phosphoramidon and Ischemic-Attack--Transient

The present study was designed to determine whether an endothelinA (ETA)-receptor antagonist BQ-123 (cyclo[Dtrp, Dasp, pro-D-Val-Leu]) or an ET-converting enzyme inhibitor phosphoramidon may prevent development of cerebral vasospasm after subarachnoid hemorrhage (SAH). A "double hemorrhage" canine model of the disease was used (n = 17 dogs), and the degree of vasospasm of the basilar artery was assessed by angiography. Mongrel dogs of either sex were divided into three experimental groups: animals treated with daily intracisternal injections of BQ-123 (10(-4) M; n = 6) or phosphoramidon (2 x 10(-4) M; n = 6) and control animals treated with saline solution (n = 5). Diameter of basilar arteries in animals treated with saline solution was reduced by SAH to 56 +/- 7% of control diameter. BQ-123 and phosphoramidon did not significantly affect SAH-induced vasospasm (diameters were 62 +/- 0% and 56 +/- 10% of control diameters for BQ-123 and phosphoramidon, respectively). In contrast, in isolated canine basilar arteries BQ-123 (10(-5) M) selectively inhibited concentration-dependent contractions to ET-1 (10(-11)-3 x 10(-8) M; n = 5). Levels of immunoreactive ET in plasma and cerebrospinal fluid were not affected by development of vasospasm. These results suggest that intracisternal injections of ETA-receptor antagonist or phosphoramidon cannot prevent SAH-induced cerebral vasospasm and that ET-1 may not be the major mediator responsible for the decrease in cerebral arterial diameter associated with SAH.

Topics: Amino Acid Sequence; Animals; Autoradiography; Basilar Artery; Dogs; Endothelin Receptor Antagonists; Endothelins; Glycopeptides; In Vitro Techniques; Ischemic Attack, Transient; Molecular Sequence Data; Muscle, Smooth, Vascular; Peptides, Cyclic; Subarachnoid Hemorrhage; Uridine Triphosphate

Since the discovery of endothelin-1 (ET-1), its involvement in cerebral vasospasm after subarachnoid hemorrhage (SAH) has been suspected. We performed various experiments, first to demonstrate the presence of ET in both patients and dogs with SAH, and second to examine the effects of ET synthesis inhibition in experimental vasospasm. Here we report that ET was present in both plasma and cerebrospinal fluid (CSF) in SAH, but did not correlate with vasospasm. However, ET was locally expressed in the vascular endothelium in vasospasm. Several therapeutic approaches causing the inhibition of ET synthesis were effective in preventing the development of vasospasm. Such approaches utilized drugs that inhibited RNA and DNA synthesis. Among them, actinomycin D treatment was most effective. We also utilized phosphoramidon, a recently found conversion inhibitor of big ET to ET. However, this product failed to ameliorate the development of vasospasm. Therefore, although we cannot yet conclude that ET is the main cause of cerebral vasospasm, it may, at least, act as one of the modifying factors in cerebral vasospasm.

Topics: Animals; Antineoplastic Agents; Basilar Artery; DNA; Dogs; Endothelin-1; Endothelins; Glycopeptides; Immunohistochemistry; In Vitro Techniques; Ischemic Attack, Transient; Protein Precursors; RNA, Messenger; Subarachnoid Hemorrhage; Transcription, Genetic

There is increasing evidence that the conversion of big endothelin-1 (big ET-1) to endothelin-1 (ET-1) is specifically inhibited by the metalloproteinase inhibitor phosphoramidon. We investigated the effect of phosphoramidon on delayed cerebral vasospasm from subarachnoid hemorrhage (SAH) using a two-hemorrhage canine model. The magnitude of the vasospasm and the drug effect were determined angiographically. On SAH Day 7, diameter of the basilar artery decreased to about 55% of the control value obtained before SAH (on Day 0). Immunoreactive ET (IR-ET) in the cerebrospinal fluid (CSF) significantly increased after SAH (on Day 7). The intracisternal pretreatment of phosphoramidon potently suppressed the decrease in diameter of the basilar artery after SAH, i.e., observed decrease was only about 20%, compared with the value before SAH. In the phosphoramidon group, IR-ET in CSF markedly increased (on SAH Day 2), but the increased levels of IR-ET significantly declined on SAH Day 7. These results clearly indicate that phosphoramidon effectively prevents delayed cerebral vasospasm. Whether the prevention is due to the inhibition of conversion of big ET-1 to ET-1 is now under study.

Topics: Animals; Cerebral Veins; Chromatography, High Pressure Liquid; Disease Models, Animal; Dogs; Endothelins; Glycopeptides; Ischemic Attack, Transient; Radiography; Radioimmunoassay; Subarachnoid Hemorrhage