Phillip W. Yates

Rostral ventrolateral medulla as a site for the central hypertensive action of kinins.

In the present study, we focused on the rostral ventrolateral medulla as a possible site of action for kinins because of its established importance in the central regulation of the cardiovascular system. Unilateral microinjections of 100 pmol to 4 nmol bradykinin into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure in Sprague-Dawley (SD) rats, Wistar-Kyoto (WKY) rats, and spontaneously hypertensive rats (SHR). The dose-response curves for the hypertensive responses to bradykinin in SD and WKY rats were essentially the same, whereas the hypertensive effect of bradykinin was significantly greater in SHR than in either SD or WKY rats. The kinin B2 receptor antagonists D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin and Hoe 140 inhibited the hypertensive responses to bradykinin in both SHR and WKY rats. The hypertensive effect of 500 pmol bradykinin was reduced 65 +/- 5% after 4 nmol of D-Arg0, Hyp3,Thi5,8,D-Phe7-bradykinin in SHR and 50 +/- 16% in WKY rats, whereas 1 nmol Hoe 140 abolished the hypertensive effect of 500 pmol bradykinin injected into the rostral ventrolateral medulla. Microinjection of D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin produced prolonged dose-dependent decreases in mean arterial pressure and heart rate. Blood pressure decreased 70 +/- 8 mm Hg and heart rate decreased 49 +/- 9 beats per minute in SHR, whereas in WKY rats mean arterial pressure decreased 12 +/- 4 mm Hg, with no change in heart rate. In a similar fashion, Hoe 140 caused a 51 +/- 7 and 17 +/- 3 mm Hg reduction in blood pressure in SHR and WKY rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation preserves retinal ganglion cell structure and function in a chronic model of ocular hypertension.

PURPOSE The current studies investigate if the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can limit retinal ganglion cell (RGC) degeneration in an ocular-hypertensive rat model. METHODS Intraocular pressure (IOP) was elevated unilaterally in Brown Norway rats by hypertonic saline injection. Rats received either vehicle or VPA (100 mg/kg) treatment for 28 days. Retinal ganglion cell function and number were assessed by pattern electroretinogram (pERG) and retrograde FluoroGold labeling. Western blotting and a fluorescence assay were used for determination of histone H3 acetylation and HDAC activity, respectively, at 3-day, 1-week, and 2-week time points. RESULTS Hypertonic saline injections increased IOPs by 7 to 14 mm Hg. In vehicle-treated animals, ocular hypertension resulted in a 29.1% and 39.4% decrease in pERG amplitudes at 2 and 4 weeks, respectively, and a 42.9% decrease in mean RGC density at 4 weeks. In comparison, VPA treatment yielded significant amplitude preservation at 2 and 4 weeks and showed significant RGC density preservation at 4 weeks. No significant difference in RGC densities or IOPs was measured between control eyes of vehicle- and VPA-treated rats. In ocular-hypertensive eyes, class I HDAC activity was significantly elevated within 1 week (13.3 ± 2.2%) and histone H3 acetylation was significantly reduced within 2 weeks following the induction of ocular hypertension. CONCLUSIONS Increase in HDAC activity is a relatively early retinal event induced by elevated IOP, and suppressing HDAC activity can protect RGCs from ocular-hypertensive stress. Together these data provide a basis for developing HDAC inhibitors for the treatment of optic neuropathies.

Latanoprost-Induced Changes in Rat Intraocular Pressure : Direct or Indirect?

INTRODUCTION The topical application of prostaglandin F(2 ) (FP)-receptor agonists has been shown to significantly lower intraocular pressure (IOP) in humans and is now considered the first-line treatment for ocular hypertension. Despite the prominent role FP-receptor agonists play in the treatment of glaucoma, our understanding of how these agents lower IOP remains incomplete. The present study was designed to evaluate the role of matrix metalloproteinase (MMP) activation and the cytokine, tumor necrosis factor alpha (TNF-alpha), in latanoprost-induced changes in IOP. METHODS Changes in IOP following an acute topical administration of latanoprost (60 ng) in normotensive Brown Norway rats were evaluated by means of a commercially available rebound tonometer. To examine the role of MMPs and TNF-alpha in this response, the rats were pretreated with a broad-spectrum MMP inhibitor, GM-6001 (100 microg), or the TNF-alpha inhibitor, thalidomide (25 microg). RESULTS The topical administration of latanoprost (60 ng) alone produced a biphasic change in ipsilateral IOP: an initial hypertension (4.21 +/- 0.52), followed by a prolonged hypotension (-4.79 +/- 0.65). In rats, pretreatment with GM-6001 blocked the latanoprost-induced reduction in IOP but did not prevent the initial rise in IOP. Pretreatment with thalidomide also blocked the ocular hypotension induced by latanoprost; however, thalidomide pretreatment enhanced the duration of the initial hypertension. CONCLUSIONS These results provide evidence that the secretion and activation of MMPs and the release of TNF-alpha play a central role in the ocular hypotension induced by FP-agonists. The administration of FP-agonists appears to lower IOP directly by inducing the activation of MMPs within the ciliary body, leading to improved uveoscleral outflow and indirectly through the release of TNF within the ciliary body. Secreted TNF-alpha may then activate TNF-receptors in the uvea and trabecular meshwork, increasing both uveoscleral and conventional outflow.

Autoradiographic localization of [125I-Tyr0]bradykinin binding sites in brains of Wistar-Kyoto and spontaneously hypertensive rats.

Abstract1. The present study was undertaken to localize and characterize bradykinin (BK) binding sites in brains from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR).2. Serial sections of brains were cut from adult WKY and SHR and specific [125I-Tyr0]bradykinin ([125I-Tyr0]BK) binding was determined using in vitro quantitative receptor autoradiographic techniques.3. Specific binding of [125I Tyr0]BK was localized in the medulla oblongata to the regions of the nucleus of the solitary tract (NTS), area postrema (AP), dorsal motor nucleus of the vagus (X), and caudal subnucleus of the spinal trigeminal nucleus in both strains of rat. The specific binding (85–90% of total binding) was of high affinity and saturable with KD values in the range of 100 pM and a Bmax of 0.75 fmol per mg tissue equivalent in the NTS–X–AP complex of both the WKY and SHR. In competition studies, the rank order of potencies was similar in both strains with BK = Lys-BK > icatibant >>> DesArg9-BK. The B2 receptor antagonist icatibant inhibited [125I-Tyr0]BK binding with a Ki value of 0.63 ± 0.19 nM in WKY and 0.91 ± 0.73 nM in SHR, while Ki values for the B> 1 receptor agonist DesArg9-BK were 1475 ± 1055 and 806 ± 362 nM in WKY and SHR, respectively.4. Our finding of specific high-affinity [125I-Tyr0]BK B2 binding sites in the NTS, AP, and the X of WKY and SHR is important because these brain areas are associated with central cardiovascular regulation. However, alterations in BK B2 receptors in the medulla that could contribute to the hypertensive state in the SHR were not detected.

Hypertensive effect of tissue kallikrein in rostral ventrolateral medulla is mediated by brain kinins

Microinjections of kallikrein, 0.5-2.0 units, in the rostral ventrolateral medulla (RVLM) of brain increased arterial pressure in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). This effect was significantly greater in SHR. The kinin B2 receptor antagonist icatibant (Hoe 140) blocked the hypertensive responses to kallikrein in both groups and caused greater hypotension and bradycardia in SHR. These results suggest that local kinins in the RVLM act to alter cardiovascular function and may be involved in the maintenance of blood pressure in the SHR.