Impaired Relaxation of Arterioles to Vasodilator Stimuli

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In addition to an enhanced response to vasoconstrictor stimuli, arterioles of hypertensive animals exhibit an impaired relaxation in response to a variety of vasodilator stimuli including hypoxia, shear stress, and endothelium-dependent vasodilators, such as acetylcholine (ACh). Impaired relaxation of arterioles to endothelium-dependent vasodilator stimuli such as ACh has also been demonstrated in human hypertensive patients. The impaired vascular relaxation in hypertensive individuals has been proposed to be due to a reduced production of endothelium-derived vasodilator compounds, such as nitric oxide (NO) or vasodilator prostaglandins, and/or to an enhanced release of vasoconstrictor factors (e.g., thromboxane or prostaglandin H2) from the endothelium. The reduction in endothelium-dependent dilation mediated by NO also may result from increased levels of oxidative stress in the tissue, which would destroy NO and reduce its availability for mediating vascular relaxation. There is also evidence that fundamental alterations in receptor-heterotrimeric G protein coupling may contribute to impaired vasodilator responses in hypertensive animals and in normotensive animals on a high-salt diet. In the latter case, arterioles and resistance arteries of hypertensive animals and normotensive animals on high-salt diet not only exhibit impaired relaxation in response to vasoactive agonists acting through the cyclic AMP pathway of vascular relaxation, but also fail to respond to direct activation of the alpha subunit of the Gs protein with cholera toxin. Taken together, these observations suggest that hypertension and high salt diet may both be associated with fundamental alterations of signaling pathways in the vascular smooth muscle cells.

Nitric oxide-dependent relaxation and prostaglandin-mediated vasodilation are both impaired in skeletal muscle arterioles of spontaneously hypertensive rats. This appears to be due to an impaired synthesis and/or action of nitric oxide (including reduced bioavailability of NO due to increased oxidative stress) and alterations in the metabolism of arachidonic acid to favor an enhanced production of the vasoconstrictor metabolite PGH2 and a reduced production of vasodilator prostaglandins in the arterioles. Findings such as these suggest that a simultaneous dysfunction of these two major endothelium-dependent vasodilator pathways could make a significant contribution to the elevated vascular resistance in hypertension. Agonists such as norepineph-rine and acetylcholine also cause an increased release of the endothelium-dependent vasoconstrictors thromboxane A2 and/or PGH2 in arterioles and resistance arteries of hypertensive rats, leading to a reduced sensitivity to acetylcholine and to an enhanced vasoconstrictor response to norepinephrine.

As noted earlier, arteriolar dilation in response to the physiological stimulus of increased flow or shear stress is also impaired in arterioles of hypertensive rats. The impaired relaxation of arterioles of spontaneously hypertensive rats in response to increased flow and shear stress appears to be due to an impairment of the NO-mediated portion of flow-dependent dilation, but may also involve an enhanced release of endothelium-derived vasoconstrictor factors such as PGH2. Current evidence suggests that augmented hemodynamic forces in the microcirculation can alter the shear stress-induced synthesis of prostaglandins and other vasoactive factors in hypertension, possibly contributing to the elevated vascular resistance in this disease.

It has been proposed that the elevated hemodynamic forces present in hypertension may initiate alterations of signaling pathways in the endothelium and smooth muscle cells of arterioles that could, in turn, enhance the release of reactive oxygen species such as superoxide. Any reduction in the availability of NO due to increased levels of superoxide released by high pressure in the arterioles (or in response to other pathophysiological alterations in hypertension) would likely cause an impaired dilation of arterioles in response to shear stress- and other NO-dependent vasodilator stimuli, leading to the maintained elevation of wall shear stress and peripheral vascular resistance that exists in hypertension. It has also been proposed that alterations in the mechanisms of functional vascular control in hypertension may eventually lead to the development of irreversible structural changes in the microcirculation. The latter hypothesis is consistent with the increasing body of evidence that elevated levels of reactive oxygen metabolites may contribute to the vascular dysfunction commonly observed in hypertension.

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