(COlactic acid, hydrogen, potassium and magnesium ions, adenosine, bradykinin, histamine)
that dilate the arterioles locally. Simple increased plasma osmolality causes local arteriolar vasodilation. Also, the lack of O2 may result in vasodilation, because O2 itself helps maintain muscular contraction of the arteriolar wall. Conversely, excess blood flow through the tissues will tend to cause vasoconstriction through this "autoregulative effect." Whereas sympathetic innervation acts on the arterioles, the autoregulative effect actually acts on more peripheral extensions of the arterioles, termed metarterioles, which lie between the arterioles and capillaries.
Interestingly, in the lung, autoregulation has an opposite effect. Low alveolar oxygen concentration results in local vasoconstriction. This helps to ensure that blood is diverted from poorly aerated areas of the lung to areas better able to supply oxygen. In atelectasis (collapse of part of the lung), the collapse in itself serves to mechanically constrict blood vessels, so that blood flow is diverted to better aerated areas.
Calcium, which is important in stimulating muscle contraction, causes vasoconstriction. Prostaglandins are spread diffusely throughout the tissues of the body. Some of them cause vasodilation and others vasoconstriction. Serotonin, concentrated in platelets and in chromaffin cells in the abdomen, may have vasoconstrictive or vasodilatory effects.
Autoregulation of peripheral blood vessels provides an immediate response to tissue anoxia (oxygen deprivation). A longer-range response consists of an increase in blood vessel number and size, through the local production of an angiogenesis factor.
Something akin to Starling's law of the heart may also apply to the peripheral vasculature. When blood vessel walls are stretched, there is local vasoconstric-
tion, which protects the capillary bed from acutely and excessively high blood pressure.
Last but not least, a growing literature indicates a very important role for nitric oxide in the regulation of blood pressure. Nitric oxide normally is found in vascular endothelium. It causes vasodilation, which may be an important reason why nitroglycerin is effective in increasing coronary dilation in response to angina. Nitric oxide becomes deficient with arteriosclerosis, providing another mechanism for pathological vasoconstriction, other than the arteriosclerosis itself.
As we have seen, the body has multiple control mechanisms to maintain blood pressure. These work fine to maintain homeostasis, unless there are marked stresses on the system or if individual components of the system are not working. For instance:
1) Marked fluid loss, through hemorrhage, diarrhea, vomiting, or sweating may severely strain the ability of the body to compensate and return blood volume to normal.
2) Renal disease. A normally functioning kidney usually suffices to excrete excess water and sodium, but water and sodium intake must be carefully regulated if the kidneys are malfunctioning (e.g. through intrinsic renal disease or renal artery stenosis). Otherwise, blood volume may increase, with consequent hypertension. Renal disease with poor renal glomerular perfusion may result in increased renin levels. Angiotensin and aldosterone levels will then increase, with consequent vasoconstriction, sodium retention, and elevated blood pressure.
3) Cardiac disease may significantly impair the heart's ability to pump blood. Thus, peripheral tissues, including the kidney, will be poorly perfused, with inadequate elimination of ingested water and salt. Increased plasma volume and increased capillary blood pressure may result, leading to leakage of fluid into the interstitial spaces (edema).
4) Destructive tumors in the pituitary-hypothalamic region may eliminate the ability to produce ADH. In the absence of ADH, the patient may urinate 20 liters per day (a condition call diabetes insipidus). This will dehydrate the patient, unless the patient compensates by imbibing an equal amount of water. Conversely, with excess production of ADH (e.g. in the syndrome of inappropriate ADH secretion, which occurs especially with certain pulmonary and brain tumors), the blood volume increases (unless there is water restriction) and so may the blood pressure.
5) Tumors of the adrenal medulla (pheochromo-cytomas) may secrete excess epinephrine and norep inephrine, thereby raising the blood pressure, as will adrenal cortical tumors that produce aldosterone (primary hyperaldosteronism). Excess aldosterone may also arise secondary to excess renin production (secondary hyperaldosteronism), which may occur with renin-producing juxtaglomerular cell tumors or, more commonly, with renal artery stenosis and many kinds of renal disorders. Plasma renin, while high in secondary hyperaldosteronism, is low in primary hyperaldosteronism, because elevated' aldosterone normally decreases renin secretion by negative feedback.
6) The greater the rigidity of the arterial wall, as in arteriosclerosis, the greater the rise in systolic blood pressure. Arteriosclerotic damage also decreases the normal endothelial cell nitric oxide, and nitric oxide then is not available to perform its normal vasodila-tory function.
7) When one stands perfectly still, the venous pump (the tendency to move the venous blood through skeletal muscle contraction) does not work efficiently in the lower extremities. Blood pools in the lower extremities, reducing the blood volume and pressure in the upper extremities. The higher resulting pressure in the veins in the legs increases the capillary pressure in the lower extremity veins, resulting in leakage of fluid into the extracellular space and edema of the lower extremities with reduction of blood volume, and hence blood pressure.
8) Idiopathic hypertension. Even when all control mechanisms are operating, they may not be so finely tuned quantitatively. The body may react to rises in blood pressure, but without sufficient control to achieve a normal baseline blood pressure. Such individuals may have normal laboratory tests for electrolyte balance and renal and cardiac function, but still have hypertension. Vascular reactivity refers to the degree of sensitivity to sympathetic stimulation of the smooth muscle in the vascular wall. Vascular reactivity may be increased in certain families who have an inherited tendency toward hypertension.
We have seen that the major factors involved in pressure regulation are fluid volume, vascular resistance, and cardiac output. It stands to reason that the major efforts to control hypertension involve:
1) Reduction of plasma volume, e.g. through salt restriction and diuretics, drugs that increase water excretion.
a) Loop diuretics (e.g. furosemide) and thiazide diuretics (e.g. hydrochlorothiazide) interfere with the active transport of sodium chloride, particularly in the ascending limb of Henle and the distal convoluted tubule (see Fig. 2-11, further explained in Chapter 3). Thus, sodium remains in the tubular lumen along with water; other molecules remain too, for osmotic reasons, as the excess water prevents them from passively leaving the lumen along a concentration gradient. Therefore, not only water but sodium, chloride, potassium, and other molecules are excreted in the urine.
b) Osmotic diuretics, such as mannitol, filter freely at the glomerulus but are not reabsorbed. Their osmotic effect keeps water and other molecules in the tubular lumen for excretion.
c) Aldosterone antagonists, such as spironolactone, interfere with the ability of aldosterone to promote sodium reabsorption and potassium secretion. Thus, sodium is excreted along with water, whereas potassium is retained. Such potassium sparing contrasts with the potassium loss that accompanies thiazide-type diuretics.
d) Carbonic anhydrase inhibitors (see Figs. 2-11 and 3-3) inhibit the reaction of C02 + H20 -» H*
+ HCO3 , thereby inhibiting H • secretion in the proximal tubule, and decreasing the absorption of HCO3" and associated Na* ions. In general, whenever sodium excretion increases, water excretion also increases, and plasma volume decreases. Water follows sodium into the urine. However, it is not always true that increased water excretion is accompanied by increased sodium excretion. It is possible for urine to increase significantly in volume while containing no significant sodium. This is because sodium reabsorption still continues beyond the loop of Henle even when ADH secretion is low. With low ADH, the permeability of the collecting ducts to water is extremely small and little can be reabsorbed despite the active reabsorption of sodium. The water then exits as a dilute urine without significant accompanying sodium.
2) Promotion of vasodilation to reduce peripheral resistance, as follows:
a) Medications that inhibit the sympathetic nervous system centrally. Stimulation of alpha-2 receptors on central sympathetic neurons inhibits sympathetic discharge. Hence, medications that stimulate alpha-2 receptors (alpha-2 agonists) will decrease blood pressure.
b) Medications that inhibit transmission from peripheral sympathetic neurons to vascular smooth muscle cells. This can be done by i) Medications that block norepinephrine release from presynaptic sympathetic neurons.
ii) Alpha-1 antagonists, drugs that are antagonistic to sympathetic alpha-1 receptors on vascular smooth muscle cells (stimulation of vascular alpha-1 receptors normally causes vasoconstriction).
c) Medications that directly vasodilate. Calcium channel blockers, which inhibit the entry of calcium into muscle cells, cause vasodilation, because calcium is necessary for muscular contraction, including that of smooth muscle in arteriolar walls. ACE (Angiotensin-Converting Enzyme) inhibitors reduce blood pressure by preventing the conversion of angiotensin I to angiotensin II, which is a vasoconstrictor. Other vasodilators may act by enhancing the'effect of vascular endothelial nitric oxide, a natural dilator.
3) Reduction of cardiac output. This may include attempts to reduce blood volume (restricting salt intake; use of diuretics) &/or the use of medications that reduce heart rate and stroke volume. Stimulation of sympathetic beta-1 receptors on heart muscle increases cardiac output. Hence, drugs that are beta-1 antagonists decrease cardiac output.
4) Stress reduction reduces the level of sympathetic activity.
5) Weight loss is also useful in reducing blood pressure, although the mechanism for this is still in debate.
Methods to deal with low blood pressure include the restoration of lost fluid volume (whether through blood or other fluids), and the use of vasoconstrictors. Medications to help restore defective cardiac functioning are also important in the control of blood pressure, whether the pressure is low or high.
Central Venous Pressure (CVP)
CVP, the pressure in the large veins, normally is close to 0 (about the same level of pressure as the right atrium). In either right or left heart failure, CVP may increase, because the heart cannot handle the blood that reaches it. CVP measurement, therefore, is a useful index of cardiac failure. The CVP can be elevated in the face of either a high or low systemic arterial pressure. Apart from cardiac pumping failure, an elevated CVP may also occur with:
1) Increased blood volume.
2) Arteriolar dilation, which allows the arterial pressure to be transmitted to the veins.
Increased CVP backs up pressure to the capillary level, where the increase in capillary hydrostatic pressure may cause water to leave the capillaries and enter the interstitial space; this results in edema. Edema of the extremities and liver, and engorgement of the neck veins will result from this backup in the case of right heart failure, whereas the same signs, plus pulmonary edema, may result from this backup in the case of left heart failure.
The CVP is an index of right atrial pressure, and its elevation may make us suspect cardiac failure in general, without specifying whether it is right or left heart failure. The pulmonary wedge pressure, in contrast, reflects left atrial pressure and helps distinguish right and left cardiac failure, as follows:
A catheter is threaded into the pulmonary artery and "wedged" up close to the pulmonary capillaries. The pressure recorded there is close to that of the left atrium. Normal mean pulmonary capillary wedge pressure is about 8 mm Hg. With left cardiac failure (or mitral valve stenosis, for example), there is backup of blood into the lungs with elevation of the pulmonary wedge pressure and CVP, and possibly pulmonary edema. In right cardiac failure, the wedge pressure is not elevated, and there is no pulmonary edema.
Pulmonary arterial pressure is lower in the superior lung fields than in the inferior fields because of gravity. This lower pressure results in decreased capillary diameter and blood flow in the superior fields, even to zero with very low pulmonary arterial pressures, as alveolar pressure collapses the capillaries. In times of oxygen need, increased cardiac output increases the pulmonary arterial pressure, which opens up collapsed capillaries and increases blood flow in all areas of the lungs.
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