Endothelial cells release relaxing factors (EDRF), of which nitric oxide (NO) appears to be the most important. Endothelium-dependent relaxations are reduced in arteries from hypertensive animals. In the spontaneously hypertensive rat (SHR) this has been attributed to the production of a yet unidentified endothelium-derived contracting factor (EDCF). The proposed research will determine the interactions between EDRF and EDCF, and determine whether or not the latter is an endoperoxide. We will also try to define whether or not platelet-derived products or endothelins can be regarded as (patho) physiological stimuli for the release of EDCF. We will begin to explore the molecular biological aspects that underlie the production of EDCF. We will explore whether or not endothelium-dependent contractions are prominent in another model of genetic hypertension, the New Zealand genetic hypertensive rat. We will examine the likelihood that the occurrence of endothelium-dependent contractions reflects premature aging of the blood vessel wall exposed to chronic hypertension. We will determine whether or not the occurrence of endothelium-dependent contractions can be induced by the cytokine interleukin-2. We hope to demonstrate that EDCF contributes to the abnormal responsiveness of hypertensive blood vessels not only by evoking vasoconstriction but also by facilitating the growth of vascular smooth muscle. We will use established techniques to bioassay the release of contracting and relaxing factors and to monitor cellular growth. We will use conventional chemical methods (gas chromatography-mass spectrometry, colorimetry) and radioimmunoassays to define the nature and the actions of EDCF and vascular smooth muscle. We will introduce molecular biological techniques to determine the degree of expression and/or of activity of the enzymes that leads to the production of EDCF. These studies will give insight into the chronic role of factors released by the endothelium and vascular .smooth muscle in the pathophysiology of hypertension, and may help to explain the transition from the vasoconstrictor stage in early hypertension to the morphological adaptation that perpetuates the hypertensive process.
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