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      Evidence for the Involvement of Protein Kinase C in Depression of Endothelium-Dependent Vascular Responses in Spontaneously Hypertensive Rats


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          The goal of the present study was to evaluate the role of protein kinase C (PKC) in the depression of endothelium-dependent vacular response in spontaneously hypertensive Okamoto rats (SHR). Aortae from SHR demonstrated a decreased relaxant response to acetylcholine (Ach) as compared to aortae from normotensive Wistar-Kyoto (WKY) rats, while papaverine lowered the force of aorta to a similar degree in both strains of rats. PKC inhibitors, H-7 (5 × 10<sup>–6</sup> M) and chelerythrine chloride (10<sup>–6</sup> M), produced a greater decrease in the force developed by the aortae from SHR vs. WKY rats both in intact and chemically permeabilized tissues. In SHR aortae PKC inhibitors enhanced relaxation to Ach to a greater extent as compared to WKY aortae. Furthermore, in the presence of PKC inhibitors, the constrictor responses of SHR aortae to Ach were transformed into relaxant responses, and the concentration-response curve to Ach was shifted to the left. The sensitivity of aortae from SHR to authentic nitric oxide (NO) was lowere compared to WKY rats. EC<sub>50</sub>s for authentic NO in SHR and WKY rat aortae were different: –2.9 ± 0.15 × 10<sup>–6</sup>  M and 4.58 ± 0.1 × 10<sup>–7</sup>  M (n = 15, p < 0.001), respectively. Bioassay experiments using SHR aortae showed that the addition of chelerythrine (10<sup>–6</sup>  M) to the detector superfusate caused relaxation during treatment of the donor segment with Ach, indicating that the sensitivity of the aortae to NO had been restored. When SHR detector ring was substituted for denuded aortae from WKY rats and PKC inhibitors were not added to the detector superfusate, the relaxation of the detector aortae was also close to the normal Ach-induced relaxation. WKY aortae demonstrated a positive relationship between Ach-stimulated NO release and relaxant response amplitudes (correlation coefficient r = 0.905, p < 0.001, n = 10). In contrast, there was a significant negative correlation in SHR aortae (r = –0.712, p < 0.05, n = 10). Detection of NO release by chemiluminescence showed no significant difference in NO release in SHR and WKY aortae. Taken together, these data suggest that the blunted endothelium-dependent relaxations seen in SHR aortae are mainly due to a decreased sensitivity of vascular smooth muscle to EDRF/NO resulting from an increased PKC activity.

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          The phosphatidylcholine pathway of diacylglycerol formation stimulated by phorbol diesters occurs via phospholipase D activation.

          Agonist-induced degradation of phosphatidylcholine (PC) is of interest as this pathway of diacylglycerol (DG) generation may provide added opportunities for the regulation of protein kinase C (PKC). In REF52 cells [3H]myristic acid is preferentially incorporated into PC; this, coupled with the use of [3H]choline, allows for quantitation of both the water-soluble and the lipid products generated when PC is degraded. In cells prelabeled with [3H]choline, TPA stimulated a time-dependent release, into the medium, of choline and not phosphocholine or glycerophosphocholine. Treatment of [3H]myristic acid-labeled cells with either phorbol diesters, sn-1,2-dioctanoylglycerol, or vasopressin elicited the formation of labeled phosphatidate (PA) and DG. The temporal pattern of PC hydrolysis in cells treated with TPA is indicative of a precursor (PA)-product (DG) relationship for an enzymatic sequence initiated by phospholipase D. Adding propranolol, a phosphatidate phosphohydrolase inhibitor, eliminated TPA-induced DG formation, whereas PA generation was unaffected. From these data we conclude that TPA elicits DG formation from PC by the sequential actions of phospholipase D and phosphatidate phosphohydrolase.

            Author and article information

            J Vasc Res
            Journal of Vascular Research
            S. Karger AG
            October 1998
            28 October 1998
            : 35
            : 5
            : 325-331
            Institute of Pharmacology and Toxicology, Academy of Medical Sciences, Kiev, Ukraine
            25602 J Vasc Res 1998;35:325–331
            © 1998 S. Karger AG, Basel

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            Page count
            Figures: 5, References: 23, Pages: 7
            Research Paper

            General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
            PKC activity,Smooth muscle,Hypertension,NO release,Sensitivity to NO


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