HYPERTENSION & REGULATION OF BLOOD PRESSURE
The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure (Table 11–1). The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension.Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure 140/90 mm Hg) increases the risk of eventual end-organ damage. Starting at 115/75 mm Hg, cardiovascular disease risk doubles with each increment of 20/10 mm Hg throughout the blood pres-sure range. Both systolic hypertension and diastolic hypertension are associated with end-organ damage; so-called isolated systolic hypertension is not benign. The risks—and therefore the urgency of instituting therapy—increase in proportion to the magnitude of blood pressure elevation. The risk of end-organ damage at any level of blood pressure or age is greater in African Americans and relatively less in premenopausal women than in men. Other posi-tive risk factors include smoking; metabolic syndrome, including obesity, dyslipidemia, and diabetes; manifestations of end-organ damage at the time of diagnosis; and a family history of cardiovas-cular disease.
It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end-organ damage is imminent or has already occurred.
A specific cause of hypertension can be established in only 10–15% of patients. Patients in whom no specific cause of hyper-tension can be found are said to have essential or primary hyper-tension. Patients with a specific etiology are said to have secondary hypertension. It is important to consider specific causes in eachcase, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing’s disease, and primary aldosteronism.
In most cases, elevated blood pressure is associated with an over-all increase in resistance to flow of blood through arterioles, whereas cardiac output is usually normal. Meticulous investigation of auto-nomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has failed to identify a single abnormality as the cause of increased peripheral vascular resistance in essential hypertension. It appears, therefore, that ele-vated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemiologic evidence points to genetic factors, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as contributing to the development of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely than normal controls to have blood pressure elevations after salt loading.
The heritability of essential hypertension is estimated to be about 30%. Mutations in several genes have been linked to various rare causes of hypertension. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), the β2 adrenoceptor, and α adducin (a cytoskeletal protein) appear to contribute to some cases of essential hypertension.
According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through pre-capillary arterioles (peripheral vascular resistance, PVR):
BP = CO × PVR
Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11–1): arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regu-lating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of vasoactive substances from vascu-lar endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 constricts and nitric oxide dilates blood vessels.
Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in normotensive subjects. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be “set” at a higher level of blood pressure. All antihypertensive drugs act by interfer-ing with these normal mechanisms, which are reviewed below.
Baroreflexes are responsible for rapid, moment-to-moment adjust-ments in blood pressure, such as in transition from a reclining to an upright posture (Figure 11–2). Central sympathetic neurons arising from the vasomotor area of the medulla are tonically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pres-sure). Baroreceptor activation inhibits central sympathetic dis-charge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disin-hibited. The reflex increase in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constric-tion of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pres-sure. The same baroreflex acts in response to any event that lowers arterial pressure, including a primary reduction in peripheral vas-cular resistance (eg, caused by a vasodilating agent) or a reduction in intravascular volume (eg, due to hemorrhage or to loss of salt and water via the kidney).
By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfu-sion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water. In addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via β adrenoceptors) stimulates production of renin, which increases production of angiotensin II. Angiotensin II causes (1) direct constriction of resis-tance vessels and (2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intra-vascular blood volume. Vasopressin released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidney.