Vascular smooth muscle process

Because baroreceptors respond to stretch or distension of the blood vessel walls, they are also referred to as stretch receptors. A change in blood pressure will elicit the baroreceptor reflex, which involves negative feedback responses that return blood pressure to normal (see Figure 15.6). For example, an increase in blood pressure causes distension of the aorta and carotid arteries, thus stimulating the baroreceptors. As a result, the number of afferent nerve impulses transmitted to the vasomotor center increases. The vasomotor center processes this information and adjusts the activity of the autonomic nervous system accordingly. Sympathetic stimulation of vascular smooth muscle and the heart is decreased and parasympathetic stimulation of the heart is increased. As a result, venous return, CO, and TPR decrease so that MAP is decreased back toward its normal value. 

The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenoceptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly a-adrenoceptors. The interaction of compounds with these adrenoceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for a-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains p2-adrenoceptors, the response in this tissue elicited by the action of p2-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for p2-adrenoceptors, cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for p2-adrenoceptors and has relatively weak bronchiolar relaxing properties. 

Available evidence suggests that a single unifying mechanism does not exist but rather that various vasodilators may act at different places in the series of processes that couple excitation of vascular smooth muscle cells with contraction. For example, the vasodilators known as calcium channel antagonists block or limit the entry of calcium through voltage-dependent channels in the membrane of vascular smooth muscle cells. In this way, the calcium channel blockers limit the amount of free intracellular calcium available to interact with smooth muscle contractile proteins (see Chapter 14). 

Effects on cell function determine whether the drug is an agonist, partial agonist, or antagonist at the relevant receptors. Isolated tissues, especially vascular smooth muscle, would be used to characterize the pharmacologic activity and selectivity of the new compound in comparison with reference compounds. Comparison with other drugs would also be undertaken in other in vitro preparations such as gastrointestinal and bronchial smooth muscle. At each step in this process, the compound would have to meet specific performance and selectivity criteria to be carried further. 

Urodilatin is synthesized in the distal tubules of the kidneys by alternative processing of the ANP precursor. It elicits potent natriuresis and diuresis, and thus functions as a paracrine regulator of sodium and water excretion. It also relaxes vascular smooth muscle. 

This hemostatic/prothrombotic process is counterbalanced by vascular prostacyclin (PGl2) derived predominantly from COX-2 activity and nitric oxide (NO) released from endothelial cells. In vascular endothelial cells, COX-2 produces primarily PGI2 that inhibits platelet aggregation, induces vasodilation, inhibits the proliferation of vascular smooth-muscle cells, and is less susceptible to inhibition by low doses of aspirin. PGI2 and NO induce an intracellular increase of second messengers. NO inhibits platelet function by stimulation of a soluble guanylyl cyclase to produce cGMR... 

Like the 5-HT1A receptor (see Section 2.1), the 5-HT2A receptor can regulate several transport processes. The 5-HT2A receptor activates the type 1 sodium-proton exchanger (NHE-1) in renal mesangial cells (187,227) and vascular smooth muscle cells (222), the Na+K+-AIPase (sodium pump) in airway smooth muscle cells (228), and the Na+/K+/2Cr cotransporter when 5-HT2A receptor transfected... 

The mechanisms by which thiazides affect erectile dysfunction or libido are unclear, but it has been suggested that they have a direct effect on vascular smooth muscle cells or reduce the response to catecholamines. Sexual dysfunction does not appear to be mediated by either a low serum potassium concentration or a low blood pressure. Since sexual dysfunction can adversely affect the quality of life of hypertensive patients, physicians or health-care providers should take an accurate baseline sexual history and monitor sexual status for changes during therapy. If there are significant changes in sexual function, diuretic therapy can be withdrawn and an alternative drug class substituted. However, not uncommonly sexual dysfunction will persist despite withdrawal of the diuretic, suggesting that elements of the hj pertensive state itself contribute to the process. 

The Ca " content of the sr is determined by a balance between the activity of the Ca -ATPase pump and mechanisms which release Ca " from the store (Fig. 9.3). These mechanisms include the opening of ion channels in the sr membrane in response to IP3 and passive leak of Ca out of the sr. Both of these processes involve the movement of Ca " " from the high concentration within the store, estimated to be 5 mM Ca (Leijten and van Breemen, 1984), to the low concentration (100 nM) within the cytosol. Functional studies in vascular smooth muscle have demonstrated that the quantity of Ca " " stored in the sr is sufficient to activate maximal... 

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