The hypothesis of the present research plan is that impairment of the endothelium of arterioles results in an increase in vascular tone in hypertension. Impairment of the endothelium not only increases basal tone of arterioles but also eliminates flow velocity-elicited arteriolar dilation leaving constrictor mechanisms (myogenic, neurogenic etc.) unopposed. Previous studies from our laboratory demonstrated an essential role for endothelium, via EDRF and prostaglandin release, in the regulation of arterioles.
The aim of the present study is to correlate the changes in the function of arteriolar endothelium with the development of hypertension is SH, DOCA and 2K-1C hypertensive rats. The arteriolar tone-regulatory function of the endothelium will be assessed by the study of arteriolar responses to agents that exert their effect via the endothelium (acetylcholine, arachidonic acid) or act directly on arteriolar smooth muscle (sodium nitroprusside, prostaglandin E2, adenosine, papaverine) and by utilizing specific inhibitors of the synthesis of endothelial mediators. The possibility of decreased reactivity to the above vasodilator agents or the enhanced reactivity of arteriolar smooth muscle to vasoconstrictor agents (norepinephrine, endothelin, angiotensin) or increased production of vasoconstrictor agents will also be examined. Flow velocity (shear stress)-sensitive and reactive hyperemic responses will be utilized to assess the changes in the capacity of arteriolar endothelium to response to hemodynamic stimuli and to regulate vascular smooth muscle tone in various physiological conditions as hypertension develops. These studies are to be performed in vivo, in third, second and first order arterioles of the rate cremaster muscle microcirculation. Arteriolar diameters and arteriolar blood flow velocity will be measured with television microscopy, and wall shear rate and blood flow will be calculated. These studies will provide information concerning what type of changes occur in the vasodilator function of arteriolar endothelium with hypertension and whether they precede or are the result of the elevation of blood pressure. The information obtained will facilitate a better understanding of the pathogenetic mechanisms leading to and associated with hypertension and may promote the development of more effective treatment and prevention of this disorder.
| Rutkai, Ibolya; Feher, Attila; Erdei, Nora et al. (2009) Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes. Cardiovasc Res 83:148-54 |
