NO and Vasodilation

NO is clearly the major endothelium-dependent vasodilator produced by large blood vessels (Figure 1). In the aorta or carotid arteries of mice deficient in eNOS (eNOS -/mice), endothelium-dependent vasodilation is eliminated, thus supporting eNOS derived NO as the source of the relaxing factor that led to the Nobel Prize-winning experiments by Furchgott, Murad, and Ignarro awarded in 1998. However, the vasodilatory roles for NO in arterioles and venules appear less unanimous, and the importance of NO as a vasodilatory agent (deciphered by the sensitivity of the response to blockage of NOS) depends on the stimulus

(flow, acetylcholine, bradykinin, and so on), the vascular bed studied (coronary, cremaster, gracilis, mesentery), the species (human, rat, mouse, hamster), and more recently, the number of endothelial-smooth muscle interconnections (i.e., myo-endothelial gaps). In eNOS (-/-) mice, the local vasodilatory actions of acetylcholine or flow induced changes in blood flow are not diminished, because of compensation by upregulation of nNOS, endothelium-derived hyperpolarizing factor (EDHF), and vasodilatory prostaglandins [1, 2]. However, the local vasodilatory action of histamine was absent from second order arterioles in eNOS (-/-) mice [3]. These are only a few of the many examples highlighting some of the differential response to NO as aforementioned. Another theory imparting NO as an important factor in microvascular blood flow control is the concept that NO bound to hemoglobin in red blood cells can serve as a stable NO adduct for delivery at sites of resistance. Clearly NO binds to the heme moiety of hemoglobin while a reactive thiol, cysteine b 93, and hemoglobin can undergo allosteric changes in structure initiated by a drop in arteriolar pO2, and release NO from these sites [4]. Although this principle can be demonstrated in model systems, the physiological role of NO via its release from hemoglobin in regulating blood flow in the microcirculation remains controversial [5]. An alternative, emerging theory of how the endothelium may control microvascular blood flow is through another endothelium-dependent vasodilator, EDHF. In systems where NOS is blocked or absent, EDHF may subserve a role as a key regulator of microvascular blood flow control.

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Essentials of Human Physiology

Essentials of Human Physiology

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