Vasodilation metabolic mediators

Coronary blood flow is enhanced by Epi or by cardiac sympathetic stimulation under physiological conditions. The increased flow, which occurs even with doses that do not increase the aortic blood pressure, is the result of two factors. The first is the increased relative duration of diastole at higher heart rates (see below) this is partially offset by decreased blood flow during systole because of more forceful contraction of the surrounding myocardium and an increase in mechanical compression of the coronary vessels. The increased flow during diastole is further enhanced if aortic blood pressure is elevated by Epi as a consequence, total coronary flow may be increased. The second factor is a metabolic dilator effect that results from the increased strength of contraction and myocardial consumption due to direct effects of Epi on cardiac myocytes. This vasodilation is mediated in part by adenosine released from cardiac myocytes, which tends to override a direct vasoconstrictor effect of Epi that results from activation of a receptors in coronary vessels. 

Active hyperemia. The increase in blood flow caused by enhanced tissue activity is referred to as active hyperemia. Assuming a constant blood pressure, then according to Ohm s law (Q = AP/R), the increase in blood flow is the result of a decrease in local vascular resistance. Tissue metabolism causes several local chemical changes that can mediate this metabolic vasodilation. These include ... 

C. Histamine stimulates gastric acid secretion through an effect on Hj-receptors of gastric parietal cells. Although certain antihistamines are metabolized by cytochrome P450 enzymes, histamine does not induce their production. Histamine helps to maintain a wakeful state through an effect on Hj-receptors. Histamine-mediated hronchoconstriction is mediated by Hj-receptors, while histamine-mediated vasodilation occurs as a result of stimulation of Hi- and Hj-receptors. 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

VASODILATOR ANTIHYPERTENSIVES PROTEASE INHIBITORS t adverse effects of bosentan by ritonavir Inhibition of CYP3A4-mediated metabolism of bosentan Co-administration is not recommended... 

SSRIs PERIPHERAL VASODILATORS -CILOSTAZOL Fluoxetine, fluvoxamine and sertraline t cilostazol levels Fluoxetine, fluvoxamine and sertraline inhibit CYP3A4-mediated metabolism of cilostazol Avoid co-administration... 

PROTON PUMP INHIBITORS PERIPHERAL VASODILATORS -CILOSTAZOL Cilostazol levels are t by omeprazole and possibly lansoprazole Omeprazole inhibits CYP2C19-mediated metabolism of cilostazol Avoid concomitant use. US manufacturer advises halving the dose of cilostazol... 

Recently Liu and Weller [84] have reviewed the arachidonic acid metabolism in filarial parasites and other helminths. Arachidonic acid (AA) is a 20 carbon polyunsaturated fatty acid derived from dietary fatty acids. In human tissues, AA is usually present in the esterified form such as glycerolipids, phospholipids and neutral lipids. The free AA, released by phospholipases, undergoes various enzymatic oxygenations to form local mediators such as prostaglandins and leukotrienes, which are collectively known as eicosanoids (Chart 9). These eicosanoids are associated with platelet aggregation, vasodilation, leukocyte inflammatory and immune functions and cellular adhesion [85]. 

Coronary blood flow is closely tied to oxygen needs of the heart. Changes in oxygen balance lead to very rapid changes in coronary blood flow. Although a number of mediators may contribute to these changes, the most important ones are likely to be adenosine, other nucleotides, nitric oxide, prostaglandins, CO2, and H. Adenosine, which is formed from adenosine triphosphate (ATP) and adenosine monophosphate (AMP) under conditions of ischemia and stress, is a potent vasodilator that links decreased perfusion to metabolically induced vasodilation, or reactive hyperemia. The synthesis and release of adenosine into coronary sinus venous effluent occur within seconds of coronary artery occlusion, and about 30% of the hyperemic response can be blocked by metabolic blockers of adenosine. " ... 

ACE inhibitors (ACEIs) (e.g., captopril) inhibit kininase II (angiotensin-converting enzyme), blocking the formation of angiotensin II and preventing its activation of AT-1 receptors in the adrenal cortex —> 4, aldosterone and its effect on vasculature, thereby i vasoconstriction. ACEIs also inhibit the metabolism of bradykinin (BK), which causes NO/EDRF-mediated vasodilation - l TPR. 

Hydralazine. Vasodilator drug which causes systemic lupus erythematosus in a significant proportion of patients. Several predisposing factors have been identified dose (>25 mg) duration of therapy (mean 18 months) acetylator phenotype (slow) HLA type (DR4) gender (females males, 4 1). Antinuclear antibodies and antihydralazine antibodies detected in serum. Causes a Type III immune reaction. Mechanism is unclear but may involve reaction of parent drug or metabolite with protein. Interference with the complement system and interaction with nucleic acids also occur. Metabolism also may be mediated by myeloperoxidase in activated neutrophils. 

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