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Biomedical subjects

S Rajanayagam

Publications and source records attributed to S Rajanayagam.

7 recordsLinked to original sources
PubMed1997

Inhibition of vascular smooth muscle cell proliferation and neointimal accumulation by adenovirus-mediated gene transfer of cytosine deaminase.

BACKGROUND: Restenosis remains a significant problem after balloon angioplasty. Previous studies have demonstrated that recombinant adenoviruses are efficient vectors for gene transfer to the arterial wall and can be used to inhibit the proliferative aspect of restenosis. We sought to extend these observations using AdCMV.CD, an adenovirus that encodes cytosine deaminase (CD) and is capable of metabolizing 5-fluorocytosine (5-FC) to 5-fluorouracil. METHODS AND RESULTS: Infection of vascular smooth muscle cells (VSMC) with AdCMV.CD increases by two to three orders of magnitude the growth-inhibitory effects of 5-FC. The degree of VSMC inhibition in vitro was a function of 5-FC concentration and the level of CD expression. Cells infected with AdCMV.CD exhibited a profound bystander effect on the growth of neighboring cells, which did not require direct cell-to-cell contact. The predominant effect of AdCMV.CD on growth of VSMC appeared to be cytostatic, not cytotoxic. Assessment of this strategy in a rabbit femoral artery model of balloon-induced injury demonstrated that compared with animals in either of two control groups, animals treated with the active combination of infection with AdCMV.CD and 1-week treatment with parenteral 5-FC had a significant reduction at 30 days in the neointimal-to-medial ratio. CONCLUSIONS: Our results suggest that adenovirus-mediated gene transfer of CD along with 5-FC administration may be a useful strategy to treat the proliferative aspects of restenosis.

Adenoviridae↗
PubMed1997

Effect of basic fibroblast growth factor on myocardial angiogenesis in dogs with mature collateral vessels.

OBJECTIVES: We sought to evaluate the potential of basic fibroblast growth factor (bFGF) to enhance coronary collateral perfusion in dogs with chronic single-vessel coronary occlusion. A secondary goal was to examine whether the salutary effects of bFGF treatment, previously proved effective in the short term, would be maintained in the long term (6 months). BACKGROUND: bFGF, an angiogenic growth factor, is currently the subject of a Phase I trial in patients with ischemic heart disease. It has been shown to promote collateral development in dogs with progressive coronary occlusion when given during the period of natural collateralization. The effect of bFGF on quiescent collateral vessels, a subject of significant clinical importance, is uncertain. METHODS: Dogs were subjected to ameroid-induced occlusion of the left circumflex coronary artery and randomized to bFGF (1.74 mg/day for 7 days), a regimen previously proved effective, or to saline solution. Maximal collateral perfusion was assessed 6 months later, and the dogs were reassigned to a course of bFGF or saline solution. Collateral perfusion was reevaluated after the second treatment course. RESULTS: At 6 months, collateral function was identical in the groups treated initially with bFGF and saline solution. The subsequent course of bFGF did not induce further collateralization. CONCLUSIONS: Although we previously demonstrated the salutary effects of this bFGF regimen in the short term (5 weeks), collateral flow in control dogs reached parity with that of bFGF-treated dogs after 6 months. bFGF did not induce further collateralization in dogs with mature collateral vessels, underscoring the priming role of ischemia for bFGF-induced collateral development.

Animals↗
PubMed1995

Effects of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart.

BACKGROUND: Recently we reported that intracoronary administration of basic fibroblast growth factor (bFGF), a potent angiogenic peptide, increases collateral blood flow in dogs subjected to progressive left circumflex coronary artery (LCx) occlusion. The aim of the present study was to examine the effect of systemically administered bFGF on collateral blood flow and to assess its pharmacokinetics and potential side effects. METHODS AND RESULTS: Forty-seven dogs were subjected to progressive ameroid-induced occlusion of the LCx, an intervention known to induce the development of collateral vessels. In phase I of the investigation, dogs were randomized to receive bFGF 1.74 mg/d (n = 10) or saline (n = 9) as a left atrial injection for 4 weeks. Relative collateral blood flow was assessed serially with radiolabeled microspheres in the conscious state during maximal coronary vasodilatation. Initiation of bFGF treatment was temporally associated with a marked acceleration of collateral development; however, collateral flow in control dogs improved toward the end of the study, approaching that of bFGF-treated dogs at the 38-day end point. Phase II of the investigation was a three-armed study of extended duration to determine whether bFGF caused a sustained increase in collateral function. Dogs were randomized to receive bFGF 1.74 mg/d for 9 weeks (n = 7), bFGF 1.74 mg/d for 5 weeks followed by placebo for 4 weeks (n = 11), or placebo for 9 weeks (n = 10). Relative and absolute collateral blood flow were assessed serially with microspheres during maximal coronary vasodilatation. Between the 10th and 17th days after ameroid placement, bFGF-treated dogs exhibited marked improvement in collateral flow such that maximal collateral conductance exceeded that of controls by 24% at the 5-week crossover point. Final collateral conductance was similar in dogs receiving bFGF for 5 and 9 weeks despite withdrawal of treatment in the former group. bFGF administration was associated with a 21% increase in final collateral conductance as well as a 49% increase in collateral zone vascular density. Prolonged bFGF administration was also associated with a decrease in arterial pressure, moderate thrombocytopenia, and moderate, reversible anemia. CONCLUSIONS: Systemic administration of bFGF enhanced collateral conductance in dogs with progressive single-vessel coronary occlusion. The beneficial effect of bFGF occurred primarily between the 7th and 14th days of therapy, and regression of collateral development was not noted after withdrawal of treatment. The present investigation provides impetus to the concept that collateral development can be enhanced pharmacologically-specifically by bFGF-raising the possibility that such an intervention might eventually be applied clinically.

Animals↗
PubMed1989

Does suppression of responsiveness to beta-adrenoceptor activation explain the enhancement of vasoconstrictor responses by alpha 2-adrenoceptor agonists?

1. The alpha 2-adrenoceptor agonist TL99, in concentrations that had no other observable effect, enhanced constrictor responses to phenylephrine in perfused segments of the rat tail artery. 2. Vasoconstrictor responses to phenylephrine were also enhanced by propranolol (0.3 mumol/L). 3. Vasoconstrictor responses to phenylephrine in the presence of propranolol were further enhanced by TL99 (10 nmol/L). 4. The enhancement of vasoconstrictor responses by alpha 2-adrenoceptor agonists is not due to the removal of a counteracting vasodilator component produced by activation of beta-adrenoceptors.

Adrenergic alpha-Agonists↗