Hypertension possible mechanisms

The possible mechanism kidney-induced hypertension is discussed in Section 2.4.2, Mechanisms of Toxicity. Lead appears to affect vitamin D metabolism in renal tubule cells, such that circulating levels of the vitamin D hormone, 1,25-dihydroxyvitamin D, are reduced. This effect is discussed later in this section under Other Systemic Effects. 

Propranolol lowers blood pressure in the majority of patients with essential hypertension. These effects can be caused by a number of possible mechanisms, including lowering cardiac output, inhibiting the release of renin, lowering sympathetic release from the central nervous system, inhibiting the release of norepinephrine from sympathetic postganglionic nerves, and others. 

FIGURE 21-1 Schematic diagram of the possible mechanisms in essential hypertension. Various factors interact to turn on sympathetic outflow to the kidneys, heart, and peripheral vasculature, resulting in elevated blood pressure. Hypertension also causes structural and functional changes in the vasculature that help maintain the elevated pressure. 

However, the levels of Gsa, Gia-1, Gia-2, Gia-3, Goa, and Gp were also shown to be unaltered in myocardium from SHRs, and adenylyl cyclase activity stimulated by PGEi, glucagon, and isoproterenol was reduced in SHRs, whereas FSK-stimulated enzyme activity was greater in SHRs as compared to WKY (McLellan et al. 1993). On the other hand, a diminished stimulation of adenylyl cyclase by stimulatory hormones, guanine nucleotides, FSK, and NaF in aorta and heart sarcolemma from SHRs (Anand-Srivastava 1992), renal hypertensive rats (Anand-Srivastava 1988) 1K1C HRs (Ge et al. 1999, 2006), and DOCA-salt HRs (Anand-Srivastava et al. 1993) has been demonstrated The reduction in the hormone receptor binding sites may be one of the possible mechanisms responsible for such an impaired response of hormones (Limas and Limas 1978 Woodcock et al. 

Fig. 1.7 Possible mechanisms involving angiotensin II, oxidative stress and nitric oxide in enhanced Gi oc protein expression in hypertension. Gi protein expression is enhanced in genetic (SHR) and experimental hypertension including 1 kidney 1 clip (1K1C) and L-NAME-induced hypertension. Inhibition of nitric oxide synthase (NOS) by L-NAME activates renin angiotensin system, and also decreases the level of NO. 1K1C hypertensive rats also exhibit enhanced levels of Ang II. Ang II increases oxidative stress that through increased MAP kinase activity results in enhanced expression of Gi oc proteins and thereby hypertension. On the other hand, increased levels of NO and cGMP decrease the expression of Gia proteins in VSMC which may be an additional mechanism through which NO decreases blood pressure in L-NAME-induced hypertensive rats.

Several cases of hypertension have been associated with clozapine (SEDA-22, 57), and alpha2-adrenoceptor blockade has been proposed as a possible mechanism (28). Four patients developed pseudopheochromocytoma syndrome associated with clozapine (33) all had hypertension, profuse sweating, and obesity. The authors suggested that clozapine could increase plasma noradrenaline concentrations by inhibiting prcsynaptic reuptake mediated by alpha2-adrenoceptors. 

Shiwach RS. Treatment of clozapine induced hypertension and possible mechanisms. Clin Neuropharmacol 1998 21(2) 139 10. 

HEPARINS VASODILATOR ANTI HYPERTENSIVES Possible t risk of bleeding with iloprost Anticoagulant effects of heparins t by an mechanism that is uncertain at present Monitor APTT closely... 

Tliese findings demonstrate that platelets finm hypertensive humans and animals exhibit a greater sensitivity not only to thrombin, which is an inducer of aggregation, but also to PGE, diich is an inhibitor of platelet aggregation. Possible mechanisms that may be resptmsible forfiie increased sensitivity to both PGEl and thrombin are discussed below. 

II is found on the surface of B cells, neutrophils, and macrophages and shows higher affinity for IL-1 p [7,59]. Types I and II are regulated differently in brain ischemia and may thus play separate roles. In spontaneously hypertensive rats, the mRNA for the type I IL-1 receptor was found to be relatively highly expressed in the normal cortex, with a marked increase 5 days after cerebral ischemia [7,58]. Type II mRNA has low basal expression and a peak 12 hours after the onset of ischemia [7,58]. The possible mechanisms of intracellular signal transduction for IL-1 on peripheral immune cells include effects on cAMP, protein kinase C, and protein phosphorylation. These effects remain to be proved in cerebral ischemia [7,59]. The IL-1-receptor interaction is quickly followed by the induction of immediate-early genes such as c-jun and c-fos [7,60]. 

When this enzyme is inhibited, the concentrations of norepinephrine within adrenergic neurons increase and drugs that stimulate its release can bring about an exaggerated response. Interactions between MAO inhibitors and indirectly acting sympathomimetic amines (e.g., amphetamine) develop by this mechanism. If amphetamine is administered to a patient whose stores of norepinephrine have been increased by MAO inhibition, the patient may experience severe headache, hypertension (possibly a hypertensive crisis), and cardiac arrhythmias. The serious consequences associated with these interactions contraindicate the use of these agents in combination. 

Taylor J, Pahl M, Rajpoot D. Erythropoietin-induced hypertensive encephalopathy in a child possible mechanisms. Dial Transplant 2002 31 170-88. 

Although -blockers have been in use for a long time, their mechanism of action in hypertension is uncertain yet, although a number of possible mechanisms are likely to be involved. There are many P-blockers now available and... 

Levin, D. L., Hyman, A. I., Heymann, M. A., and Rudolph, A. M. (1978). Fetal hypertension and the development of increased pulmonary vascular smooth muscle A possible mechanism for persistent pulmonary hypertension of the newborn infant.. Pediatr. 92, 265-269. 

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 chemopreventive activity of hibiscus extracts has been extensively studied recently. The protective effect was demonstrated against human carcinomas, chemically induced toxicity,and hepatotoxici-jy 11,21-27 Antimutagenic activity has also been demonstrated both in vitro and in vivo The chemopreventive activity is attributed mainly to the antioxidant effect of the anthocyanins present in hibiscus extracts. Roselle decoction or infusion reportedly has hypotensive properties with no side effects. This effect has been investigated in more depth in experimental animals and in humans over the past decade and the results seem to support earlier studies especially in mild to moderate hypertension. Suggested mechanisms of action for the hypotensive activity include inhibition of Ca influx into vascular smooth muscle, NO-cGMP-relaxant pathway, and possible acetylcholine-and histamine-like vasorelaxation. ... 

This mechanism of action unlike the previously discussed ones, would account for the delay in onset of the hypertensive action. It would also fit in well with the results from the comparative studies, that provided sufficient drug is given to adequately block the cardiac 3-receptors, all 3-blockers are roughly equally effective. A further point which may possibly explain why the cardioselective drug ICI 66082 is marginally more effective than the non-selective propranolol, is that the former could assist the relaxation of the peripheral vessels by not blocking the vascular 3-receptors. 

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. 

The molecular mechanism of diuretics acting as antihypertensive agents is not completely clear however, use of diuretics causes a significant increase in the amount of water and electrolytes excreted in urine, which leads to a reduction in the volume of extracellular fluid and plasma. This in turn leads to a reduction of cardiac output, which is the main parameter responsible for a drop in arterial blood pressure and venous blood return. Cardiac output is gradually restored, but the hypotensive effect remains, possibly because of the reduced peripheral resistance of vessels. It is also possible that diuretics somehow lower vascular activity of noradrenaline and other factors of pressure in the organism. Methods of synthesizing thiazide diuretics used for hypertension are described in the preceding chapter. Chapter 21. 

When given rapidly, protamine causes hypotension due to a decrease in vascular resistance, possibly linked to the release of nitric oxide from endothelium. Flypotension can be minimised by slow administration over 10-15 minutes. Protamine does not affect myocardial contractility. In some patients, systemic hypotension occurs in conjunction with pulmonary hypertension and, in severe cases, right ventricular failure. The mechanism is activation of the complement pathways by the heparin-protamine complex leading to release of thromboxane A2, which mediates pulmonary vasoconstriction. Unlike in anaphylaxis, plasma histamine concentrations are not increased. When this syndrome develops protamine administration should be stopped, and some have recommended giving heparin in an attempt to reduce the size of the heparin-protamine complex. 

Arterial hypertension, one of the most important diseases under modern social and economic conditions, presents a major problem to biochemistry the discovery of specific therapeutic measures for its alleviation. This paper discusses known humoral substances, examines each in the light of its possible relation to hypertension, and considers other evidence of the existence of such substances and their chemical structure. Humoral pressor mechanisms are probably initiated by neurogenic ones and therefore comprise only one link in the chain of events that lead to chronic hypertension. 

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