The Effect of Flutamide on Systemic and Renal Hemodynamics in Zucker Diabetic Rats: Paradoxic Renal Vasodilator Response to Endothelin-1 and TXA2 Receptor Activation in Female Sex

Abstract

Flutamide administration to FZDR resulted in the reversal of abnormal systemic and renal alpha-1-mediated vasoconstriction and enhanced nitric oxide-mediated vasodilation. Flutamide caused a paradoxic but specific increase in renal perfusion during ET-1 and TXA2 receptor activation, which could be renoprotective in females. The salutary effects of flutamide on vascular reactivity in the FZDR may be mediated by a protein kinase C-dependent mechanism. These results are compatible with the notion that endogenous testosterone may regulate systemic and renal microcirculation in the female sex and in the type 2 diabetic state.

Acute Renal Failure Following Near-Drowning

“…Interestingly, male gender was found to specifically predispose to hypoxic AKI, 27 , 28 with androgen-related reduced renal vasodilatory capacity, as compared with women. 29 , 30 Male predominance thus potentially supports our proposed hypothesis, with a more pronounced renal vasoconstriction in response to stress among men that leads to an intensified and protracted hypoxic insult. A plausible additional role of a larger muscle mass among male patients with a more pronounced rhabdomyolysis is not supported by our data (creatine kinase values of 1102 ± 1949 IU/μl vs. 760 ± 1520 IU/μl in men and women, respectively).…”

Pathomechanisms of Diabetic Kidney Disease

“…Treatment with rottlerin, a calcium-independent PKC inhibitor, mitigates excessive basal contraction [27,28]. Similar findings were observed in diabetic Zucker rats, where the nonselective PKC agonist phorbol-12,13 dibutyrate reduced renal cortical blood flow and raised mean arterial pressure [29]. These outcomes highlight the association of PKC activation with decreased blood flow, heightened renal perfusion pressure, glomerulosclerosis, and reduced glomerular filtration.…”

The role of protein kinase C in diabetic microvascular complications

“…Treatment with rottlerin, a calcium-independent protein kinase C (PKC-d) inhibitor, alleviated basal overcontraction (37,38). Similar results were observed in diabetic Zucker rats; the nonselective PKC agonist phorbol-12,13 dibutyrate (PDBU) significantly reduced renal cortical blood flow and increased the mean arterial pressure (39). The results indicate that PKC activation is associated with decreased blood flow and increased renal perfusion pressure, causing glomerulosclerosis and reducing glomerular filtration.…”