Interactions between angiotensin II, sympathetic nerve‐mediated pressor response and cyclo‐oxygenase products in the pithed rat

1 The aim of this study was to investigate whether nitric oxide (NO) and/or vasodilator prostaglandins (PGs) are involved in the sympathoinhibitory effects exerted by losartan versus the vascular responses elicited by spinal cord electrical stimulation (SCS) in pithed spontaneously hypertensive rats (SHRs).2 SHRs were given orally and for 8 days either losartan (10 mg kg-' daily) or distilled water (controls).After pithing, blood pressure, heart rate, cardiac output, renal and muscular blood flows (pulsed Doppler technique) and the corresponding vascular resistance values were measured or calculated at baseline. Then, animals from both groups were given i.v. either saline, or NG-nitro-L-arginine methyl ester (L-NAME, 1 mg kg-1), or diclofenac (4 mg kg-'). Thereafter, haemodynamic parameters were determined in the six subgroups of animals in response (a) to SCS at increasing frequencies, and (b) to a noradrenaline bolus injection. 3 Losartan significantly decreased mean arterial pressure as well as renal and total peripheral resistances. In addition, losartan exhibited strong vascular sympathoinhibitory effects, significantly decreasing the systemic pressor and regional vasoconstrictor responses to SCS, but did not affect those to exogenous noradrenaline. In contrast, SCS-induced tachycardia was not modified by losartan. 4 L-NAME significantly increased total peripheral and regional vascular resistances but did not affect blood pressure and heart rate basal values. L-NAME potentiated the haemodynamic responses to SCS in control and, to a larger extent, in losartan-treated SHRs so that, with the exception of the renal vascular bed, the sympathoinhibitory effects of losartan were attenuated in all vascular beds studied. L-Arginine (300 mg kg-1) caused reversal of L-NAME effects in both control and losartan-treated SHRs. 5 Diclofenac did not affect the basal values of haemodynamic parameters in control and losartantreated SHRs. Diclofenac potentiated the pressor and vasoconstrictor responses to SCS and to a similar extent, in both control and losartan-treated SHRs, so that the sympathoinhibitory effects of losartan were fully maintained. 6 These results demonstrate that in pithed SHRs: (a) NO but not PGs contribute to the basal vasomotor tone, (b) both NO and PGs attenuate the pressor and vasoconstrictor responses to SCS, (c) NO plays a major role in the vascular sympathoinhibitory effects of losartan, except at the renal level, and (d) endogenous PGs are not involved in these sympathoinhibitory effects.

Section: Introductionmentioning

confidence: 71%

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

Richer

Domergue

Vincent

et al. 1996

“…In fact, manipulation of the isolated preparations in such a manner achieves conditions similar to that observed in the pithed rat, in which vascular tone is maintained by high levels of circulating angiotensin II (Grant & McGrath, 1988), and in human platelets, where pro-aggregatory responses to some 'selective' C2-adrenoceptor agonists are dependent upon an existing aggregatory response to a submaximal concentration of ADP (Clare et al, 1984). The obligatory role of pre-existing 'tone' for a2-adrenoceptor-mediated responses (prazosin-resistant, rauwolscine-sensitive) is highlighted by many accounts of susceptibility of these responses to physiological and non-receptor pharmacological antagonism (see Reid & McGrath, 1985).…”

Section: Identification Offunctional Postjunctional A2-adrenoceptors mentioning

confidence: 83%

Evidence for prazosin‐resistant, rauwolscine‐sensitive α‐adrenoceptors mediating contractions in the isolated vascular bed of the rat tail

Templeton

Macmillan

McGrath

et al. 1989

Self Cite

1 The postjunctional x-adrenoceptors mediating contractions in the isolated vascular bed of the perfused rat tail have been investigated, in the presence and absence of an increase in perfusion pressure by arginine vasopressin (AVP). 2 In the absence of AVP, bolus doses of noradrenaline (NA) and phenylephrine produced pressor responses of similar time course, while UK-14,304 was practically inactive. Responses to noradrenaline were inhibited more by 0.05 yM prazosin than by 1 yM rauwolscine, suggesting the presence of ax-adrenoceptors.3 Following a sustained elevation in perfusion pressure by AVP, both UK-14,304 and NA (the latter in the presence of 0.05pM prazosin to inhibit a1-adrenoceptors) elicited dose-dependent pressor responses. The maximum response to UK-14,304 under these conditions was approximately 30% of the maximum response to NA in the absence of prazosin and AVP. Responses to phenylephrine were not affected by the AVP-induced increase in vascular tone. 4 In the presence of AVP, pressor responses to UK-14,304 were resistant to 0.05pM prazosin and susceptible to antagonism by 1 yM rauwolscine (-log Kb 7.65 + 0.15). Similarly, responses to NA in the presence of 0.05 pM prazosin and AVP were inhibited by 1 ,M rauwolscine. This represents the first demonstration of prazosin-resistant, rauwolscine-sensitive a2-adrenoceptor-mediated responses in the vasculature of the rat tail. 5These results suggest that in isolated vascular preparations, functional populations of postjunctional LX2-adrenoceptors may be 'uncovexed' by the presence of AVP.

“…However, we could not reach the maximum effects with these agonists, as higher doses, particularly of 5-CT, produced a marked hypotension (not shown), which is mediated by postjunctional 5-HT1-like receptors (Saxena & Villalon 1990a). In addition to recognizing the possible interference by pharmacokinetic factors in our experimental model, it is noteworthy that a fall in diastolic blood pressure of 10 mmHg evoked by an infusion of nitroprusside (which acts directly on vascular smooth muscle to cause relaxation independently of 5-HT receptors), inhibits the sympathetically-induced pressor responses per se (Grant & McGrath, 1988).…”

Section: Above)mentioning

confidence: 99%

Characterization of prejunctional 5‐HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat

Villalón

Contreras

Juan³

et al. 1995

1 It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-Tg) sympathetic stimulation in pithed rats pretreated with desipramine (50 mg kg- ', i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-1 Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 pg kg-' min-'). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2 The inhibition induced by 5.6 Mg kg-' min-' of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-'), ritanserin (0.1 mg kg-'), MDL 72222 (0.15 mg kg-') or tropisetron (3 mg kg-'), which did not modify the sympatheticallyinduced pressor responses per se, but was significantly antagonized by the 5-HTI-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3 Unexpectedly and contrasting with methysergide, the 5-HT,-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-') and metergoline (1 and 3 mg kg-'), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular a,-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HTI-like receptors. 4 Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HTI-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > methysergide. 5 Taken together, the above results suggest that the inhibitory action of 5-HT on the electricallyinduced pressor responses is primarily mediated by an action on inhibitory prejunctional 5-HTI-like receptors leading to a decrease in the sympathetic nerve discharge. Interestingly, 5-HT-induced excitatory mechanisms could be made manifest once the inhibitory action of 5-HT had been antagonized.