Hypertensive crisis can develop either de novo or as a complication of preexisting essential or secondary hypertension (Table 112.2). Any disorder that causes hypertension can give rise to hypertensive crisis. The endothelium in resistance vessels plays a central role in BP homeostasis, as it attempts to compensate for changes in vascular resistance through increased autocrine and paracrine release of vasodilator molecules, such as nitric oxide and prostacyclin. With sustained severe hypertension, these compensatory endothelium-mediated vasodilator responses are overwhelmed, which leads to endothelial decompensation, endothelial failure, and vasoconstriction (5). Although the detailed pathophysiology of hypertensive crisis remains to be elucidated, an initial abrupt increase in vascular resistance seems to be a necessary step and is likely related to a sudden surge in humoral vasoconstrictors (6). Activation of the renin-angiotensin system, nitric oxide (NO), endothelin, vasopressin, and catecholamines has been postulated to play important roles in the pathophysiology of hypertensive crises (7,8,9).

Of these trigger factors, the role of renin-angiotensin system in the pathogenesis of end-organ injury has been the most studied. (For in-depth discussion of renin-angiotensin system, see Chapter 107.) In humans, a rapid elevation of circulating renin levels occurs during transition to malignant hypertension, (10) and in transgenic mice, evidence suggests that the renin-angiotensin system is important for transformation to malignant hypertension and lethality (11). Mice that express the murine renin gene, Ren-2, develop severe hypertension compared with controls (12), and rats that are double transgenic for human renin and human angiotensinogen genes develop not only severe hypertension but also an inflammatory vasculopathy similar to that seen in human severe hypertension (13). Angiotensin II has been shown to have direct cytotoxic effects on the vessel wall, some of which seem to be mediated through activation of expression of genes for proinflammatory cytokines (e.g., IL-6) and activation of the transcription factor, NF-κβ (14,15). Furthermore, inhibition of angiotensin-converting enzyme (ACE) prevents the development of malignant hypertension in transgenic rats that express the murine renin gene (11). Activation of the renin-angiotensin-aldosterone system may be primary or secondary to renal ischemia produced by arteriolar occlusion. The BP elevation may induce pressure natriuresis, intravascular volume depletion, and a further increase in renin secretion. Increased angiotensin II causes further renal vasoconstriction and, hence, worsening hypertension.

The ensuing increase in BP generates mechanical stress and injury of the microvasculature, endothelial damage, activation of the renin-angiotensin system, and oxidative stress (4). The endothelial injury results in increased vascular permeability, activation of coagulation cascade, and platelet deposition of fibrin (Fig. 112.1). Further progression leads to fibrinoid necrosis of the arterioles with resulting ischemia and the release of additional vasoactive mediators generating a vicious cycle of repeated injury (6,16,17). Activation of the renin-angiotensin system leads to further vasoconstriction and production of proinflammatory cytokines such as interleukin-6 (IL-6) (14,18). The process also triggers an increase in NADPH oxidase activity, which generates the release of reactive oxygen species (ROS) and further tissue injury (19,20).

Nitric oxide (NO) plays a major role in vascular smooth muscle relaxation and vasodilation (nitric oxide is discussed in detail in Chapter 21). NO is predominantly synthesized in the vascular endothelium by the action of endothelial nitric oxide synthase (eNOS) on L-arginine. NO diffuses from the endothelial cells to activate soluble guanylate cyclase and form cGMP in the vascular smooth muscle cells, which causes vascular smooth muscle relaxation, prevention of platelet adhesion, and aggregation, and anti-inflammatory, antiproliferative, and anti-migratory effects on leukocytes, endothelial cells, and vascular smooth muscle cells (21,22). The main characteristic of endothelial dysfunction present in arterial hypertension is the attenuated NO bioavailability (23). Hypertensive patients have increased generation of ROS, which act as potent NO scavengers and reduce NO bioavailability. Additionally, studies in animals have shown that deletion of the eNOS gene as
well as chronic inhibition of NO synthesis with N-nitro-L-arginine methyl ester (L-NAME) leads to development of arterial hypertension (24,25). Studies in both humans and animals show that the restoration of NOS activity by administration of NOS cofactors such as tetrahydrobiopterin (BH₄) or L-arginine result in increased bioavailability of NO, improved endothelial function, and prevention of hypertension (26,27).

Other agents responsible for vasodilation include endothelial-derived hyperpolarizing factor (EDHF) and prostaglandin I₂ (PGI₂). EDHF is potent non-NO, non-prostaglandin-mediated endothelium-dependent vasodilator with a predominant effect on resistance vessels (28). PGI₂ is an eicosanoid of the cyclooxygenase pathway that causes vascular smooth muscle relaxation and inhibits platelet aggregation (29). Endothelin, another endothelium-derived agent, on the other hand, has a potent vasoconstrictor effect and may act alone or in concert with other agents such as thromboxane A₂ (TXA₂), prostaglandin F_2α (PGF_2α), or endothelial-derived constrictor factor (EDCF) to cause vasoconstriction. The relative amounts of the various factors released by the endothelial cell are kept in a tight equilibrium and are dependent on the physiologic circumstance and pathophysiologic status. Disturbance of this equilibrium can result in an acute hypertensive episode.