Anteroposterior distribution of AT1 angiotensin receptors in caudal brainstem cardiovascular regulatory centers of the rat

Abstract

Angiotensin II acts on Ang II type 1 (AT 1 ) receptors in areas of the caudal brainstem involved in cardiovascular regulation. In particular, activation of AT 1 receptors in the rostral ventrolateral medulla (RVLM) has been suggested to contribute to hypertension. However, the characteristics of AT 1 receptors in the RVLM of rat, the species in which the most experimental work has been done, is not well documented. This study evaluated AT 1 receptor binding along a 2.7 mm length of rat medulla, which included the full extent of the RVLM and the caudal ventrolateral medulla (CVLM). Sections of medulla from female rats cut on a cryostat were incubated with five concentrations of 125 I-sarcosine 1 ,isoleucine 8 angiotensin II to assess the density (Bmax) and dissociation constant (K D ) of the receptors for the radioligand. The dorsomedial medulla (DMM) displayed a high density of AT 1 binding (1207±100 fmol/g), which peaked at 0.4 mm rostral to the calamus scriptorius (approximately 14 mm caudal to Bregma). The RVLM and CVLM displayed significantly lower (p < 0.01) densities of AT 1 binding, 278±38 and 379±64 fmol/g, respectively. However, the dissociation constants were significantly lower (i.e., higher affinity) in RVLM and CVLM (164±38 and 178±27 pM, respectively,) than in DMM (328±12 pM, p < 0.01 and p < 0.05 respectively). These results provide an anatomical and pharmacological framework for future studies on the role in cardiovascular regulation of AT 1 receptors in the caudal brainstem.

Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat

“…In a previous study (10), microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the nucleus tractus solitarius (NTS) elicited decreases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). In the rostral ventrolateral medullary pressor area (RVLM) and hypothalamic paraventricular and arcuate nuclei, microinjections of ANG-(1-12) elicited increases in MAP, HR, and SNA (4,5,11).…”

“…The CVLM neurons involved in the baroreflex are GABA-containing neurons, and they project to the RVLM (16,17,25,34,37). The presence of AT 1 Rs has been reported in the CVLM, and microinjections of ANG II into the CVLM decrease blood pressure (BP) (3,8). Microinjections of ANG-(1-7) into the CVLM have been reported to elicit depressor responses (2).…”

“…Unlike ANG II, renin is not involved in the formation of ANG-(1-12) (15,40), prompting the suggestion that ANG-(1-12) may act as a renin-independent alternative substrate for the formation of ANG II in several organs (40). In the periphery, ANG-(1-12) may exert its actions via a rapid conversion to ANG II because pressor responses elicited by intravenous injections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the rat were blocked by prior injections of an ANG type 1 receptor (AT 1 R) antagonist (29). Because it is known that ANG I and ANG II can be converted into ANG-(1-7) (41), there is a possibility that ANG-(1-7) may be formed from ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the brain.…”

“…In the periphery, ANG-(1-12) may exert its actions via a rapid conversion to ANG II because pressor responses elicited by intravenous injections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the rat were blocked by prior injections of an ANG type 1 receptor (AT 1 R) antagonist (29). Because it is known that ANG I and ANG II can be converted into ANG-(1-7) (41), there is a possibility that ANG-(1-7) may be formed from ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the brain. The receptors via which ANG- (1)(2)(3)(4)(5)(6)(7) exerts its actions [Mas receptors (MasRs)] have been identified in medullary brain tissue (14).…”

“…Direct application of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) has an excitatory effect on neurons (10,31). Based on this information, we hypothesized that microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the CVLM may elicit decreases in BP, HR, and SNA and modulate baroreflex function. This hypothesis was tested in anesthetized Wistar rats.…”