Changes in cardiovascular sensitivity of alloxan‐treated diabetic rats to arachidonic acid

Abstract

1 Arachidonic acid (AA, 0.125-2.0mgkg-') administered intravenously to male Wistar rats produced a dose-dependent fall in diastolic blood pressure. However AA (0.125 -1.0 mg kg-') injected into the autoperfused hindquarters via the aorta produced a dose-dependent increase in perfusion pressure. Both these responses to AA were inhibited by indomethacin (5 mg kg-'). 2 The thromboxane A2 receptor antagonist AH23848 (5 mg kg-', i.v.) inhibited pressor responses to AA in the autoperfused hindquarters, but potentiated depressor responses to AA (0.125-0.5 mg kg ') in the whole animal. 3 Alloxan-treated diabetic rats (14 days after a single s.c. injection of alloxan, 175mg kg-')displayed reduced sensitivity to the depressor effects of AA (1-2mgkg-1) in the whole animal, increased sensitivity to the pressor effects of AA (0.5-1.0 mg kg-1) in the perfused hindquarters, and reduced sensitivity to the pressor effects of the thromboxane A2 mimetic U46619 (0.5-8.0 fig kg-', i.a.) in the perfused hindquarters. 4 These results suggest that AA can be predominantly converted to either pressor or depressor metabolites depending on the vasculature. In the diabetic state the ratio of the metabolites formed appears to change favouring a major pressor metabolite, which is probably thromboxane A2.

Changes in Arachidonic Acid Metabolite Patterns in Alloxan-Induced Diabetic Rats

“…This finding is in accord with the idea that a temporal factor may influence the changes in the depressor responses to arachi donic acid [1] and in the proportion of uri nary arachidonic acid metabolites [15] in experimental diabetes.…”

“…As the depressor action of prostacyclin was overshadowed by the pressor effect of thromboxane A2, this led to the weaker hypotensive response to arachidonic acid in diabetic rats. The present findings with thromboxane B2 are supported by those of other workers in dia betic animals [1,2] and patients [8,13,22]. Non-specific effects in the radioimmunoas say method, if any, although not examined for, cannot be excluded.…”

“…An imbalance in arachidonic acid metab olism occurs in diabetic patients [6,12] and in animals with experimentally induced dia betes [ 1,15], involving the vascular metabo lite prostacyclin, a potent vasodilator and an anti-platelet aggregator, as well as thrombox ane A2, a potent vasoconstrictor which also induces platelet aggregation [14], Throm boxane A2, produced largely by platelets [18], is also generated by the blood vessels and myocardial cells [ 10]. The vasodepressor responses to arachidonic acid given intrave nously to non-diabetic rats in the present study indicate that this effect could be the dominant action due to the depressor metab olites that are formed.…”

Role of COX-2 in the Enhanced Vasoconstrictor Effect of Arachidonic Acid in the Diabetic Rat Kidney

“…9,11 Because the earlier studies were performed before the discovery of COX-2, the contribution of this isoform to the vasoconstrictor effect of AA could not be addressed. Because of recent observations of increased renal expression of COX-2 in the diabetic rat, 14 we addressed the role of COX-2 in the enhanced renal vasoconstrictor response to AA that was associated with increased release of prostanoids.…”

“…9 A study of the autoperfused hindquarters of the diabetic rat also revealed increased vasoconstrictor responsiveness to AA that was COX-dependent and mediated through stimulation of PGH 2 /TxA 2 receptors. 11 At the time of these studies, only one type of COX was recognized, and it was assumed that this isoform was responsible for the increased conversion of AA in the diabetic rat kidney. However, the discovery of an inducible enzyme, COX-2, which is constitutively expressed in some parts of the kidney 12 and may be expressed in endothelial cells, 13 raises the possibility that the enhanced responsiveness to AA in the diabetic rat kidney may involve this COX isoform.…”