Role of K⁺ channels in the coronary and renal vascular reactivity to vasopressin in diabetic rats

Abstract

To study the role of K⁺ channels in the coronary and renal vascular response to vasopressin during diabetes mellitus, and whether there are gender differences in this role, we have examined the isometric response to this peptide of 2-mm-long arterial segments from male and female, normoglycemic and streptozotocin-induced diabetic rats. Vasopressin (10⁻¹²–3×10⁻⁸ M) produced arterial concentration-dependent contraction, and during normoglycemia, this contraction was lower in coronary arteries from female than from male rats, and it was similar in renal arteries from both genders. This contraction was reduced by diabetes in coronary arteries, and increased in renal arteries, from both genders. The blocker of Ca²⁺-sensitive K⁺ channels charybdotoxin (10⁻⁷ M) increased the contraction to vasopressin in coronary arteries of diabetic females, but not in the other cases (diabetic males and normoglycemic females or males). This blocker also increased the contraction to vasopressin in renal arteries from diabetic, but not in those from normoglycemic female rats, and also increased it in a higher magnitude in arteries from diabetic than in those from normoglycemic male rats. The blocker of ATP-sensitive K⁺ channels glybenclamide (10⁻⁵ M) or the scavenger of superoxide radicals superoxide dismutase (100 U/ml) did not modify the contraction to vasopressin in any experimental group. These results suggest that diabetes activates the modulatory role of K⁺ channels in the coronary and renal vasoconstriction to vasopressin, but it alters in a different way the vasoconstriction to vasopressin in these two types of arteries. The effects of diabetes on this vasoconstriction are not related to increased release of superoxide radicals.

Introduction

There is increasing evidence that the alterations induced by diabetes mellitus in the vascular system may show gender differences. It is known that cardiovascular diseases in the general, nondiabetic population are less frequent in premenopausal women than in men Douglas, 1997, Hayward et al., 2000, and this has been related to the protective effects of ovarian hormones in premenopausal females (Mendelsohn and Karas, 1999). However, diabetes may produce a relatively greater impairment in the cardiovascular system of premenopausal females, so the difference between men and women regarding cardiovascular disease disappears in the diabetic patients (Farmer and Gotto, 1997).

Previous studies from our laboratory suggest that these gender differences in the effects of diabetes on the vascular system may occur with regard to the vascular response to vasopressin. We have observed that the contraction to vasopressin may be modified by diabetes, as this response was reduced in pial and coronary arteries, and increased in renal arteries, from diabetic rats (Garcı́a-Villalón et al., 2003), and that subthreshold concentrations of vasopressin increased the sympathetic contraction of rat tail arteries, and the mechanism of this modulating effect may be modified in arteries from diabetic female rats (Sanz et al., 2001). In these studies, we found that these alterations were related, in part, to changes in the effects of nitric oxide and prostanoids during diabetes. Vasopressin may be of relevance for diabetic cardiovascular pathophysiology, as osmoregulation is disturbed during diabetes, and it has been reported that the plasmatic levels of vasopressin are consistently elevated during this disease, both in rats with experimental diabetes (Brooks et al., 1989) and in diabetic patients (Vokes et al., 1987), and the vascular response to this peptide may be reduced in diabetic rats Hebden et al., 1987, Sarubbi et al., 1989, Lawrence and Brain, 1992.

Other mechanism, in addition to nitric oxide and prostanoids, that may modulate vascular responses during diabetes is the activation of K⁺ channels. Mainly, Ca²⁺-sensitive K⁺ channels and ATP-sensitive K⁺ channels may be involved in modulating the vascular response (Brayden, 2002), although other subtypes may also be involved in some cases. As the effects of K⁺ channels may be modified during diabetes (Sobey, 2001), this mechanism might be involved in the changes of the vasopressin response in this condition. One possible mechanism through which diabetes may affect K⁺ channel function is the production of superoxide radicals (Liu and Gutterman, 2002b), which is markedly increased during diabetes (West, 2000). Superoxide radicals may impair channel function, although this impairment may be dependent of the subtype of K⁺ channel (Liu and Gutterman, 2002a).

Therefore, the aim of this work was to extend previous studies by analyzing whether the changes in the vascular response to vasopressin during diabetes, and the gender differences in these changes, could be related to alterations in the function of K⁺ channels, or to the action of superoxide radicals. To this, the contraction to vasopressin was recorded in coronary and renal arteries from control (normoglycemic) and diabetic, male and female rats, and the effects of Ca²⁺-sensitive and ATP-sensitive K⁺ channel blockers and of a superoxide scavenger on this response were analyzed. Diabetes was induced by injection of streptozotocin, a model of experimental diabetes frequently used (Öztürk et al., 1996).