by pacing. There was no relation between expression of mRNA for basic fibroblast growth factor and CD in sham-operated and paced rabbit hearts. In contrast, mRNA for TGF beta was increased in paced hearts, and the possible role of this factor in the regulation of capillary growth induced by bradycardia is discussed.

Angiogenesis Inducing Agents↗

PubMedDate not supplied

Intraoperative rhythm analysis using pulmonary venous Doppler: importance of atrioventricular interval.

Inappropriate timing or duration of the atrioventricular (AV) interval with DDD pacing can lead to hemodynamic compromise. Intraoperative pulmonary venous Doppler interrogation by transesophageal echocardiography can be a valuable tool to assess subtle rhythm abnormalities that may go unnoticed by electrocardiogram and hemodynamic monitoring. We describe a dramatic example of hemodynamic improvement following pacemaker adjustment after pulmonary venous Doppler identified an inappropriately short AV interval.

Aortic Valve Insufficiency↗

PubMedDate not supplied

Cyclosporine A.

Explore the source record for details and available documents.

Administration, Oral↗

PubMedDate not supplied

Preliminary characterization of novel amino acid based polymeric vesicles as gene and drug delivery agents.

The amino acid homopolymers, poly-L-lysine and poly-L-ornithine, have been modified by the covalent attachment of palmitoyl and methoxypoly(ethylene glycol) (mPEG) residues to produce a new class of amphiphilic polymers-PLP and POP, respectively. These amphiphilic amino acid based polymers have been found to assemble into polymeric vesicles in the presence of cholesterol. Representatives of this new class of polymeric vesicles have been evaluated in vitro as nonviral gene delivery systems with a view to finding delivery systems that combine effective gene expression with low toxicity in vivo. In addition, the drug-carrying capacity of these polymeric vesicles was evaluated with the model drug doxorubicin. Chemical characterization of the modified polymers was carried out using (1)H NMR spectroscopy and the trinitrobenzene sulfonic acid (TNBS) assay for amino groups. The amphiphilic polymers were found to have an unreacted amino acid, palmitoyl, mPEG ratio of 11:5:1, and polymeric vesicle formation was confirmed by freeze-fracture electron microscopy and drug encapsulation studies. The resulting polymeric vesicles, by virtue of the mPEG groups, bear a near neutral zeta-potential. In vitro biological testing revealed that POP and PLP vesicle-DNA complexes are about one to 2 orders of magnitude less cytotoxic than the parent polymer-DNA complexes although more haemolytic than the parent polymer-DNA complexes. The polymeric vesicles condense DNA at a polymer:DNA weight ratio of 5:1 or greater and the polymeric vesicle-DNA complexes improved gene transfer to human tumor cell lines in comparison to the parent homopolymers despite the absence of receptor specific ligands and lysosomotropic agents such as chloroquine.

Amino Acids↗

PubMedDate not supplied

Present status of chymopapain and chemonucleolysis.

An analysis of recent events and newly published data on Chymopapain and the technique of Chemonucleolysis including an objective analysis of clinical and basic research as well as the circumstances leading to the FDA curtailment of the use of Chymopapain in the United States, indicate that the drug should be reapproved for investigational use.

Chymopapain↗

PubMedDate not supplied

Effects of chemonucleolysis demonstrated by MR imaging.

In a study designed to assess the diagnostic and prognostic usefulness of magnetic resonance (MR) imaging in patients to be treated with chymopapain, 39 patients with a clinicoradiographic picture of herniated lumbar disk were scanned. Twenty-one of these, who were actually treated, were rescanned 3 months following the intradiskal administration of chymopapain. In both pretreatment and posttreatment scans sagittal T1 and T2 weighted spinecho technique was used. Prior to therapy, disks that were later injected demonstrated narrowing of the intervertebral disk space (95% of cases); an extradural defect (86% of cases); diminished signal intensity on the T1 weighted images (50% of cases); and decreased signal intensity on the T2 weighted image when compared with normal controls (100% of cases). Additionally, the adjacent endplates of the injected disk showed increased signal intensity on the T1 weighted image in 32%; 18% of the cases displayed increased signal intensity on the T2 weighted image. Following chymopapain, 100% of injected disks demonstrated decrease in disk height; 36% of the extradural defects diminished in size and 9% increased; 91% of injected disks showed loss of signal intensity on the T1 weighted image; and 86% lost signal in the T2 weighted study with 14% remaining unchanged. Vertebral body endplates adjacent to the level of injection demonstrated a decreased signal intensity on the T1 weighted image in 32% of cases, and 40% demonstrated increased signal in the T2 weighted study. Even though these findings could not be correlated with clinical success or failure using the criteria in this study, six of the original 39 patients were diagnosed as having free disk fragments on the basis of their initial MR scans, a fact that does have management implications for the use of chymopapain in treatment of herniated disk disease.

Adult↗

PubMedDate not supplied

Pathoanatomy and pathophysiology of nerve root compression.

The anatomy and physiology of the nerve root complex in the lumbar spine are reviewed, with special reference to the effects of mechanical deformation of nerve roots in association with intervertebral disc herniation and spinal stenosis. Biomechanical aspects of nerve root deformation induced by compression are discussed. The functional changes induced by compression can be caused by mechanical nerve fiber deformation but also may be a consequence of changes in nerve root microcirculation, leading to ischemia and formation of intraneural edema. Nerve root compression can, by different neurophysiologic mechanisms, induce motor weakness and altered sensibility or pain. Intraneural edema and demyelination seem to be critical factors for the production of pain in association with nerve root compression.

Capillary Permeability↗

PubMedDate not supplied

Effects of collagenase on nerve tissue. An experimental study on acute and long-term effects in rabbits.

Intradiscal injection of proteolytic enzymes implies a potential risk for exposure of nervous tissue to the enzyme solution. In the present study, the effects on peripheral nerve tissue of application of a solution containing a clinically recommended concentration of collagenase have been evaluated. Acute experiments showed that the enzyme induces transient swelling at the site of application and edema in the epineurium. There were, however, no detectable effects on the permeability of the perineurium or the endoneurial microvascular bed. Four and 8 weeks later, there was a slight fibrosis in the epineurium, but neurophysiologic tests did not reveal any impairment of the nerve function. The results are discussed in terms of the clinical use of collagenase for dissolution of herniated intervertebral discs.

Animals↗

PubMedDate not supplied

Alterations in reactivity of small arterioles in rat skeletal muscle as a result of chronic ischaemia.

In a model of chronic hind limb ischaemia, we examined whether impaired muscle blood flow, particularly during exercise, is partly due to modification of the reactivity of skeletal muscle resistance vessels by prolonged low blood flow. Two or 5 weeks after unilateral iliac artery ligation, terminal (A4) and preterminal (A3) arterioles of extensor digitorum longus muscle were viewed by intravital microscopy using epi-illumination, and diameter changes to topical application of endothelium-dependent (bradykinin, acetylcholine) and endothelium-independent (adenosine, sodium nitroprusside and noradrenaline) agonists measured. Chronic ischaemia had no effect on resting diameters of A3 or A4 vessels. Two weeks after ligation, dilation to bradykinin was attenuated by 75% for A3 and 50% for A4 arterioles (p < 0.01 vs. control) and responses to acetylcholine were reversed from dilation to constriction (A3: control diameter change +29%, 2-week-ligated -17%; A4: control 18%, 2-week-ligated -13%). Five weeks after ligation, these effects were still apparent and, additionally, dilation to adenosine and sodium nitroprusside and constriction to noradrenaline were reduced. Thus, impaired dilation, most likely due to endothelial dysfunction, is an early manifestation of altered reactivity in the microcirculation of chronically ischaemic muscles, with functional impairment of vascular smooth muscle as a later consequence. These changes occurred despite modest improvements in muscle blood flow and perfusion pressure over the same time. These changes will act to the detriment of blood flow in contracting muscles and could limit the outcome of interventions to restore flow such as angioplasty or surgical bypass.

Animals↗

PubMedDate not supplied

Postnatal growth of the heart and its blood vessels.

Although rapid growth of the heart during early postnatal development ceases with maturation of the organism, the potential for cardiomyocyte growth is not lost and may be observed even in senescent hearts. Rapid developmental heart growth is accompanied by a proportional growth of capillaries but not always of larger vessels, and thus coronary vascular resistance gradually increases. Growth of adult hearts can be enhanced by thyroid hormones, catecholamines and the renin-angiotensin system hormones, but these do not always stimulate growth of coronary vessels. Likewise, chronic exposure to hypoxia leads to growth, mainly of the right ventricle and its vessels but without vascular growth elsewhere in the heart. On the other hand, ischaemia is a potent stimulus for the release of various growth factors involved in the development of collateral circulation. Heart hypertrophy develops in response to training, pressure or volume overload. Training usually leads to growth of larger coronary vessels but little growth of capillaries, except in young animals. However, growth of the capillary bed, but not the resistance vasculature capacity, can be induced by either increased coronary blood flow, bradycardia (electrically or pharmacologically induced) or increased inotropism, all of which are involved in the training stimulus. Thus, what actually promotes growth of larger vessels as opposed to capillaries in training is unclear. Pressure overload hypertrophy is mediated by both the renin-angiotensin system and the response of cardiomyocytes to stretch; both lead to activation of early oncogenes (c-fos, c-jun, c-myc) and angiotensin II activates several protein kinases involved in cell growth. In this condition, growth of larger vessels is inadequate, although some capillary growth may occur. Volume overload leads to cardiomyocyte hypertrophy and hyperplasia and some increase in vascular supply. Deficits in capillary supply in pressure or volume overload hypertrophy can be reversed by chronic administration of ACE inhibitors, dipyridamole, the bradycardic drug alinidine or pacing-induced bradycardia respectively, but in neither case is training effective. Mechanical and humoral factors are involved in growth of cardiomyocytes and vessels. For cardiomyocytes, stretch is most important, activating oncogenes, protein kinases and possibly the inositol phosphate pathway, but not ion channels, with regulation by the balance of angiotensin II, TGF-beta 1 and IGF-1, but not FGFs. For vessels, growth is stimulated by stretch and shear stress, possibly with involvement of VEGF. Increased shear stress disrupts the glycocalyx on the luminal side of vessels and releases plasminogen activator and metalloproteinases which disrupt the basement membrane and enable endothelial cell migration and proliferation. It also causes rearrangement of the endothelial cytoskeleton and transmission of mechanical signals to the abluminal side disturbing extracellular matrix and causing distortion of capillary basement membrane. Stretch acting from the abluminal side has a similar effect resulting also in basement membrane disruption and endothelial cell proliferation.

Aging↗

PubMedDate not supplied

Low-molecular-mass endothelial cell-stimulating angiogenic factor in relation to capillary growth induced in rat skeletal muscle by low-frequency electrical stimulation.

The involvement of endothelial cell-stimulating angiogenic factor (ESAF) in capillary growth was studied in adult rat skeletal muscles (tibialis anterior, TA, and extensor digitorum longus, EDL) in which capillary growth was induced by chronic unilateral electrical stimulation (10 Hz, 8 h/day for 7 days), and in sham-operated and unoperated control muscles. ESAF was assayed by its ability to activate latent collagenase in units per hour per milligram protein. Anatomical capillary density (CD, number of capillaries per mm2) and capillary per fibre ratio (C/F) were estimated in frozen sections from the same muscles after staining for endothelial alkaline phosphatase. In control muscles, ESAF levels were inversely related to capillary supply, being highest (1.82 +/- 0.25 units) in the glycolytic cortex of TA (CD 273 +/- 18/mm2, C/F 1.26 +/- 0.07), lowest (1.04 +/- 0.02 units) in its oxidative highly capillarized core (CD 862 +/- 60/mm2, C/F 2.05 +/- 0.04), and intermediate in EDL (ESAF 1.59 +/- 0.37 units, CD 527 +/- 26/mm2, C/F 1.44 +/- 0.06). Neither capillary supply nor ESAF levels were affected by sham operation. However, chronic electrical stimulation increased capillary supply significantly in EDL (CD 61% greater than in controls, C/F 45% greater) and ESAF levels were elevated 3-fold to 4.77 +/- 0.74 units. In TA muscles, stimulation increased capillary supply specifically in the glycolytic cortex (C/F 2.51 +/- 0.09, p < 0.0001 vs. control) and ESAF levels were increased significantly in this region to 3.19 +/- 0.55 units (p < 0.05, vs. control). C/F ratio and ESAF in the oxidative core of TA (2.31 +/- 0.05 and 1.48 +/- 0.23 units, respectively) were not significantly different from control values. Thus, chronic electrical stimulation, which is known to increase both shear stress and wall tension in capillaries and induce angiogenesis, also increased ESAF activity.

Animals↗

PubMedDate not supplied

Vasoactive effects of basic and acidic fibroblast growth factors in hamster cheek pouch arterioles.

Fibroblasts growth factors (FGFs) exhibit well-known angiogenic actions, but there is some controversy about whether they have vasoactive effects on blood vessels which might contribute to angiogenesis per se. To clarify this, changes in arteriolar diameter were recorded during observation by videomicroscopy of 3rd- and 4th (terminal)-order arterioles (resting diameters 22.5 +/- 0.5 microns and 14.4 +/- 0.3 microns, respectively) in the hamster cheek pouch in response to FGF application. Recombinant human bFGF (basic) and aFGF (acidic) were applied from micropipettes positioned 5-10 microns from the adventitial surface of vessels. Maximum vasodilator effects of adenosine (10(-4) M) applied in a similar way were also observed. Adenosine increased the diameters of 4th-order arterioles by 37.2 +/- 3.8% and those of 3rd-order arterioles by 38.7 +/- 2.7. bFGF produced vasodilatation (threshold dose 0.1 ng ml-1) in both classes of arterioles, while aFGF produced dose-dependent constriction (threshold dose 0.01 ng ml-1). A maximal dilator effect in 4th-order arterioles was obtained with 100 ng ml-1 bFGF, when diameters reached 82.6 +/- 2.4% of those with adenosine. Maximal constrictor effect (-48.2 +/- 5.6% of resting diameter) occurred with a dose of 100 ng ml-1 aFGF. Vehicle alone (MOPS or bicarbonate buffer used as solvents for FGFs) had no effect. As vasoconstrictors are known to stimulate growth of smooth muscle cells while dilators stimulate growth of endothelial cells, it is possible that the opposing vasoactivities demonstrated for aFGF and bFGF are linked with their selective mitogenicity for smooth muscle and endothelial cells, respectively, and contribute to their angiogenic actions.

Adenosine↗