Hydralazine compensatory responses

Vasodilators. Hydralazine causes direct relaxation of arteriolar smooth muscle. An important consequence of this vasodilation, however, is reflex tachycardia (T CO). It may also cause sodium retention (T plasma volume). The resulting increase in CO tends to offset effects of the vasodilator. Therefore, these drugs are most effective when administered along with sympathetic agents such as P-adrenergic receptor antagonists, which prevent unwanted compensatory responses by the heart. 

Drugs that dilate blood vessels by acting directly on smooth muscle cells through nonautonomic mechanisms are useful in treating many hypertensive patients. Three major mechanisms are utilized by vasodilators release of nitric oxide, opening of potassium channels (which leads to hyperpolarization), and blockade of calcium channels (Table 11-3). Compensatory responses are marked for some vasodilators (especially hydralazine and minoxidil) and include salt retention and tachycardia (Table 11-2). 

A. Hydralazine and Minoxidil These older vasodilators have more effect on arterioles than on veins. They are orally active and suitable for chronic therapy. Hydralazine apparently acts through the release of nitric oxide. However, it is rarely used at high dosage because of its toxicity therefore, its efficacy is limited, fts toxicities include compensatory responses (tachycardia, salt and water retention Table 11-2) and drug-induced lupus erythematosus, which is reversible upon stopping the drug. However, this effect is uncommon at dosages below 200 mg/d. 

The compensatory responses to hydralazine use are tachycardia and salt and water retention. These responses are generated by the baroreceptor and renin-angiotensin-aldosterone mechanisms summarized in Figure 6-4. The motor limb of the sympathetic response consists of outflow from the vasomotor center to the heart and vessels, as shown in Figure 11-3. You should be able to reproduce these diagrams from memory. 

For example, because an adequate dose of hydralazine causes a significant decrease in peripheral vascular resistance, there will initially be a drop in mean arterial blood pressure, evoking a strong response in the form of compensatory tachycardia and salt and water retention (Figure 11-5). The result is an increase in cardiac output that is capable of almost completely reversing the effect of hydralazine. The addition of a B-blocker prevents the tachycardia addition of a diuretic (eg, hydrochlorothiazide) prevents the salt and water retention. In effect, all three drugs increase the sensitivity of the cardiovascular system to each other s actions. 

Hydralazine was one of the first orally active antihypertensive drugs marketed in the United States. Its structure is shown in Figure 12.4. Initially, the drug was used infrequently because of its propensity to produce reflex tachycardia and tachyphylaxis. However, with a better understanding of the compensatory cardiovascular responses that accompany use of arteriolar vasodilators (the drug has little or no effect on venous smooth muscle), hydralazine was combined with sympatholytic agents and diuretics with greater therapeutic success. 

If hydralazine in moderate dosage is administered for several weeks, compensatory cardiac and renal responses will be observed. Specify the exact mechanisms and structures involved in these responses. The Skill Keeper Answer appears at the end of the chapter. 

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