Angiotensin AT₁ receptor‐mediated excitation of rat carotid body chemoreceptor afferent activity

Abstract

A high density of angiotensin II receptors was observed in the rat carotid body by in vitro autoradiography employing 125I‐[Sar1,Ile8]‐angiotensin II as radioligand. Displacement studies demonstrated that the receptors were of the AT1 subtype. The binding pattern indicated that the AT1 receptors occurred over clumps of glomus cells, the principal chemoreceptor cell of the carotid body. Selective lesions of the sympathetic or afferent innervation of the carotid body had little effect on the density of receptor binding, demonstrating that the majority of AT1 receptors were intrinsic to the glomus cells. To determine the direct effect of angiotensin II on chemoreceptor function, without the confounding effects of the vasoconstrictor action of angiotensin II, carotid sinus nerve activity was recorded from the isolated carotid body in vitro. The carotid body was superfused with Tyrode solution saturated with carbogen (95 % O2, 5 % CO2), maintained at 36 °C, and multi‐unit nerve activity recorded with a suction electrode. Angiotensin II elicited a dose‐dependent excitation of carotid sinus nerve activity (maximum increase of 36 ± 11 % with 10 nM angiotensin II) with a threshold concentration of 1 nM. The response was blocked by the addition of an AT1 receptor antagonist, losartan (1 μM), but not by the addition of an AT2 receptor antagonist, PD123319 (1 μM). In approximately 50 % of experiments the excitation was preceded by an inhibition of activity (maximum decrease of 24 ± 8 % with 10 nM angiotensin II). This inhibitory response was markedly attenuated by losartan but not affected by PD123319. These observations demonstrate that angiotensin II, acting through AT1 receptors located on glomus cells in the carotid body, can directly alter carotid chemoreceptor afferent activity. This provides a means whereby humoral information about fluid and electrolyte homeostasis might influence control of cardiorespiratory function.

Chronic hypoxia upregulates the expression and function of AT(1) receptor in rat carotid body

“…In addition, it is known that AT 1 receptor may also express in the pre-synaptic terminals of sympathetic innervation (Castren et al 1987). Consistent with previous finding that sympathetic denervation does not change the Ang II binding in the carotid body (Allen 1998), our results also suggests the sympathetic AT 1 receptors if any would be in small amount in the carotid body. Glomus cells are believed to be the chemoreceptors and are the catecholamine-containing cells for the secretion of catecholamines during hypoxia (Fidone et al 1982).…”

“…Chronic hypoxia regulates the expression of RAS in a number of tissues, including the kidney (Neylon et al 1996), the lung (Zhao et al 1996), the heart (Morrell et al 1997) and the pancreas (Chan et al 2000). In the carotid body, Ang II-binding sites have been demonstrated by in vitro autoradiography (Allen 1998). The present study provides evidence for the gene expression of both AT 1 and AT 2 receptors in the carotid body during normoxic condition.…”

“…Interestingly, peripheral infusion of Ang II stimulates cardiorespiratory functions (Ohtake & Jennings et al 1993) and the plasma Ang II level increases during hypoxia (Zakheim et al 1976). Recently, Ang II has been demonstrated to increase the carotid body afferent activity, presumably via the mediation of the AT 1 receptor (Allen 1998). Thus activation of Ang II receptors in the carotid body may stimulate cardiorespiratory functions and play a role in the fluid and electrolyte homeostasis during hypoxia.…”

Carotid body function in heart failure

“…However, neither Ang II nor L158,809 had effects on baseline CB chemoreceptor activity in either sham or CHF rabbits . On the other hand, perfusion of the CB with Ang II at levels much higher than we observed in CHF animals (> 1 nM) induces excitation of rat CB chemoreceptor activity under normoxic conditions (Allen, 1998). Although it is possible that very high levels of Ang II may contribute to an elevated basal CB chemoreceptor activity in the normoxic state in CHF rabbits, it is likely that other mechanisms are responsible for this effect, such as a decrease in CB nitric oxide (NO) production, as discussed below.…”

“…Ang II enhances CB chemoreceptor activity via the AT 1 receptor (AT 1 R) in the CB (Allen, 1998). Furthermore, a locally generated Ang II system has been shown to be operational , and chronic hypoxia upregulates the expression of the AT 1 R in the rat CB (Fung et al 2002).…”