form angiotensin I By action of the angiotensin converting enzyme, which is predominantly expressed on the surface of endothelial cells in the pulmonary circulation, angiotensin I is converted to angiotensin II Angiotensin II is a potent vasoconstrictor and acts directly by stimulating the angiotensin II type I (AT1) receptor and indirectly by increasing sympathetic tone and the release of vasopressin A local paracrine renin-angiotensin system also exists in the vasculature.88,89 Vascular production of angiotensin II has been shown to be mediated by the endothelium.90 The tissue renin-angiotensin system has dual effects on vessel function, being mediated through opposing effects of two receptors Stimulation of AT1 receptor causes contraction of vascular smooth muscle by directly increasing intracellular calcium and indirectly stimulating synthesis of endothelin-1 and other vasoconstrictors.91 Furthermore, promotion of oxidative stress via the AT1 receptor may possibly reduce nitric oxide bioavailability.92,93 On the other hand, stimulation of angiotensin II type 2 receptor appears to mediate vasodilation by activating the nitric oxide pathway.94 The local tissue angiotensin II hence also plays an important role in maintaining vascular homeostasis Other biologically active aminopeptides of the circulating renin-angiotensin system, such as angiotensins III and IV, may act in the central nervous system to raise blood pressure through the AT1 receptor.95 Three peptides of the natriuretic peptide family—atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide—also participate in the control of circulation Atrial natriuretic peptide is primarily produced by the atrial myocardium, while brain natriuretic peptide is synthesized by the ventricular myocardium The main stimulus for their release is stretching of the myocardium Other stimuli include endogenous vasoactive factors, neurotransmitters, proinflammatory cytokines, and hormones.96,97 Atrial and brain natriuretic peptides reduce sympathetic tone through suppression of sympathetic outflow from the central nervous system, reduction of release of catecholamines from autonomic nerve endings, and probably damping of baroreceptors.98,99 The consequence is decrease in vascular tone and increase in venous capacitance Both of these peptides also inhibit the activities of the reninangiotensin system, endothelins, cytokines, and vasopressin.96,100,101 The renal hemodynamic effects include the induction of diuresis secondary to increased glomerular filtration due to vasodilation of afferent renal arterioles and vasoconstriction of the efferent arterioles102 and the promotion of natriuresis Despite preload reduction, reflex tachycardia is suppressed as these peptides lower the activation threshold of vagal afferents C-type natriuretic peptide is a more potent dilator of veins than the other natriuretic peptides and acts in an autocrine or paracrine fashion Adrenomedullin was first isolated from human pheochromocytoma cells.103 It is produced in a wide range of cells, including vascular endothelial and smooth muscle cells,104,105 and plays a significant role in the control of circulation.106,107 Infusion of adrenomedullin via the brachial artery in humans induces dosedependent vasodilation to increase blood flow.108 Furthermore, blockade of the vasodilating effect of adrenomedullin by inhibition of nitric oxide synthase suggests that nitric oxide may be an important mediator for adrenomedullin.109–111 The endothelium-derived vasoactive substances and their role in the control of vascular tone and homeostasis have already been discussed The three classes of eicosanoids, prostaglandins, thromboxanes, and leukotrienes are generated by metabolism of arachidonic acid present in the phospholipids of cell membranes Endothelial cells produce predominantly prostacyclin and lesser amounts of prostaglandin E1, also a vasodilator, and prostaglandin F2α, a vasoconstrictor.112 Nonetheless prostacyclin appears to have a limited role in humans in the control of basal vascular tone Thromboxane A2, although predominately generated by platelets, is also synthesized by the endothelium113 and induces vasoconstriction and platelet aggregation Under normal physiologic conditions, eicosanoids— primarily prostacyclin, produced by the cyclooxygenase pathway—induce vasorelaxation.114 Furthermore, the cyclooxygenase-dependent vasodilators can compensate for the deficiency of other vasorelaxants.115 By way of the lipoxygenase pathway, leukotrienes are produced from arachidonic acid Leukotrienes C4, D4, and E4 cause arteriolar constriction, whereas leukotrienes B4 and C4 induce pulmonary vasoconstriction by activating cyclooxygenase to produce thromboxane A2.112 Several other endogenous substances affect the systemic circulation Vasopressin, produced in the supraoptic and paraventricular nuclei of the hypothalamus, is probably the most potent known endogenous constrictor It is released in quantities sufficient to exert a pressor effect when volume depletion is significant but has little role in normal vascular control.116,117 Serotonin exists in large amounts in the enterochromaffin cells of the gastrointestinal tract Although serotonin exerts vasoconstrictor and vasodilator effects, depending on the vasculature, its function in regulating the circulation is unknown Kinins are among the most potent endogenous vasodilators; examples include bradykinins and kallidin Bradykinin is believed to play a role in the control of blood flow in the skin, gastrointestinal glands, and salivary glands Histamine is released from mast cells and basophils upon stimulation by injury, inflammation, or allergic reaction to induce vasodilation and increase capillary permeability Neural Control Neural control of the systemic circulation involves feedback mechanisms that operate in both the short and long term through the autonomic, primarily the sympathetic, nervous system.118 Short-term changes in sympathetic activity are triggered either by reflex mechanisms involving peripheral receptors or by a centrally generated response Long-term changes, on the other hand, are evoked through modulation of sympathetic nervous system by other humoral factors and possibly by central mechanisms involving the hypothalamus Peripheral receptors constitute the afferent limb of the reflex These include arterial baroreceptors, arterial chemoreceptors, and cardiac stretch receptors Arterial baroreceptors are located in the walls of the carotid sinus and aortic arch Afferent fibers run in the glossopharyngeal and vagal nerves and terminate within the nucleus of the solitary tract The neurons at the nucleus then excite neurons within the caudal and intermediate parts of the ventrolateral medulla to cause inhibition of the sympathoexcitatory neurons in the rostral ventrolateral medulla.119 Hence stretching of arterial baroreceptors increases afferent input and results in the reflex slowing of heart rate, a decrease in cardiac contractility, and vasodilation, thereby providing a negative feedback mechanism for the homeostasis of arterial pressure.120 Peripheral chemoreceptors are located in the carotid and aortic bodies and are stimulated primarily by decreased arterial partial pressure of oxygen Their afferent fibers also run in the glossopharyngeal and vagus nerves Activation of peripheral chemoreceptor results in hyperventilation and sympathetically mediated vasoconstriction of vascular beds with the exception of those of the heart and brain.121 Hence oxygen conservation is attempted by increasing oxygen uptake and reducing tissue oxygen consumption These chemoreflexes are subjected to negative feedback interaction, with inhibition of the chemoreflex-mediated sympathetic activation through the stimulation of baroceptors and thoracic afferents.122