Vasodilation Venous dilatation

Unhke the vasodilators, which have a more prominent effect on arterial beds than on venous beds, the a-blockers prevent vasoconstriction in both vascular beds. Because of the venous dilation, postural hypotension is a feature of a-blockade, although less so with prazosin than with the classical a-blockers. 

In addition to these traditional vasodilators, nesir-itide (Natrecor) was developed as a newer method for producing arterial and venous dilation in people with heart failure.58 This substance was derived from human B-type natriuretic peptide (BNP) using recombinant DNA techniques. BNP is a naturally occurring substance that is released from the ventricles when the heart is subjected to increased blood volume and pressure.12 This substance dilates peripheral arteries and veins, thus reducing cardiac afterload and preload, respectively. Hence, nesiritide can be administered intravenously to reduce cardiac workload in certain patients with severe or acute heart failure.12,58... 

Direct vasodilator agents T Renal vascular resistance (hydralazine, minoxidil) Arterial vasodilation plus dilatation of venous capacitance vessels (nitroprusside) Increase in RBF and no effect on GFR Decrease in GFR and RBF (acute effect)... 

Diazoxide is a parenteral, rapid, and direct-acting vasodilating antihypertensive used in hypertensive emergencies. An IV injection can drop blood pressure by as much as 80 mmHg in 5 minutes. Unlike sodium nitroprusside, however, venous dilation is not part of its mechanism. Chemically it is a benzothiadiazide without the sulfamoyl function at the 7 position (see diuretics). In fact, diazoxide is not a diuretic. Chronic use of diazoxide reflexly increases renin release, which actually counteracts the antihypertensive effect of the drug by expanding the volume of circulating fluid. 

CARDIOVASCULAR SYSTEM In the supine patient, therapeutic doses of morphine-like opioids have no major effect on blood pressure or cardiac rate and rhythm. Such doses do produce peripheral vasodilation, reduced peripheral resistance, and an inhibition of baroreceptor reflexes. Therefore, when supine patients assume the upright position, orthostatic hypotension and fainting may occur. The peripheral arteriolar and venous dilation produced by morphine involves several mechanisms. Morphine and some other opioids provoke release of histamine, which sometimes plays a large role in the hypotension. However, vasodilation usually is only partially blocked by Hj antagonists, but it is effectively reversed by naloxone. Morphine also blunts the reflex vasoconstriction caused by increased Pco (see Chapter 15). 

Nifedipine (Table 3) is a potent vasodilator that selectively dilates resistance vessels and has fewer effects on venous vessels. It does not cause reflex tachycardia during chronic therapy. Nifedipine is one of the first-line choices for black or elderly patients and patients having concomitant angina pectoris, diabetes, or peripheral vascular diseases. Nifedipine, sublingually, is also suitable for the treatment of hypertensive emergencies. Nifedipine does not impair sexual function or worsen blood Hpid profile. The side effects are flushing, headache, and dizziness. 

Mechanism of Action A potent vasodilator used to treat emergent hypertensive conditions acts directly on arterial and venous smooth muscle. Decreases peripheral vascular resistance, preload and afterload improves cardiac output. Therapeutic Effect Dilates coronary arteries, decreases oxygen consumption, and relieves persistent chest pain. 

Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle (Figure 12-2). 

Vascular smooth muscle tone is regulated by adrenoceptors consequently, catecholamines are important in controlling peripheral vascular resistance and venous capacitance. Alpha receptors increase arterial resistance, whereas 2 receptors promote smooth muscle relaxation. There are major differences in receptor types in the various vascular beds (Table 9-4). The skin vessels have predominantly receptors and constrict in the presence of epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether ffor 13 receptors are activated. Consequently, the overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at and 8receptors and the anatomic sites of the vessels affected. In addition, Di receptors promote vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels. Activation of the Di receptors in the renal vasculature may play a major role in the natriuresis induced by pharmacologic administration of dopamine. 

In CHF, the impaired contractile function of the heart is exacerbated by compensatory increases in both preload and afterload. Preload is the volume of blood that fills the ventricle during diastole. Elevated preload causes overfilling of the heart, which increases the workload. Afterload is the pressure that must be overcome for the heart to pump blood into the arterial system. Elevated afterload causes the heart to work harder to pump blood into the arterial system. Vasodilators are useful in reducing excessive preload and afterload. Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance arterial dilators reduce systemic arteriolar resistance and decrease afterload. 

GTN is a nitrate. This class of drugs are potent vasodilators. At therapeutic doses the main effect of nitrates is to act on vascular smooth muscle to dilate the veins, thus reducing central venous pressure (preload) and ventricular end-diastolic volume. The overall effect is to lower myocardial contraction, wall stress and oxygen demand, thereby relieving the angina. Nitrates also promote vasodilation of the coronary blood vessels. 

A number of compounds have been reported which have coronary dilator properties or other activities which have culminated in their clinical trial for use in angina pectoris. Lidoflazlne (IV) is claimed to be a specific, long acting coronary vasodilator. This agent appears to reduce coronary vascular resistance in dogs and causes an Increase in coronary venous pO. ... 

These drugs are potent coronary vasodilators and can increase blood flow to the myocardium. However, in many cases of angina, the coronary arteries are partially occluded and blood flow through them does not increase significantly. Nitrates appear to dilate collateral coronary blood vessels allowing partially blocked arteries to be bypassed. In addition, they dilate veins. This brings about a reduction in venous return and reduces the preload on the heart. This decreases the workload of the left ventricle and myocardial oxygen consumption is reduced. 

Vasodilation increased peripheral blood flow hypotension Dilation peripheral poohng of blood decreased venous return decreased cardiac output Tachycardia Mydriasis... 

Hydralazine (apresoline) causes direct relaxation of arteriolar smooth muscle, possibly secondary to a fall in intracellular Ca concentrations. The drug does not dilate epicardial coronary arteries or relax venous smooth muscle. Hydralazine-induced vasodilation is associated with powerful stimulation of the sympathetic nervous system, likely due to baroreceptor-mediated reflexes, which results in increased heart rate and contractility, increased plasma renin activity, and fluid retention all of these effects counteract the antihypertensive effect of hydralazine. Although most of the sympathetic activity is due to a baroreceptor-mediated reflex, hydralazine may stimulate NE release from sympathetic nerve terminals and augment myocardial contractility directly. Most of hydralazine s effects are confined to the cardiovascular system the decrease in blood pressure after administration is associated with a selective decrease in vascular resistance in the coronary, cerebral, and renal circulations, with a smaller effect in skin and muscle. Because of preferential dilation of arterioles, postural hypotension is not common, and hydralazine lowers blood pressure equally in the supine and upright positions. 

Minoxidil (loniten) is efficacious in patients with the most severe and drug-resistant forms of hypertension. A small fraction of minoxidil is metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate. Minoxidil sulfate activates the ATP-modulated channel in smooth muscle, causing hyperpolarization and relaxation of arteriolar smooth muscle. Minoxidil produces arteriolar vasodilation with essentially no effect on capacitance vessels. Minoxidil preferentially increases blood flow to skin, skeletal muscle, the GI tract, and the heart. The disproportionate increase in blood flow to the heart may have a metabolic basis, in that administration of minoxidil is associated with a reflex increase in myocardial contractility and in cardiac output. The cardiac output can increase by as much as three- to fourfold, primarily due to enhanced venous return to the heart. The increased venous return probably results from enhanced flow in vascular beds with a fast response for venous return to the heart. The adrenergic increase in myocardial contractility contributes to the increased cardiac output, but is not the predominant factor. The renal effects of minoxidil are complex it dilates renal arteries, but systemic hypotension produced by the drug actually can decrease renal blood flow. Renal function usually improves in patients who take minoxidil for the treatment of hypertension, especially if renal dysfunction is secondary to hypertension. Minoxidil potently stimulates renin secretion, an effect mediated by renal sympathetic stimulation. 

Sodium nitroprusside is used for the short-term control of severe hypertension and can improve cardiac function in patients with left ventricular failure see Chapter 34). Nitroprusside acts by releasing nitric oxide (NO). NO activates the guanylyl cyclase-cyclic GMP-PKG pathway, leading to vasodilation. The mechanism of release of NO likely involves both enzymatic and nonenzymatic pathways. Tolerance does not develop to nitroprusside. Nitroprusside dilates both arterioles and venules the hemodynamic response results from a combination of venous pooling and reduced arterial impedance. In subjects with normal left ventricular function, venous pooling affects cardiac output more than does the reduction of afterload cardiac output thus tends to fall. In patients with severely impaired left ventricular function and diastolic ventricular distention, the reduction of arterial impedance leads to a rise in cardiac output see Chapter 33). Sodium nitroprusside is a nonselective vasodilator, and regional distribution of blood flow is little affected by the drug. In... 

In patients with elevated systemic vascular resistance and normal-to-elevated systemic blood pressure, afterload reduction with nitroprusside is logical it should be emphasized that nitroprus-side also increases venous capacitance, thereby also decreasing preload. In the context of myocardial dysfunction, afterload reduction will typically lead to improved forward cardiac output. Nitroprusside may also be effective when the systemic vascular resistance is elevated and systemic blood pressure is reduced the caveat in this more complex hemodynamic setting is that the load reduction produced by nitroprusside must be counterbalanced by an increase in stroke volume. This derivative increase in stroke volume may not occur in the patient with advanced heart failure rather, the result will be a further reduction in mean arterial pressure and the potential risk of peripheral organ hypoperfusion. An alternative approach would be the use of an inotropic-dilator drug such as milrinone, which will provide both preload and afterload reduction its concurrent positive inotropic effect may offset the reduction in mean arterial pressure that can occur from vasodilation alone. 

Nicorandil induces nitrate-like activation of soluble guanylate cyclase, increasing intracellular levels of cGMP with resultant dilation of venous capacitance vessels. Increases in cGMP are less than those observed with conventional nitrates, although the degree of vasodilation produced appears to be similar. Its oral bioavailability ranges from 75 to 80%. Food reduces the rate, but not the extent, of absorption. Nicorandil is extensively metabolized via denitration to inactive... 

Before beginning the discussion of the sympatholytics and vasodilators, it is important to review the nature of vascular tone. The term vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance (arteries) and capacitance (venous) vessels under basal conditions exhibit some degree of smooth muscle contraction, which determines the diameter and, hence, the tone of the vessel. 

Vasodilator drugs relax the smooth muscle in blood vessels, which causes the vessels to dilate. Dilation of arterial vessels leads to a reduction in systemic vascular resistance, which leads to a fall in arterial blood pressure. Dilation of venous vessels decreases venous blood pressure. 

In vivo vasodilation Two methods observe the release of NO by the endothelium by measuring changes in blood flow in humans. In flow-mediated dilatation, the diameter of the brachial artery is measured with ultrasound. The vasodilation is induced by the increase of arterial shear stress after the release of an inflatable cuff around the arm. Plethysmography measures the blood flow via the volume changes of the forearm after venous occlusion. Quantification of NO is not possible in either method and the diagnostic value is limited as individuals show considerable variations in systemic response. 

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