The α₁-adrenergic receptor not the DA₁-dopaminergic receptor mediates cyclosporine–SKF38393 renovascular interaction

Abstract

In this study, we investigated the effect of acute exposure to cyclosporine A (CyA) on renal vasodilations evoked by the DA(1) dopaminergic agonist SKF38393 and whether dopamine DA(1) receptors are directly involved in the interaction. Changes evoked by CyA in SKF38393 vasodilations were evaluated in phenylephrine-preconstricted isolated perfused rat kidneys in the absence and presence of SCH23390, a DA(1) receptor antagonist. SKF38393 (3 x 10(-8) to 3 x 10(-6) mol) produced dose-dependent reductions in the renal perfusion pressure that were significantly attenuated in tissues pretreated with SCH23390 or CyA. Unlike SKF38393, the vasodilatory action of sodium nitroprusside, a nitrovasodilator, was not altered by CyA. The attenuating effect of CyA on SKF38393 vasodilations was preserved in preparations pretreated with SCH23390, suggesting that sites other than DA(1) receptors may be involved in CyA-SKF38393 interaction. The study was then extended to investigate the possible involvement of renal alpha1-adrenoceptors in the interaction. Blockade of alpha(1)-adrenoceptors by prazosin (30 nmol/L) significantly reduced the vasodilatory effect of SKF38393 and virtually abolished the CyA-induced attenuation of SKF38393 responses. Further, CyA failed to alter SKF38393 vasodilations when the renal tone was raised with prostaglandin F2alpha (PGF2alpha), a vasoconstrictor whose effect is independent of alpha(1)-adenoceptors. Together, these findings support earlier reports that both DA(1) and alpha(1)-receptors mediate the renal vasodilatory action of SKF38393 and suggest that CyA interacts selectively with the alpha(1)-receptor component to compromise SKF38393 responses.

Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes

“…3T3-L1cells may also express D 2 R (35) ( Figure 1). Dopamine and some dopamine receptor agonists are also able to stimulate α-and β-adrenergic receptors in the cardiovascular system and in adipocytes (11,23,24,35,36 ) and this effect in vivo is observed at a higher dopamine dose in human (37). Dopamine also suppresses leptin release in 3T3-L1 cells but the effect is blocked not by the dopamine receptor antagonists but by propranolol, indicating the involvement of β-adrenergic receptors (11).…”

Cyclosporine A Impairs Norepinephrine-Induced Vascular Contractility

“…The existence of α-adrenoceptors in rat aorta [36,37] as well as in rat mesenteric resistance arteries [38] was shown previously by several groups. An interaction of α 1 -adrenoreceptors under exposure to CsA has already been described [39] and Tavares et al [37] also detected a significant downregulation of α-adrenoreceptor expression after CsA treatment. In contrast, in our study the expression level of α-adrenoreceptors was only significantly downregulated in the mesenteric resistance arteries, whereas it remained unchanged in the aorta.…”

Exacerbation by Nicotine of the Cyclosporine A‐induced Impairment of Β‐adrenoceptor‐mediated Renal Vasodilation in Rats

“…An equilibration period of 30 min was allowed at the beginning of the experiment to ensure stabilization of kidney perfusion pressure. To study the vasodilatory effects of isoprenaline, the renal vascular tone was elevated by continuous infusion of the α 1 ‐adrenoceptor agonist phenylephrine (10 µmol/L), which caused a net increase in the perfusion pressure of 100–150 mmHg, as reported previously 13,14,23,24 …”

“…The rat kidney was isolated and perfused according to methods described previously 13,14,23 . Briefly, rats were anaesthetized with thiopental sodium (50 mg/kg, i.p.…”

“…The rat kidney was isolated and perfused according to methods described previously. 13,14,23 Briefly, rats were anaesthetized with thiopental sodium (50 mg/kg, i.p. ), the abdomen was opened by a midline incision and the left kidney was exposed.…”