title: Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver.
abstract: After transplantation, hepatocytes entering liver sinusoids are engrafted, whereas cells entrapped in portal spaces are cleared. We studied whether hepatic sinusoidal dilatation will increase the entry of transplanted cells in the liver lobule, improve cell engraftment, and decrease microcirculatory perturbations. F344 rat hepatocytes were transplanted intrasplenically into syngeneic dipeptidyl peptidase IV (DPPIV)-deficient rats. Animals were treated with adrenergic receptor blockers (phentolamine, labetalol), a calcium channel blocker (nifedipine), and splanchnic vasodilators (nitroglycerine, calcitonin gene-related peptide [CGRP], glucagon). Transplanted cells were localized by histochemistry. The hepatic microcirculation was studied with in vivo videomicroscopy. Changes in cell translocations were analyzed by injection of (99m)Tc-labeled hepatocytes. Pretreatment with phentolamine and nitroglycerine increased transplanted cell entry in liver sinusoids, whereas labetalol, nifedipine, CGRP, and glucagon were ineffective. Increased deposition of transplanted cells in sinusoids resulted in greater cell engraftment. In vivo microscopy showed disruption of sinusoidal blood flow immediately after cell transplantation with circulatory restoration requiring more than 12 to 24 hours after cell transplantation. However, in nitroglycerine-treated animals, sinusoidal blood flow was perturbed less. Nitroglycerine did not meaningfully increase intrapulmonary cell translocations. In conclusion, these findings indicate that hepatic sinusoidal capacitance is regulated by alpha-adrenergic- and nitroglycerine-responsive elements. Sinusoidal vasodilatation benefited intrahepatic distribution of transplanted cells and restored hepatic microcirculation after cell transplantation. This shall facilitate optimization of clinical cell transplantation and offers novel ways to investigate vascular mechanisms regulating hepatic sinusoidal reactivity.
authors.affiliation: Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Slehria
authors.forename: Pankaj
authors.initials: P
authors.lastname: Rajvanshi
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Rana P
authors.initials: RP
authors.lastname: Sokhi
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Bhargava
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Palestro
authors.forename: Robert S
authors.initials: RS
authors.lastname: McCuskey
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics; D005934:Glucagon / Q000494:pharmacology; D022781:Hepatocytes / Q000637:transplantation*; D007741:Labetalol / Q000494:pharmacology; D008099:Liver / Q000098:blood supply* / Q000166:cytology*; D008102:Liver Circulation / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D013152:Splanchnic Circulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D005996:Nitroglycerin; D009543:Nifedipine; D015740:Calcitonin Gene-Related Peptide; D007741:Labetalol; D010646:Phentolamine