Role of nitric oxide and angiotensin II in the regulation of sympathetic nerve activity in spontaneously hypertensive rats.

Abstract

This study evaluated the actions of nitric oxide on the blood pressure and renal sympathetic nerve activity responses produced by angiotensin II (Ang II) blockade in conscious spontaneously hypertensive rats. Two days after implantation of electrodes, we measured mean arterial pressure, heart rate, and renal sympathetic nerve activity. Baroreceptor reflex function was assessed with a logistic function curve; the maximum slope of the curve estimated the baroreceptor reflex gain. Data were obtained in rats given acute intravenous administration of either vehicle, the Ang II type 1 receptor antagonist losartan, the type 2 antagonist CGP 42112A, or the converting enzyme inhibitor lislnopriL In comparison with vehicle (-l.l±02 %/rara Hg), both losartan (-1J$±O.3 %/mrn Hg) and lisinopril (-2.4±0.2 %/rara Hg) significantly increased the maximum gain of the baroreceptor reflex control of nerve activity (/><0.05). In contrast, the type 2 receptor antagonist did not alter baroreceptor reflex function. Similar studies were performed in rats that received an intravenous injection of A rG -monomethyl L-arginine (10 ing/kg). The nitric oxide synthase inhibitor increased baseline blood pressure and decreased renal sympathetic nerve activity. Subsequent administration of losartan or lisinopril returned blood pressure to initial hypertensive level, whereas sympathetic nerve activity was increased to a level above the initial control value. The maximum gain of the baroreceptor reflex control of renal nerve activity was increased after the nitric oxide inhibition. The present study demonstrates that blunted baroreceptor reflex function in conscious spontaneously hypertensive rats is mediated by an Ang II type 1 receptor. Moreover, nitric oxide may play a dual role in the antihypertensive effect of Ang II blockade. 1 In conscious rabbits with Ang II-dependent hypertension, the Ang II receptor antagonist [Sar 1 , Ala^Ang II not only reversed the high blood pressure but increased the maximum gain of the baroreceptor reflex control of renal sympathetic nerve activity (RSNA).3 These data support the hypothesis that the antihypertensive effects of angiotensin converting enzyme (ACE) inhibitors are in part due to a centrally mediated decrease in sympathetic outflow.Because there are no in vivo studies on the Ang II receptor subtype that is functionally involved in the baroreceptor reflex, we compared the effects of angiotensin type 1 (AT^ and type 2 (AT 2 ) receptor antagonists on the baroreceptor reflex control of RSNA and heart rate (HR) in conscious spontaneously hypertensive rats (SHRs). We contrasted the effects of these two Ang II receptor antagonists with results obtained in rats treated with the ACE inhibitor lisinopril to assess the role of the renin-angiotensin system in the actions of lisinopril. Recent data have demonstrated that the antihypertensive effects of both an ATj receptor antagonist and an ACE inhibitor are in part mediated by release of endothelium-derived nitric oxide (NO).4 -3 Moreover, Lewis et al 67 found that ...

Involvement of nitric oxide, but not prostaglandins, in the vascular sympathoinhibitory effects of losartan in the pithed spontaneously hypertensive rat

“…Our results demonstrate that the cyclo-oxygenase inhibitor, diclofenac (a) had no effect on the basal values of blood pressure and regional vascular resistances, and (b) (Tesfeimariam et al, 1987;1989;Sakuma et al, 1992;Vo et al, 1992;Toda et al, 1993;MacLean et al, 1994), and conversely NO synthase inhibition has been shown to increase sympathetic nerve activity (Sakuma et al, 1992;Harada et al, 1993;Kumagai et al, 1993;Toda et al, 1993;Zanzinger et al, 1994). The mechanisms by which NO appears to interact with the sympathetic nervous system comprise a reduction of the central sympathetic tone (decrease in peripheral sympathetic nerve activity) and an inhibition of its peripheral vasoconstrictor effects.…”

“…It appears from our study that losartan decreases blood pressure and regional vascular resistances in the pithed SHR which indicates either that AII contributes to the vascular tone in this preparation, or that losartan administration results in the release of vasodilator agents, among which NO (Cachofeiro et al, 1992; Kumagai et al, 1993;Sudhir et al, 1993) and PGs (Jaiswal et al, 1991;Catalioto et al, 1994) have previously been proposed as candidates. Our results also show that losartan significantly reduces or even abolishes the systemic pressor and renal and muscular vasoconstrictor responses elicited by electrical stimulation of the spinal cord but does not affect the simultaneously induced tachycardia, thus confirming the vascular selective sympathoinhibitory effects of the drug (Moreau et al, 1993).…”

“…Recently, nitric oxide (NO) has been reported to be involved in the vasodilator and antihypertensive effects of losartan in different experimental models (Cachofeiro et al, 1992; Kumagai et al, 1993;Pollock et al, 1993;Sudhir et al, 1993) and to modulate sympathetic neurotransmission (Zanzinger et al, 1994). Moreover, in porcine cultured endothelial vascular smooth muscle cells (Jaiswal et al, 1991) and in rabbit vas deferens tissue (Catalioto et al, 1994), losartan has been reported to increase vasodilator prostaglandin (PGs) synthesis and/or release.…”

Nitric oxide and hypertension: not just an endothelium derived relaxing factor!

“…Pretreatment with L-arginine prevented the late increase in RSNA suggesting that the potentiating effects of L-NMMA on sympathetic activity were due specifically to inhibition of NO synthesis. Other investigators have also shown increases in renal 45 and cardiac sympathetic nerve activity 46 during systemic NOS inhibition when baroreflex activation was prevented. Conversely, in baroreceptor intact rabbits, stimulation of NO synthesis with intravenous L-arginine caused a decrease in cervical sympathetic nerve activity and RSNA despite a fall in blood pressure.…”

“…Some studies have suggested that NO inhibits baroreceptor-RSNA gain, as evidenced by an increase in reflex gain during acute systemic NOS inhibition. 45,49,61 However, a number of studies have failed to show any influence of NO on the reflex control of sympathetic activity. 47,62 This inconsistency is only partially explained by species differences or the effect of anaesthetics.…”