Hypotensive action mechanism

Mode-of-Action Hypotheses. May we now turn to consider some of the suggested mechanisms put forward to explain the hypotensive action of the 3-blocking drugs and see if any are compatible with the clinical and pharmacological data. Before doing so however, it perhaps would be useful to summarise the characteristics of the anti-hypertensive action of the drugs. 

The relevance of either the experimentally demonstrated central hypotensive action of the 3-blockers, or their ability to antagonise sympathetically mediated renin release remains to be proven. While it is still possible that the mechanism of the anti-hypertensive action of the 3-blocking drugs could contain both a central and a renin-inhibitary component, the clinical evidence would appear to rule against the possibility of either being a major component of the mode-of-action. 

Clonidine is a selective o -adrenergic agonist. Clonidine has expressed hypotensive action, which is associated with a reduction of general peripheral vascular resistance, reduced frequency of cardiac beats, and a reduction of cardiac output. The mechanism of action of clonidine is caused by stimulation of o -adrenoreceptors of the inhibitory structures of the brain as well as a reduction of sympathetic impulses to the blood vessels and brain. 

Most types of smooth muscle are dependent on transmembrane calcium influx for normal resting tone and contractile responses. These cells are relaxed by the calcium channel blockers (Figure 12-3). Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. In the vascular system, arterioles appear to be more sensitive than veins orthostatic hypotension is not a common adverse effect. Blood pressure is reduced with all calcium channel blockers. Women may be more sensitive than men to the hypotensive action of diltiazem. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina of effort. Reduction of coronary artery tone has been demonstrated in patients with variant angina. 

Ketanserin (Figure 16-2) blocks 5-HT2 receptors on smooth muscle and other tissues and has little or no reported antagonist activity at other 5-HT or Hi receptors. However, this drug potently blocks vascular adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin s hypotensive action probably involves Kj adrenoceptor blockade more than 5-HT2 receptor blockade. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. 

Sodium nitroprusside was first prepared and investigated in the middle of the nineteenth century, and a comprehensive summary of the earlier chemical investigations has been published (17). Up to 1910-1930, the addition reactions of bases to NP were explored, involving the characterization of colored intermediates (e.g., with SH-, SR-, and SO3 ), useful for analytical purposes. The hypotensive action of NP was first demonstrated in 1929, and a considerable research effort has attempted to establish the mode of action of NP and its metabolic fate. Questions still arise on the mechanism of NO release from NP in the biological fluids, and we refer to them below. New accounts dealing with modern structural and reactivity issues associated with the coordination of nitrosyl in NP and other complexes have appeared (18-20). From the bioinorganic and environmental viewpoint, nitrosyl iron complexes have been studied with... 

When given topically to individuals with elevated lOP, levobimolol induces a long-lasting ocular hypotension. The mean reduction in lOP with twice-daily 0.5% and 1% levobimolol is equivalent to that of timolol. As with timolol, the predominant mechanism of levobunolol s ocular hypotensive action is a decrease in the production of aqueous humor, with no significant effect on fecility of outflow. 

The AB KO adds a degree of confusion because this mouse had no change in BP measured by tail cuff (5). Possibly, the AB KO has increased sympathetic activity, causing increased activation of the D, although it is unclear why the same mechanism would not normalize BP in the single A KO. Much more speculative is that the B normally has a hypotensive action, so that A and B deletion have offsetting effects on final BP. 

The mechanism of the clinical hypotensive action of p-blockers remains contentious, but several papers29 have demonstrated further the... 

The "False Neurotransmitter" concept as a basis for explaining the mechanism of the hypotensive action of MAO-I s is presented in greater detail by Gohen et al.61. The delayed action of the MAO-I s with respect to their clinical antidepressant and hypotensive activities is presumably due to an indirect effect dependent on the gradual accumulation of monoamines at the adrenergic nerve fibres. According to the... 

Mebutamate - The mechanism of the hypotensive action of mebutamate was investigated in cross circulation experiments in anesthetized dogs. The results suggested that the initial and transient hypotension may be largely due to the direct vasodilator action and that the sustained effect may be accounted for by an inhibition of the sympathetic vasomotor tone at the spinal and ganglionic levels. ... 

General. Noteworthy reports- and reviews pertaining to the pharma-cologicalj endocrinological > and clinical aspects of diuretics have appeared in the recent literature. The use of diuretics in the treatment of hypertension has been reviewed with especial emphasis on the hypotensive action of the aldosterone antagonist, spironolactone.° Fundamental studies on the mechanism of transport of electrolyte across the tubular epithelium have indicated that phospholipids may play a critical role. Phospholipase C and pancreatic lipase markedly reduced the rate of reabsorption of saline droplets infused into rat proximal tubules. Likewise, phospholipase C reduced the ability of extractable lipids to bind sodium and potassium ions in rat kidney homogenates whereas, phospholipase D and ribonuclease appear to enhance cation binding. ... 

Varga K, Lake KD, Huangfu D, Guyenet PG, Kunos G (1996) Mechanism of the hypotensive action of anandamide in anesflietized rats. Hypertension 28 682-686... 

Now, suppose the lABG team has successfully shown that the system can be manufactured and it works both in bench studies and in animal models. The sensor set is deemed ready to be taken to the relatively unknown territory of the radial artery of a sick patient. The radial artery has been used for pressure measurement but only an intact blood column to the central arteries is needed for pressure measurement and there is not necessarily substantial blood flow. Blood sampling is often performed as a passive activity that allows a syringe to fill by the action of the pressure. lABGs require reasonable flow to bring sample to the sensors. Cold, peripheral vasoconstriction, hypotension, and mechanical... 

Murakami et al. reported that Chlorella administration suppressed the rise of blood pressure and elongated the life-span in stroke-prone spontaneously hypertensive rats (SHRSP) [54]. The mechanism of hypotensive action and the elongation of the life-span by Chlorella administration involved the lowering of the plasma rennin activity, and depressing the reduction of elastin content in the aorta of SHRSP. Moreover, it has been reported that intravenous, intraperitoneal, or oral administration of Chlorella alkali extract showed a fall of the blood pressure in SHRSP [55], Thus, Chlorella was expected to have a hypotensive effect in SHRSP. 

The mechanism of the central hypotensive action for methyidopa is attributed to its transport into the CNS via an aromatic amino acid transport mechanism, where it is decarboxylated and hydroxylated into a-methyInorepinephrine... 

Studies of the phenolic constituents of Morus root bark were originally undertaken to characterize the hypotensive components of the root bark. Kuwanons G (25) (33), H (26) (34), M (160) (136), mulber-rofurans C (130) (111), F (131) (112), and G (27) (112) were shown to be hypotensive components of the root bark of the cultivated mulberry tree. Compounds 25, 26, 130, 131 and 27 were almost equally effective in causing a transient decrease in arterial blood pressure in doses of 0.1-1 mg/Kg (i.v.) in rabbits. Kuwanon M (160) (136) showed hypotensive action in hypertensive rats (2 mg/Kg, i.v,). On the other hand, sanggenons C (164) (140) and D (165) (141) were characterized as the hypotensive compounds of the crude medicine Sang-Bai-Pi . Sanggenon C (164) showed a marked hypotensive effect (1 mg/Kg, i.v.) in rabbits, and 165 showed the same effect (0.5-2.0 mg/Kg, i.v.) in rats. The mechanism of the hypotensive action of 25 and 26 has been discussed (95). 

Prostaglandins - The hypotensive action of prostaglandins continues to be of interest as a possible basis for the development of a new type of anti-hypertensive agent. Arterial infusion of FGEg ( 10 M.) reduced the amount of norepinephrine released by nerve stimulation. Such inhibition was suggested as a possible mechanism for its hypotensive effect. ... 

The hypotensive action of XV in hypertensive rats was almost completely blocked by the decarboxylase inhibitor Ro U-lt602. A possible central action was indicated, but a "false transmitter" mechanism could not be ruled out. ... 

Propranolol - The mechanism of the potent hypotensive action of propranolol was studied. Frequently high doses were required and the onset of effect was slow, but problems... 

Renal Antlhvpertensive Factors - In addition to a prohypertensive mechanism it has been recognized for many years that the kidney possesses an antihypertensive mechanism. Loss of the antihypertensive function may be as important to the pathogenesis of hypertension as activation of the hypertensive mechanism. Work in this area has been kindled in recent years by the demonstration that explants of renomedullary tissue will prevent the onset of renoprival hypertension or lower the blood pressure of animals with renal hypertension. Extracts of renal medullary tissue have been shown to lower the blood pressure of animals with experimental hypertension by a number of investigators. Extracts possess both an acute transient hypotensive action and a slow onset, protracted effect. The acute effect is due to the presence of prostaglandins . The substance responsible for the delayed response is also lipid in character, however, it appears to be a neutral lipid and not in the prostaglandin family " . 

Nortriptyline. Nortriptyhne, a tricychc antidepressant, has been shown in double-blind, placebo-controlled randomized trials to be superior to placebo for smoking cessation (Prochazka et al. 1998). Nortriptyline appears to have efficacy comparable to that of bupropion for smoking cessation (Hall et al. 2002). The efficacy of this agent may be improved with more intensive behavioral therapies (Hall et al. 1998). Nortriptyline s mechanism of action is thought to relate to its noradrenergic and serotonergic reuptake blockade, because these two neurotransmitters have been implicated in the neurobiology of nicotine dependence. Side effects of nortiptyline are typical of tricyclic antidepressants and include dry mouth, blurred vision, constipation, and orthostatic hypotension. Nortriptyline appears to have some utility for smokers with a past history of major depression, and it can be recommended as a second-... 

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