Vasodilation, control

In low doses, inhaled NO may have a beneficial therapeutic effect, since NO in the inspired air leads to pulmonary vasodilation. In persistent pulmonary hypertension of the newborn, NO inhalation has already been used with some success. NO inhalation as the treatment for acute respiratory distress syndrome, however, has been disappointing. Only transient improvements of oxygenation were detected and the outcome of placebo-controlled trials did not show any improvement... 

The answer is a. (Hardman, pp 228-229.) Phentolamine is a non-selective a-adrenergic receptor blocker (i.e., it has affinity for both - and ct2-adrenergic receptor sites). It also has a prominent direct relaxant (musculotropic spasmolytic) effect on arterioles, which results in vasodilation and reflex tachycardia. In addition, phentolamine can block the effects of serotonin and will increase hydrochloric acid and pepsin secretion from the stomach. Phentolamine is used for the short-term control of hypertension in patients with pheochromocytoma (i.e., a type of secondary hypertension) because of the high incidence of tachycardia associated with the compound, it is not used chronically for the treatment of essential hypertension... 

Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, D Anna R, Lasco A, Squadrito G, Gaudio A, Cancellieri F, Arcoraci V, Squadrito F (2001) Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vase Biol 21 1512-1519... 

Hypertension is a well known contributor to a number of diseases, but hypotension can be equally dangerous as tissues rely upon pressure to maintain a constant delivery of nutrients via the micro-circulation of fluid around individual cells. As pressure and volume are interdependent, blood pressure is controlled by either changing the internal diameter of the vessels (vasoconstriction or vasodilation) or by increasing the fluid volume contained within the vasculature. 

Amiodarone (11), a benzofuran derivative, was initially developed as a coronary vasodilator in the early 1960 s [11,12]. Several years later, the efficacy of the compound as an antiarrhythmic agent began to be exploited. The first clinical trials with amiodarone were reported in 1974 [13]. Amiodarone was effective in controlling the tachyarrhythmias of eleven patients with Wolff-Parkinson-White syndrome. Since that time the compound has been studied extensively [14,15]. Recently, in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), amiodarone was shown to reduce mortality during a mean 18 month period following myocardial infarction (13.8% deaths in placebo group vs. 2.1 % deaths in the treatment group) [16]. 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Chiral /3,/3-diaryIpropionic acid moieties are often found in compounds showing biological activities, such as antiarrhythmics vasodilators antidepressives " , antihistamines and controllers of cerebral insufficiency ". In the course of synthetic studies of chiral -diaryIpropionic acid derivatives, Merck researchers developed stereoselective conjugate addition of aryllithium reagents to the a,/ -unsaturated fert-butyl esters 18 bearing a chiral imidazolidine or oxazolidine auxiliary at the ortho position of an aryl group. The addition furnished chiral -diaryIpropionic acid derivatives 19 with... 

The mechanism of action of these drugs is not completely understood. However, it is very likely that they inhibit cellular phosphodiesterase of the myocardium, which leads to an elevation in the cellular level of cyclic AMP, which in turn facihtates contraction of myocardial cells. It is clear that these drags are not 8-adrenoreceptor antagonists, and that their effect is not mediated by inhibition of (Na -K+) ATPase. They simultaneously increase the flow of calcium ions into the cell. They are used for short-term control of patients that inadequately react to cardiac glycosides, diuretics, and coronary vasodilating agents. 

Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators, including sildenafil, tadalafil, and vardenafil Those with left ventricular outflow obstruction (eg, aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. 

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