PubMed · 10716486
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W W Parmley. 2000-03-01. Pharmacy madness.. https://doi.org/10.1016/s0735-1097(00)00529-5
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Although the angiotensin-converting enzyme (ACE) inhibitor-induced bradykinin enhances nitric oxide (NO) release, bradykinin may also stimulate the production of an additional vasodilator, endothelium-derived hyperpolarizing factor (EDHF). This study examined the role of EDHF in mediating the NO-independent action of ACE inhibitors in canine renal microcirculation in vivo. We used intravital CCD camera videomicroscopy that allowed direct visualization of renal microcirculation in superficial and juxtamedullary nephrons in an in vivo, in situ, and relatively intact setting. In the presence of E4177 (an angiotensin receptor blocker), cilazaprilat (30 microg/kg) had no effect on diameter of superficial afferent arterioles (Aff), but it increased renal contents of bradykinin and nitrate plus nitrite, and it elicited dilation of juxtamedullary Aff (from 24.0+/-0.2 to 28.2+/-0.8 microm), juxtamedullary efferent arterioles (Eff) (from 24.2+/-0.2 to 28.0+/-0.8 microm), and superficial Eff (from 18.2+/-0.2 to 19.7+/-0.2 microm). These changes in diameters were prevented by N(alpha)-adamantaneacetyl-d-Arg-[Hyp(3),Thi(5,8),D-Phe(7)]bradykinin, a bradykinin receptor antagonist. The pretreatment with nitro-l-arginine methylester (l-NAME) plus E4177 eliminated the dilator response of juxtamedullary/superficial Eff and the increase in renal nitrate plus nitrite levels induced by cilazaprilat. In contrast, in the presence of E4177+l-NAME, cilazaprilat still caused 8%+/-3% dilation of juxtamedullary Aff, which was completely eliminated by proadifen, a cytochrome-P450 and K(Ca) channel blocker. Collectively, the ACE inhibitor exerts multiple vasodilator mechanisms, including the inhibition of angiotensin II formation; blockade of angiotensin II activity appears to be a dominant mechanism in superficial Aff, whereas the bradykinin-induced NO acts on superficial Eff and juxtamedullary Aff/Eff. Furthermore, a putative EDHF is an additional mechanism for the ACE inhibitor-induced vasodilation of juxtamedullary Aff in vivo.
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The possible importance of intra-individual variations in respiratory rate and tidal volume has recently gained interest in psychiatric research, as a result of the observations that patients with panic disorder or premenstrual dysphoric disorder display enhanced respiratory variability as compared to controls. Although the role of brain neurotransmitters in the regulation of breathing has been extensively studied, as yet data on the central regulation of respiratory variability is sparse. Prompted by previous studies indicating that angiotensin II (ANG II) may influence ventilation as well as anxiety, we have studied the effect of intracerebroventricular administration of an ANG II receptor antagonist, saralasin, on respiratory variability in unrestrained, freely moving male Wistar rats. Treatment with saralasin, 5 mug dissolved in 1 mul saline followed by 9 mul saline in each lateral cerebral ventricle, did not influence tidal volume, but markedly reduced tidal volume variability (p=0.0005), as compared to saline injections (10 mul). Respiratory rate was reduced by saralasin (p=0.02), and there was also a non-significant tendency for a reduction in respiratory rate variability. Both minute volume (p=0.005) and volume/10 s variability (p=0.0006) were reduced. It is suggested that ANG II in the brain of Wistar rats may regulate respiratory rate and tidal volume variability.