Participation of 5-HT and AT1 Receptors within the Rostral Ventrolateral Medulla in the Maintenance of Hypertension in the Goldblatt 1 Kidney-1 Clip Model
The hypothesis that changes in neurotransmission within the rostral ventrolateral medulla (RVLM) are important to maintain the high blood pressure (BP) was tested in Goldblatt one kidney-one clip hypertension model (1K-1C). Male Wistar rats were anesthetized (urethane 1.2？g/kg, i.v.), and the effects of bilateral microinjections into the RVLM of the following drugs were measured in 1K-1C or control groups: glutamate (0.1？mol/L, 100？nL) and its antagonist kynurenic acid (0.02？mol/L, 100？nL), the angiotensin AT1 receptor antagonist candesartan (0.01？mol/L, 100？nL), and the nonselective 5-HT receptor antagonist methiothepin (0.06？mol/L, 100？nL). Experiments in 1K-1C rats were performed 6 weeks after surgery. In anesthetized rats glutamate response was larger in hypertensive than in normotensive rats (H: ; N: ？mmHg). In contrast, kynurenic acid microinjection into the RVLM did not cause any change in BP in either group. The blockade of either AT1 or 5-HT receptors within the RVLM decreased BP only in 1K-1C rats. A largest depressor response was caused by 5-HT receptor blockade. The data suggest that 5-HT and AT1 receptors act tonically to drive RVLM in 1K-1C rats, and these actions within RVLM contribute to the pathogenesis of this model of hypertension. 1. Introduction The importance of sympathetic nervous system activation in the pathogenesis of hypertension has been demonstrated, and the therapeutic value of sympathetic nervous inhibition in hypertensive patients is already evident and has been widely studied [1]. Ongoing activity of premotor rostral ventrolateral medulla (RVLM) neurons is responsible for the tonic generation of sympathetic vasomotor tone; inhibition of RVLM neurons causes a large decrease in both arterial blood pressure (BP) and sympathetic nervous system activity, while stimulation of this medullary region increases sympathetic vasomotor outflow and BP [2, 3]. Therefore, changes in the local neurotransmission within the RVLM can be a mechanism involved in the sympathetic activation in hypertension. Previous studies demonstrated that microinjection into the RVLM of excitatory amino acid (EAA) receptor antagonists has no effect on basal level of BP [4]. This fact has been interpreted as suggesting that the ongoing RVLM activity is not dependent on EAA inputs to the RVLM. However, we showed previously that, in Goldblatt 2-kidneys, one-clip (2K1C) model, microinjection of kynurenic acid, a broad spectrum EAA receptor antagonist, into the RVLM, reduced BP to the same extent as autonomic blockade [5]. Similar results were later shown in SHR
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