Vasodilators 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. 

Chapter 12 contains additional discussion of vasodilators. All the vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Sodium nitroprusside and the nitrates also relax veins. Decreased arterial resistance and decreased mean arterial blood pressure elicit compensatory responses, mediated by baroreceptors and the sympathetic nervous system (Figure 11-4), as well as renin, angiotensin, and aldosterone. Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction. 

Compensatory responses to vasodilators basis for combination therapy with 13 blockers and diuretics. Effect blocked by diuretics. Effect blocked by 13 blockers. 

Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6-7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13-2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. The result is a vicious cycle that is characteristic of heart failure (Figure 13-3). Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. Neurohumoral antagonists and vasodilators... 

Cardiovascular The anesthetic barbiturates produce dose-dependent decreases in blood pressure that are due primarily to vasodilation, particularly venodUation, and to a lesser degree to a direct decrease in cardiac contractility. Typically, heart rate increases as a compensatory response to a lower blood pressure, although barbiturates also blunt the baroreceptor reflex. 

Cardiovascular System Isoflurane produces a concentration-dependent decrease in arterial blood pressure cardiac output is maintained and hypotension is the result of decreased systemic vascular resistance. Vasodilation occurs in most vascular beds, particularly in skin and muscle. Isoflurane is a potent coronary vasodilator, simultaneously producing increased coronary blood flow and decreased myocardial consumption. Patients anesthetized with isoflurane generally have mildly elevated heart rates as a compensatory response to reduced blood pressure however, rapid changes in isoflurane concentration can produce both transient tachycardia and hypertension due to isoflurane-induced sympathetic stimulation. 

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. 

Marked tachycardia and fluid retention are compensatory responses usually seen with strong vasodilators. The fact that the unknown drug also increases hair growth points strongly at minoxidil. The answer is (C). 

Cardiovascular Effects. Palpitations, low blood pressure, and tachycardia were described in subjects exposed to 1,3-DNB by the inhalation (Okubo and Shigeta 1982), oral (Kumar et al. 1990), and dermal (White and Hay 1901) routes of exposure. These responses are consistent with effects of organic nitrates. 1,3-DNB is an organic nitrate and shares many of the cardiovascular properties of therapeutic nitrates. Organic nitrates induce relaxation of the vascular smooth muscle which can result in peripheral vasodilation and a fall in blood pressure followed by a compensatory vasoconstriction (Abrams 1980). The general information available on organic nitrates suggests that exposure to 1,3-DNB or 1,3,5-TNB at ammunition waste sites or at work places where these chemicals are used may lead to adverse cardiovascular effects. 

When the diagnosis is correct and the drug is appropriate, an unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihypertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic result. 

Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses. (See Resistant Hypertension Polypharmacy.)... 

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. 

Figure 3. Mechanism by which NSAIDs disrupt the compensatory vasodilation response of renal prostaglandins to vasoconstrictor hormones in patients with prerenal conditions.

DNP at 3.5 mg/kg/day 2,4-DNP for 4-12 days (Stockton and Cutting 1934). Systolic and diastolic blood pressures were not affected pulse rate increased as much as 12%. The changes in venous pressure and pulse rate tended to occur during episodes of peripheral vasodilatation and appeared, therefore, to be compensatory mechanisms for the maintenance of normal blood pressure. The episodes of peripheral vasodilation may have been a cooling response to the pyretic effects of... 

Hypoxia decreases resistance to blood flow in many vascular beds. This could be a compensatory mechanism to increase blood flow to the hypoxic region. In the coronary, cerebral, renal, and skeletal muscle circulations this hypoxic vasodilation is attenuated by glibenclamide, suggesting a role for K xp channels in the response (von Beckerath et al., 1991 Daut et al.,... 

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