Aspirin and prostacyclin treatment of diabetic dogs.

Spontaneously diabetic dogs were treated initially (the first 1/2 yr) with i.v. prostacyclin and oral aspirin and then for 1 yr with varying doses of aspirin alone. At this time cataracts prevented visualization of retinae, and one eye of each animal was removed for examination of the vasculature of the trypsin digested retinae. Studies of the blood during the course of treatment showed an elevation of plasma cyclic adenylic acid and marked lowering of inordinately high platelet count and platelet aggregation. Treatment was stopped and after an additional 1/2 year the animals were euthanized and the fellow eye removed for retinal study. Although just three diabetic animals survived for binocular retinal histology, there were no discernible differences in the retinal vasculature in the fellow eyes of a given animal, and in only one of these three animals were there clear signs of diabetic retinopathy. We must conclude, therefore, that in spite of relative normalization of platelet function in the parameters measured during the course of treatment, we cannot yet claim a salutary effect of treatment on the diabetic retina. Cataracts prevented us from having better information on diabetic retinae prior to treatment and a redesigned study would have to include unilateral histological retinal examination before any treatment is started to determine if, indeed, improved platelet physiology slows or reverses changes in the diabetic retina.

Prostaglandins in ocular pathophysiology with special reference to diabetic retinopathy and glaucoma.

This report reviews evidence for influences of prostaglandins (PGs) on intraocular pressure in glaucoma and on the progressive vascular and blood cell dysfunction in diabetes mellitus, of which retinopathy is a manifestation, and includes a brief outline of evidence for roles of PGs in ocular inflammation. Sequences in pathways of biosynthesis and conversion of PGs are summarized, and PG assay methods are evaluated briefly.

Introductory comments for session V "neovasculogenesis" presented at the fifth symposium, the International Society on Metabolic Eye Disease October 24-26, 1982.

Physiopathologic or metabolic alterations in retinal blood vessels resulting in an ischemic state may be a prime trigger mechanism in neovasculogenesis and scar tissue formation. Rate of oxygen delivery may be the primary factor so the end-state disease may be rapid as in retrolental fibroplasia (marked reduction in vascular flow due to acute vasoconstriction) or delayed as in diabetes mellitus (chronic metabolism-induced low oxygen release rates parallel with chronic vasodilation).

Proposed metabolic dysfunctions in diabetic microthromboses and microangiopathy.

This report describes, at least in part, the role of prostaglandin and cyclic nucleotide metabolism in the etiology of the vascular disease associated with diabetes mellitus. Alterations in this metabolism seem associated with induction of platelet aggregation leads to microthromboses leads to microangiopathy sequences that are subtle but inexorable over a long period of time. Prostaglandins are generally elevated in blood from patients having frank signs of diabetic retinopathy when compared with nondiabetic subjects. Prostaglandin concentration remained elevated in diabetic retinopathy patients receiving indomethacin. We formed, therefore, the working hypothesis--yet to be fully tested either in patients or animal models with and without indomethacin treatment--that the increased prostacyclin (synthesized by endothelial microsomes) and cyclic-AMP production, both of which favor prevention of platelet aggregation, accompany the increased concentration of one or more of the prostaglandin E and F compounds. Concurrently, there may be an accompanying reduction of thromboxane A2 (synthesized by platelet microsomes) and cyclic-GMP (both of which favor platelet aggregation) production in the diabetic patients. The elevated prostaglandin in the diabetic patients not receiving indomethacin could possibly be directed toward slowing but not preventing the progression of the complex disease process in diabetes.

Effects of prostaglandins and norepinephrine on ocular pressure and pupil size in rabbits following bilateral cervical ganglionectomy.

We wish to report an early (10 to 30 min) 6 to 7 mm Hg increase in IOP above predrug levels following topical norepinephrine (NE) (5mumol) administration in conscious normal rabbits. This early elevation in IOP was significantly more pronounced in bilateral superior cervical ganglionectomized (BG) rabbits. The time course for peak IOP elevation slightly preceded the accompanying peak mydriatic effect in all groups. IOP returned to baseline levels in about 60 min in the BG rabbits, but the mydriasis persisted. Pretreatment with topical indomethacin significantly reversed the early hypertonic NE effect on IOP in the BG animals implying the involvement of prostaglandin synthesis. The IOP continued to fall significantly after 60 min in the BG group with indomethacin pretreatment. This latter result suggests a predominant long-lasting NE effect. The indomethacin pretreatment had no effect on pupil size of any group, but phenoxybenzamine (PBA) reduced the mydriatic effect, implying a direct or a predominant role of NE on iris muscle.

Prostaglandins in blood of diabetic versus non-diabetic humans.

We have found a higher concentration of prostaglandins in blood from the diabetic patient under long-term indomethacin therapy as compared with blood from non-diabetics. These findings are generally (qualitatively) similar to previous reports with studies of blood serum from diabetic patients, not on indomethacin treatment, compared with non-diabetics. Certain rationale are presented in an effort to explain the reason why blood prostaglandins in the diabetic are not lowered when the patients are treated with a drug which is clearly established as a blocker of prostaglandin synthesis.

Effects of cervical sympathetic ganglionectomy on cyclic-AMP and prostaglandins in brain and eye tissues and fluids.

Studies were conducted confirming supersensitivity to catecholamines on intraocular pressure and pupil size following bilateral superior cervical ganglionectomy in rabbits. At the termination of these studies we examined changes in cyclic adenylic acid and prostaglandin content in jugular vein effluent and various brain and ocular tissues and fluids of the sympathectomized versus control animals. In the blood effluent we found significant elevation of cyclic adenylic acid and significant lowering of prostaglandin F1alpha in the sympathectomized animals. Although we found elevation of prostaglandin in certain tissues of the sympathectomized animals, there were no significant changes in cyclic adenylic acid levels between sympathectomized and control animals in the tissues examined. The findings of prostaglandin (blood and tissue) and cyclic adenylic acid (blood) changes in sympathectomized animals, associated with known changes in intraocular pressure and pupil size (due to catecholamine supersensitivity) must elicit further interest in the correlation and interpretation of various other central physiological and metabolic events in cervical sympathectomized animals.

Metabolic approaches to studies on diabetic microangiopathy.

The chief purposes of this report are (a) to focus attention on various metabolic and pathophysiologic parameters relating prostaglandins (PGs) and thromboxanes to the slow but inexorable progression of vascular and blood cell dysfunction in diabetes mellitus and (b) to suggest areas of investigation that may be of fundamental importance for expanded areas of diabetes research. The prime thrust of these investigations would be to correlate these metabolic and pathophysiologic parameters with the vasculopathy of diabetes mellitus.

Changes in prostaglandin concentration in blood subjected to repetitive freezing and thawing.

Successive freezing and thawing of whole blood results in a consistently higher yield of various prostaglandin (PG) compounds. Evaluations were made with radioimmunological assay. The increase in PG concentrations seems to be more associated with cell fragmentation and not with the dissociation of albumin-PG complex. Our data suggest that there may be some dissociation of non-albumin-PG complexes. Artifactually high PG concentrations due to in vitro PG synthetase activity appears minimal at least with respect to indomethacin blocking of this enzyme. There are, in general, only slight differences in PG concentrations in samples with and without indomethacin.