Specific Role of α_2A‐ and α_2B‐, but not α_2C‐, Adrenoceptor Subtypes in the Inhibition of the Vasopressor Sympathetic Out‐flow in Diabetic Pithed Rats

Abstract

Several lines of evidence have shown an association of diabetes with a catecholamines' aberrant homeostasis involving a drastic change in the expression of adrenoceptors. This homeostatic alteration includes, among other things, atypical actions of a 2 -adrenoceptor agonists within central and peripheral a 2 -adrenoceptors (e.g. profound antinociceptive effects in diabetic subjects). Hence, this study investigated the pharmacological profile of the a 2 -adrenoceptor subtypes that inhibit the vasopressor sympathetic out-flow in streptozotocin-pre-treated (diabetic) pithed rats. For this purpose, B-HT 933 (up to 30 lg/kg min) was used as a selective a 2 -adrenoceptor agonist and rauwolscine as a non-selective a 2A/2B/2C -adrenoceptor antagonist; in addition, BRL 44408, imiloxan and JP-1302 were used as subtype-selective a 2A -, a 2B -and a 2C -adrenoceptor antagonists, respectively (all given i.v.). I.v. continuous infusions of B-HT 933 inhibited the vasopressor responses induced by electrical sympathetic stimulation without affecting those by i.v. bolus injections of noradrenaline in both normoglycaemic and diabetic rats. Interestingly, the ED 50 for B-HT 933 in diabetic rats (25 lg/kg min) was almost 1-log unit greater than that in normoglycaemic rats (3 lg/kg.min). Moreover, the sympatho-inhibition induced by 10 lg/kg min B-HT 933 in diabetic rats was (i) abolished by 300 lg/kg rauwolscine or 100 and 300 lg/kg BRL 44408; (ii) partially blocked by 1000 lg/kg imiloxan; and (iii) unchanged by 1000 lg/kg JP-1302. Our findings, taken together, suggest that B-HT 933 has a less potent inhibitory effect on the sympathetic vasopressor responses in diabetic (compared to normoglycaemic) rats and that can probably be ascribed to a down-regulation of a 2C -adrenoceptors.Based on structural, transductional and operational criteria, a 2 -adrenoceptors consist of the a 2A -, a 2B -and a 2C -adrenoceptor subtypes [1]. These receptors play a wide array of functions, including cardiovascular modulation and sympatho-inhibition via autoreceptors [2]. In the particular case of healthy Wistar pithed rats, cardiac sympatho-inhibition is mediated by prejunctional a 2A -and a 2C -adrenoceptors [3], while systemic vascular (vasopressor) sympatho-inhibition has recently been reported to involve a 2A -, a 2B -and a 2C -adrenoceptors [4]. However, in some pathologies (including metabolic diseases), the modulatory role of these receptors seems to be altered. For example, the early stages of streptozotocin-induced diabetes in Wistar rats are characterized by (i) an up-regulation of central a 2 -adrenoceptors [5][6][7]; (ii) an increased noradrenaline overflow and sympathetic tone [8]; and (iii) impaired neurogenic vasomotor mechanisms [9]. Nevertheless, no study has thus far analysed possible alterations in the specific role of the a 2 -adrenoceptor subtypes mediating inhibition of the vasopressor sympathetic out-flow in diabetic rats. On this basis, this study investigated the pharmacological profile of the a 2 -adrenoceptor subtyp...

Differential cardiac sympatho‐inhibitory responses produced by the agonists B‐HT 933, quinpirole and immepip in normoglycaemic and diabetic pithed rats

“…treatment with vehicle (citrate buffer) or STZ, the values of: (i) blood glucose (mg/dL) remained without significant changes after vehicle ( T 50 = 2170.5; P = .808)), but markedly increased after STZ ( T 55 = 1540; P < .001); (ii) body weight (g) increased after vehicle ( T 50 = 666; P < .001), but decreased after STZ ( T 55 = 4564; P < .001). These results are consistent with previous reports …”

“…Based on the cardiac autonomic abnormalities previously shown in STZ‐pretreated (diabetic) rats, our study further shows differential alterations in the cardiac sympatho‐inhibition produced by B‐HT 933, quinpirole and immepip between normoglycaemic and STZ‐pretreated (diabetic) pithed rats, namely, in diabetic animals: (i) the cardiac sympatho‐inhibition produced by B‐HT 933 and quinpirole is more pronounced than that in normoglycaemic rats (Figures and ; Tables and ); and (ii) immepip failed to produce cardiac sympatho‐inhibition (Figures D,E and B), contrasting with normoglycaemic rats (Figures B and A). The simplest interpretation of these findings suggests that the cardioaccelerator sympathetic outflow in diabetic (as compared to normoglycaemic) rats involves a differential activation of α 2 ‐adrenergic, dopamine D 2 ‐like and histamine H 3 /H 4 receptors.…”

“…These significantly lower values of heart rate, irrespective of the experimental (pithed or conscious) conditions, may be related with: (i) changes in the electrophysiological properties of the heart; and/or (ii) alterations in the expression and/or density of cardiac β‐adrenergic receptors during diabetes, keeping in mind that modulation of cardiac function is modulated by β‐adrenergic receptors . In contrast, the systemic vascular tone is not markedly affected in diabetic animals . Consistent with this view, baseline values of diastolic blood pressure were not significantly different ( U = 1103; P = .079): (i) in diabetic (51 ± 1 mm Hg) and normoglycaemic (48 ± 5 mm Hg) pithed rats (see section); and (ii) in conscious rats (93 ± 8, 109 ± 8, 97 ± 10, 102 ± 9, 78 ± 7 mm Hg, n = 6; at 0, 7, 14, 21 and 28 days after STZ; t 6 = −1.434 with 8 degrees of freedom, P = .189; t 6 = −0.427 with 8 degrees of freedom, P = .680; t 6 = −.724 with 8 degrees of freedom, P = .490; t 6 = 1.746 with 8 degrees of freedom, P = .119; unpublished data).…”

“…In set 1, diabetes was induced by an intraperitoneal (i.p.) injection of STZ (50 mg/kg) which was dissolved in citrate buffer (pH = 4.5); whereas set 2 received an ip injection of vehicle (citrate buffer, 1 mL/kg) as previously reported . Both sets were kept for 4 weeks.…”

“…The remaining 40 rats, representing the fourth, fifth, ninth and tenth groups (i.e. 20 rats from set 1 and 20 rats from set 2, see Figure ) were prepared as described above, but the pithing rod was left and the administration of both gallamine and desipramine was omitted, as previously described . After a stable haemodynamic condition for 30 minutes, baseline values of diastolic blood pressure and heart rate were determined.…”