The matrix metalloproteinases (MMPs) have been implicated in a number of diseases involving inflammation or cellular invasion.' GM 6001 (FIG. 1) is an inhibitor of most of these enzymes with Ki's in the low nanomolar range. Though potent in vitro, this molecule is short-lived in circulation with a half-life of a few minutes.We show here that topical GM 6001 prevents the infiltration of inflammatory cells into the alkali-burned rabbit cornea and into phorbol ester-stimulated mouse skin. It thus prevents ulceration in the former and psoriasis-like inflammation and proliferation in the latter. When given systemically it blocks the infiltration of cells into the peritoneal cavity of mice stimulated with thioglycollate. Topical administration of this drug inhibits angiogenesis in the chick chorioallantoic membrane. When given intravenously, it inhibits angiogenesis in rat corneas implanted with a pellet containing tumor extract, a process requiring penetration of vascular basement membrane by endothelial cells. Finally, systemic GM 6001 increases survival of mice in a B16-Fl0 melanoma metastasis model, presumably by inhibiting cellular invasion or tumor growth.In addition to the potential for preventing direct destruction of connective tissue

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Aortic ligation between the origins of the renal arteries in the rat produces a left renal ischemia, renin-dependent hypertension, and a transitory hindlimb paralysis of less than 2 h. Removal of the left ischemic kidney at the time of aortic ligation curtails the rise of blood pressure, plasma renin activity is normal, and paralysis is still present 24 h after surgery. Administration of an angiotensin-converting enzyme inhibitor or saralasin also prevents recuperation from paralysis after aortic ligation. Independent manipulation of the mean arterial pressure or plasma renin activity by pretreatment with reserpine or deoxycorticosterone before surgery shows that the presence or absence of paralysis is dependent on the plasma renin activity and not on the high blood pressure. Blood flow measurements show that paralysis is due to a persistent impairment of blood supply to the hindlimb muscle and not to ischemia of the spinal cord. Infusion of angiotensin II to aortic-ligated, left-renoprival animals tends to restore blood flow to muscle. It is concluded that after renal ischemia the renin-angiotensin system, independent of its hypertensive effect, restores blood flow by stimulating the development of collateral circulation.

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Significant proliferation of capillaries with hyperplastic vascular endothelium is one of the characteristic histologic features of glioblastoma multiforme (GBM). It has been shown that the renin-angiotensin II cascade stimulates new vessel formation. The presence of renin in several types of highly vascularized neoplasm suggests that it may also be implicated in the mechanism of tumor angiogenesis. In order to study the possible relationship of renin to GBM, immunohistochemical search for human renin was carried out in ten instances of such a tumor. Eight of these cases demonstrated renin-containing neoplastic astrocytes, whereas seven cases of reactive gliosis and six cases of low-grade astrocytoma revealed no renin-containing cells. The immunostaining was not present after preabsorption of the renin antiserum with pure human renin or substitution of preimmune serum for the specific renin antiserum. Because it has also been demonstrated that a product of renin, angiotensin II, has angiogenic properties, it seems reasonable to postulate that renin, through angiotensin II, may play a role in the mechanism of GBM-associated neovascularization.

Most of the deleterious effects of angiotensin II (Ang II) on blood pressure (BP), cardiovascular remodeling, and atherosclerosis are mediated by Ang II type 1 (AT1)-receptor activation. This explains why Ang-II-decreasing or blocking drugs have been successful in decreasing global cardiovascular morbimortality in patients with cardiac complications. However, in primary or secondary stroke prevention trials in patients with low cardiac risk, b-blockers and angiotensin-converting enzyme inhibitors (ACEIs), which decrease Ang II formation, seem to be less protective than thiazides and dihydropyridines, which increase Ang II. When compared with a beta-blocker, an Ang II-increasing AT1-receptor blocker better protects against stroke but not against cardiac events, whereas an ACEI gives the same protection against both cardiac and cerebral events. This dissociation between blood-pressure-independent cardiac and cerebral protection between b-blockers or ACEIs versus AT1-blockers in patients with low cardiac risk can be best explained if, besides the beneficial vascular effect of AT1-receptor blunting, there is evidence of a beneficial effect of non-AT1-receptor activation. In this review, we present experimental evidence for AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEIs to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardiac complications.