Prostacyclin and Pathogenesis of Hemodynamic Abnormalities of Diabetic Ketoacidosis in Rats

Abstract

The pathogenesis of the hemodynamic abnormalities of diabetic ketoacidosis (DKA) is not well understood. Previous studies suggest that prostacyclin (PGI₂) production by adipose tissue is increased in DKA. We investigated the role of PGI₂ in the pathogenesis of the reduced vascular resistance in DKA. Rats with streptozocin-induced DKA were anesthetized with pentobarbital sodium, and flow was measured with an electromagnetic probe on the infradiaphragmatic aorta The plasma level of 6-keto-PGF_1α (stable derivative of PGI₂) was higher (mean ± SE 0.91 ± 0.05 ng/ml) and vascular resistance lower (4.9 ± 0.2 mmHg · ml⁻¹ · min⁻¹ · 100 g⁻¹ [resistance units, RU]) in 67 rats with DKA than in 21 normal rats (0.34 ± 0.03 ng/ml, P < .01, and 9.0 ± 0.7 RU, P < .01, respectively). Inhibition of cyclooxygenase activity with either indomethacin or meclofenamic acid reduced the plasma 6-keto-PGF_1α level but failed to raise vascular resistance. Infusions of PGI₂ in rats with DKA demonstrated that the vasculature was responsive to PGI₂. Inhibition of cyclooxygenase activity not only reduced PGI₂ production but also suppressed renin release. When the effects of the renin-angiotensin system were excluded by bilateral nephrectomy, indomethacin caused a significant increase (P < .05) in vascular resistance. Thus, the failure of cyclooxygenase inhibitors to raise vascular resistance in DKA was a result of concurrent suppression of vasodilator (PGI₂) and vasoconstrictor (renin-angiotensin system) mechanisms that are activated in DKA. Insulin administration increased vascular resistance (P < .01) and decreased the level of plasma 6-keto-PGF_1α (P < .01). Combined administration of PGI₂ and insulin did not alter vascular resistance, suggesting that the increase in vascular resistance with insulin was predominantly due to the reduction of circulating PGI₂. Thus, vascular resistance is decreased in DKA primarily as a result of the vasodilator effects of PGI₂ produced by adipose tissue. The activation of the renin-angiotensin system represents a partial compensation. The increase in PGI₂ production may contribute to the hypotension and mortality of DKA.