Effect of the Endothelium on the Response to Phorbol Ester in Smooth Muscle from Spontaneously Hypertensive Rats

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Problem: The phorbol ester-induced contractile response of blood vessels from spontaneously hypertensive rats (SHR) is greater than that from normotensive Wistar-Kyoto rats (WKY), which suggests that protein kinase C activity is abnormally high in vascular smooth muscle from SHR. However, the role of the overlying endothelium in these responses has not been tested. Hypothesis: The response of vascular smooth muscle to protein kinase C activation is influenced by the presence of the endothelium. Methods: We examined the isotonic contraction of aortic rings (with or without endothelium) from 12-14-week-old SHR and WKY in response to KCl, norepinephrine, and the phorbol ester PDBu (with and without staurosporine). We also tested these responses in the presence of L-NMMA. Results: PDBu (1nM-1 mM) dose-dependently increased contractile force, with an EC₅₀ of 100nM. Aortic rings from SHR were more sensitive than those from WKY at all doses tested. Removal of the endothelium abolished this difference: the sensitivity of aortic rings from WKY increased and the contractility of rings from SHR decreased. Preincubation with L-NMMA (10^-5M) for 20min also abolished the difference in contractile response in the same fashion. The response to norepinephrine was increased by L-NMMA in both SHR and WKY. Conclusions: The difference between SHR and WKY in phorbol ester-induced contraction of aortic rings is due to a difference in endothelial cell function, rather than to a difference in vascular smooth muscle. We suggest that PKC may mediate the release from endothelial cells of a vasodilator, which may be nitric oxide. This effect may be abnormally weak in the endothelium of SHR. (Hypertens Res 1994; 17: 193-197)