Attenuated Agonist Evoked Vasoconstrictor Responses in the Perfused Mesenteric Vascular Bed of Streptozotocin Diabetic Rats

Abstract

We compared agonlst-evoked responses In the perfused mesenteric vascular bed (MVB) of streptozotocln (STZ) diabetic Sprague-Dawley rats 2 and 14 weeks after Induction of diabetes. Endothelln-1 (ET-1h methoxamine (MTXh and KCI-evoked vasoconstrictor responses were unchanged In 2-week-old diabetic rats. In contrast, both the sensitivity (P < 0.01) and the maximal vasoconstrictor responses (P < 0.05) to ET-1 were attenuated In 14-week-old diabetic rats, whereas endothelln plasma levels were Increased (P < 0.05). Although no differences were observed In responses to KCI In either the 2-or 14-week-old diabetic groups, MTX-evoked maximal responses were attenuated In the 14-week-old group (P< 0.01). Changes In agonlst-evoked responses In the 14-week-old diabetic group were unaffected by the protein kinase C (PKC) Inhibitor, staurosporlne, the phospholipase C (PLC) Inhibitor, U73122,the calcium channel blocker, nlfediplne, the calcium pump Inhibitor, cycloplazonlc acid (CPA),or by endothelial denudation. Sodium fluoride (NaF), an activator of guanosine triphosphate binding proteins (G proteins) normalized the responses In the 14-weekold diabetic group. These data suggest that advanced stages of STZ are associated with alterations In G protein receptor coupling and/or activity leading to the attenuation of responses to vasoconstrictor agonlsts.

Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat

“…In addition to impaired acetylcholine-evoked responses in diabetic models, attenuated pressor responses to vasoconstrictor agonists, such as methoxamine and endothelin (ET)-1, have been reported [9,10]. Indeed, we have observed attenuated responses to ET-1 and methoxamine both in vivo and in vitro in the isolated perfused mesenteric vascular bed [11]. Thus, for comparison with vasodilator responses evoked by acetylcholine, we also recorded vasoconstrictor responses to ET-1 and methoxamine.…”

“…Both attenuated and exaggerated responses to α-1 agonists have been reported [11,32]. The ability of VEGF to activate protein kinase C, through both flt-1 and flk-1 receptors, has been reported [33].…”

ATP and norepinephrine contributions to sympathetic vasoconstriction of tail artery are altered in streptozotocin-diabetic rats

“…Whatever the effects, it is often thought that autonomic neuropathy underlays these (4,8,16,27). A common finding is that vessels from diabetic rats (7, 28 -30) and rabbits (8,26) have increased sensitivity to adrenergic agonists, although this observation is not universal (16,19,22,25). Similarly, effects of diabetes on sympathetically evoked responses have varied from vasoconstriction being increased (26,29,30), remaining the same (8,21,25), or decreasing (16).…”

Acute Hyperglycemia and Hyperinsulinemia Enhance Adrenergic Vasoconstriction and Decrease Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in Pithed Rats

“…Many studies have shown that an altered vascular responsiveness characterized by increased reactivity to vasoconstrictors and impaired vasodilation exists in the diabetic state (13)(14)(15)(16)(17). We have demonstrated that chronic hyperinsulinemia in fructose-drinking rats, an experimental model for insulin resistance and type 2 diabetes, facilitates adrenergic nerve-mediated vasoconstriction, which is associated with attenuated CGRPergic nerve-mediated vasodilation (18).…”