Mechanisms of Transmural Heparin Transport in the Rat Abdominal Aorta After Local Vascular Delivery

Lovich, Mark A.; Edelman, Elazer R.

doi:10.1161/01.res.77.6.1143

Cited by 74 publications

(92 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…I t now appears that the success of drug-eluting stents is predicated to as great a degree upon the extent of drug deposition and distribution through the arterial wall as virtually any other factor (1)(2)(3)(4)(5). The biological effects of a candidate drug are essential, but, ultimately, tissue residence time will determine effect and toxicity (6,7).…”

mentioning

confidence: 99%

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Levin

Vukmirovic

Hwang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

222

165

View full text Add to dashboard Cite

Endovascular drug-eluting stents have changed the practice of medicine, and yet it is unclear how they so dramatically reduce restenosis and how to distinguish between the different formulations available. Biological drug potency is not the sole determinant of biological effect. Physicochemical drug properties also play important roles. Historically, two classes of therapeutic compounds emerged: hydrophobic drugs, which are retained within tissue and have dramatic effects, and hydrophilic drugs, which are rapidly cleared and ineffective. Researchers are now questioning whether individual properties of different drugs beyond lipid avidity can further distinguish arterial transport and distribution. In bovine internal carotid segments, tissue-loading profiles for hydrophobic paclitaxel and rapamycin are indistinguishable, reaching load steady state after 2 days. Hydrophilic dextran reaches equilibrium in several hours at levels no higher than surrounding solution concentrations. Both paclitaxel and rapamycin bind to the artery at 30 -40 times bulk concentration. Competitive binding assays confirm binding to specific tissue elements. Most importantly, transmural drug distribution profiles are markedly different for the two compounds, reflecting, perhaps, different modes of binding. Rapamycin, which binds specifically to FKBP12 binding protein, distributes evenly through the artery, whereas paclitaxel, which binds specifically to microtubules, remains primarily in the subintimal space. The data demonstrate that binding of rapamycin and paclitaxel to specific intracellular proteins plays an essential role in determining arterial transport and distribution and in distinguishing one compound from another. These results offer further insight into the mechanism of local drug delivery and the specific use of existing drug-eluting stent formulations.

show abstract

mentioning

confidence: 99%

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Levin

Vukmirovic

Hwang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

222

165

View full text Add to dashboard Cite

show abstract

“…13 The fast phase is considered to represent extracellularly bound LPL, whereas the delayed phase may originate from a separate compartment. Because heparin has been demonstrated to traverse the endothelial barrier, 14 we suggested that conventional Langendorff retrograde perfusion of the heart with heparin can release not only LPL bound to the luminal side of the capillary endothelium but also that present at the abluminal surface, the interstitial space, and the myocyte surface. Interestingly, in streptozotocin (STZ)-diabetic rats, the initial fast phase of heparin-releasable LPL activity was significantly elevated after 2 or 12 weeks of hypoinsulinemia, whereas the second, or delayed, phase of LPL release was absent.…”

mentioning

confidence: 99%

Localization of Lipoprotein Lipase in the Diabetic Heart

Sambandam

Abrahani

Pierre

et al. 1999

ATVB

View full text Add to dashboard Cite

Abstract-Vascular endothelium-bound lipoprotein lipase (LPL) is rate limiting for free fatty acid (FFA) transport into tissues. In streptozotocin (STZ)-diabetic rats, we have previously demonstrated an increased heparin-releasable LPL activity from perfused hearts. Because heparin can traverse the endothelial barrier, conventional Langendorff retrograde perfusion of the heart with heparin could release LPL from both the capillary luminal and abluminal surfaces. To determine the precise location of the augmented LPL, a modified Langendorff retrograde perfusion was used to isolate the enzyme at the coronary lumen from that in the interstitial effluent. In response to heparin, a 4-fold increase in LPL activity and protein mass was observed in the coronary perfusate after 2 weeks of STZ diabetes. Release of LPL activity into the interstitial fluid of control hearts was slow but progressive, whereas in diabetic hearts, peak enzyme activity was observed within 1 to 2 minutes after heparin, followed by a gradual decline. Immunohistochemical studies of myocardial sections confirmed that the augmented LPL in diabetic hearts was mainly localized at the capillary endothelium. To study the acute effects of insulin on endothelial LPL activity, we examined rat hearts at various times after the onset of hyperglycemia. An increased heparin-releasable LPL activity in diabetic rats was demonstrated shortly (6 to 24 hours) after STZ injection or after withdrawal from exogenous insulin. Heparin-releasable coronary LPL activity was also increased after an overnight fast. These studies indicate that the intravascular heparin-releasable fraction of cardiac LPL activity is acutely regulated by short-term changes in insulin rather than glucose. Thus, during short periods (hours) of hypoinsulinemia, increased LPL activity at the capillary endothelium can increase the delivery of FFAs to the heart. The resultant metabolic changes could induce the subsequent cardiomyopathy that is observed in the chronic diabetic rat.

show abstract

“…A number of models have appeared in the literature [9][10][11][12][13][14][15][16]. The individual models take account of different physical processes.…”

Section: Impact Of Balloon Permeability On Drug Deliverymentioning

confidence: 99%

Controlling the rate of penetration of a therapeutic drug into the wall of an artery by means of a pressurized balloon

Stark¹,

Gorman²,

Sparrow³

et al. 2013

JBiSE

View full text Add to dashboard Cite

The focus of this paper is to propose, model, and characterize a means of accelerating the rate of delivery of therapeutic drugs to human tissues. The investigated means is a pressurized, permeable-walled balloon filled with a homogeneous mixture of the drug and the carrier fluid. The fluid mixture, driven by pressure, traverses the thickness of the balloon wall through laser-drilled pores. The number and deployment of the pores can be controlled to a high degree of precision. As a consequence, the wall of the balloon can be regarded as a homogeneous porous medium, and the traversing fluid flow can be analyzed by means of porous media models. When the balloon is in intimate contact with the surface of a tissue bed, the therapeutic fluid flows in series as it passes through the balloon wall and penetrates the tissue. The flow rate can be controlled by proper selection of the balloon permeability, the viscosity of the flowing medium, and the pressure internal to the balloon. The delivered concentration of the drug was predicted by coupling the present balloon-focused theory with a previously developed tissue-bed model that includes both diffusion and advection processes. The tribologic interaction of the pressurized balloon with an artery wall was investigated experimentally to assess the possible formation of aneurysms.

show abstract

Mechanisms of Transmural Heparin Transport in the Rat Abdominal Aorta After Local Vascular Delivery

Cited by 74 publications

References 27 publications

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Localization of Lipoprotein Lipase in the Diabetic Heart

Controlling the rate of penetration of a therapeutic drug into the wall of an artery by means of a pressurized balloon

Contact Info

Product

Resources

About