AT ₁ and AT ₂ Receptor Blockade and Epinephrine Release During Insulin-Induced Hypoglycemia

Abstract

Abstract-AngotensmII faclhtates epmephrme release durmg msuhn-induced hypoglycenua, and this effect appears to be independent of type 1 angotensm II (AT,) receptors m man In the present study, we hypothesized that the action of anglotensm II on adrenomedullary epmephrme release IS mediated by an AT2 receptor-dependent mechamsm In conscious chronically mstrumented rats, we measured plasma concentrations of catecholammes durmg acute msuhninduced hypoglycenua m groups of rats pretreated with the AT, receptor antagonist losartan (10 mg/kg IV), the AT, receptor antagonist PD123319 (30 mg/kg IV), combined losartan + PD123319, the convertmg enzyme mhlbltor enalapnl (1 mg/kg IV), or vehicle In vehicle-treated rats, the area under the curve for changes m plasma epmephrme concentration [AUC ( However, in contrast with other sympathoexcltatory stlmuh such as hemorrhage, exercise, or environmental stress, severe hypoglycemia produces a relatlvely selective stimulation of the adrenal medulla Thus, m humans, severe hypoglycenua causes a 50-fold increase in the plasma concentration of epmephrme while the plasma concentration of norepmephnne only Increases about 3-fold ' The increased level of epmephnne 1s considered one of the most important counterregulatory hormones released dunng severe hypoglycerma, and therefore, any substance that impairs the release of epmephrme may potentially provoke episodes of hypoglycemia m patients with insulin-dependent diabetes mellitus ' Anglotensm II interacts with the sympathetic nervous system at several levels It stimulates central sympathetic outflow and neurotransmlsslon m sympathetic ganglia, and it facilitates norepmephrme release from sympathetic nerve endings 3 Furthermore, several lines of evidence suggest that anglotensm II may also stimulate adrenomedullary epmephrme release High concentrations of anglotensm II sttmulate epmephrme release m the isolated perfused rat adrenal gland 4s In anesthetized cats, it was reported that nonselective anglotensm II receptor blockade with Sar-Ile-Ang II abolished adrenomedullary catecholamme release durmg msulm-induced hypoglycemia" as well as durmg hemorrhage ' Slmllar findings were reported m anesthetized rats, where the increase m plasma epmephrme concentration observed during hypoglycemia was reduced by CEI ' To examine the role of the remn-angotensm system for adrenomedullary epmephnne release dunng msulm-induced hypoglycenua m humans, we studled the effect of CEI with enalapnl and the effect of AT, receptor blockade with losartan m healthy subJects "" Whereas captopnl attenuated epmephnne release dunng hypoglycemia, losartan did not affect the plasma epmephnne concentration either dunng rest or dunng hypoglycemia These findings are consistent with the hypothesis that the AT, receptor may be involved m the action of anglotensm II on adrenomedullary epmephnne release m humans This nooon 1s supported by recent studies which have demonstrated that the AT2 receptor 1s the predominant angotensm II receptor m both human and rat adrenal medulla " I...

Naloxone, but Not Valsartan, Preserves Responses to Hypoglycemia After Antecedent Hypoglycemia

“…Acute inhibition of angiotensin II production by an ACE inhibitor attenuates acute sympathetic responses to hypoglycemia in humans (13), but specific blockade of the angiotensin receptor A1 subtype does not block responses to hypoglycemia in humans (14), suggesting that the AT2 receptor may mediate acute counterregulatory responses. Furthermore, in a wide variety of circumstances, the AT1 receptor antagonizes effects of the AT2 receptor.…”

Interactions Between Furosemide and the Renal Sympathetic Nerves

“…Since furosemide increases renal renin release even in absence of volume depletion, our results are compatible with the notion that increased angiotensin I1 may facilitate adrenomedullary epinephrine release by an AT2-receptor mediated mechanism in response to furosemide administration. This theory is supported by our recent finding that angiotensin I1 facilitates adrenomedullary epinephrine release by an AT2-receptor dependent mechanism (Worck et al 1998). Thus, the additive antihypertensive effect of ACEinhibition during treatment with diuretics may in part be mediated by an attenuation of the compensatory increase in plasma epinephrine concentration.…”

Inhibitory Effects of Olmesartan on Catecholamine Secretion from the Perfused Rat Adrenal Medulla

“…Furthermore, both PD 123319 and CGP 42112 inhibited the increase in adrenal CA secretion induced by local administration of Ang II [14]. Worck and his colleagues [15] have speculated that Ang II through binding to both receptor subtypes (both AT1 and AT2) facilitates the sympathoadrenal reflex response by actions at several anatomical levels of the neural pathways involved in the sympathoadrenal reflex response elicited during insulin-induced hypoglycemia in conscious chronically instrumented rats.…”