Antihypertensive effects

Prazosin, a selective a -adrenoceptor antagonist, exerts its antihypertensive effect by blocking the vasoconstrictor action of adrenergic neurotransmitter, norepinephrine, at a -adrenoceptors in the vasculature (200,227,228). Prazosin lowers blood pressure without producing a marked reflex tachycardia. It causes arteriolar and venular vasodilation, but a significant side effect is fluid retention. Prazosin increases HDL cholesterol, decreases LDL cholesterol, and does not cause glucose intolerance. 

P-Adrenoceptor Blockers. There is no satisfactory mechanism to explain the antihypertensive activity of P-adrenoceptor blockers (see Table 1) in humans particularly after chronic treatment (228,231—233). Reductions in heart rate correlate well with decreases in blood pressure and this may be an important mechanism. Other proposed mechanisms include reduction in PRA, reduction in cardiac output, and a central action. However, pindolol produces an antihypertensive effect without lowering PRA. In long-term treatment, the cardiac output is restored despite the decrease in arterial blood pressure and total peripheral resistance. Atenolol (Table 1), which does not penetrate into the brain is an efficacious antihypertensive agent. In short-term treatment, the blood flow to most organs (except the brain) is reduced and the total peripheral resistance may increase. 

Better antihypertensive effect of P-adrenoceptor blockers is found in patients having high PRA and most are not efficacious in patients having low PRA or in elderly patients. P-Adrenoceptor blockers usually lower arterial blood pressure about 10 mm Hg (1.3 kPa). Side effects include lethargy, dyspnea, nausea, dizziness, headache, impotency, cold hands and feet, vivid dreams and nightmares, bronchospasm, bradycardia, and sleep disturbances. 

Intake of a large amount of sodium chloride negates the antihypertensive effects of diuretics. Other mechanisms, such as direct vasodilating action, decreased responsiveness to vasopressor agents, stimulation of prostacyclin [35121 -78-9] production, and reduction in the intracellular calcium... 

Potassium Sparing Diuretics. Triamterene and amiloride, potassium sparing diuretics, by themselves produce only slight antihypertensive effects. The main use is to prevent or to treat the hypokalemia induced by thiazide-type and high ceiling loop diuretics, such as furosemide and bumetanide. 

Methyldopa, through its metaboHte, CX-methyInorepinephrine formed in the brain, acts on the postsynaptic tt2-adrenoceptor in the central nervous system. It reduces the adrenergic outflow to the cardiovascular system, thereby decreasing arterial blood pressure. If the conversion of methyldopa to CX-methyl norepinephrine in the brain is prevented by a dopamine -hydroxylase inhibitor capable of penetrating into the brain, it loses its antihypertensive effects. 

The efficacy of these diuretics led to their extensive use in the clinic, particularly in treatment of hypertension. In theory at least, reduction of the blood volume by diuresis should lead to a lowering of pressure (PV=RT). This expectation was in fact met in actual practice. Recent research does, however, seem to indicate that the thiazides have an antihypertensive effect beyond that explainable by a simple lowering of blood volume. 

The amphetamines and the anorexiants should not be given during or within 14 days after administration of monoamine oxidase inhibitors (see Chap. 31) because the patient may experience hypertensive crisis and intracranial hemorrhage. When guanethidine is administered with the amphetamines or the anorexiants, the antihypertensive effect of guanethidine may decrease. Coadministration of the amphetamines or the anorexiants with the tricyclic antidepressants may decrease the effects of the amphetamines or the anorexiants. 

NSAIDs or phenobarbital, their antihypertensive effects may be decreased. 

The hypotensive effects of most antihypertensive dru are increased when administered with diuretics and other antihypertensives. Many dnigp can interact with the antihypertensive drugs and decrease their effectiveness (eg, antidepressants, monoamine oxidase inhibitors, antihistamines, and sympathomimetic bronchodilators). When the ACE inhibitors are administered with the NSAIDs, their antihypertensive effect may be decreased. Absorption of the ACE inhibitors may be decreased when administered with the antacids. Administration of potassium-sparing diuretics or potassium supplements concurrently with the ACE inhibitors may cause hyperkalemia. When the angiotensin II receptor agonists are administered with... 

Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with P-blockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including P-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed.66 The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients.49 For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include P-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure.2,49... 

Compound 686 (PNU-97018) is an orally active nonpeptide angiotensin II receptor antagonist without any agonistic activity that has an insurmountably high antihypertensive effect <2002CPB1022, 1995JEP1042, 1995MI880>. 

Thiazide diuretics (e.g., hydrochlorothiazide) are relatively weak diuretics and are used alone infrequently in HF. However, thiazides or the thiazide-like diuretic metolazone can be used in combination with a loop diuretic to promote effective diuresis. Thiazides may be preferred over loop diuretics in patients with only mild fluid retention and elevated blood pressure because of their more persistent antihypertensive effects. 

Unlike ACE inhibitors, ARBs do not block the breakdown of bradykinin. While this accounts for the lack of cough as a side effect, there may be negative consequences because some of the antihypertensive effect of ACE inhibitors may be due to increased levels of bradykinin. Bradykinin may also be important for regression of myocyte hypertrophy and fibrosis, and increased levels of tissue plasminogen activator. 

Aliskiren blocks the renin-angiotensin-aldosterone system at its point of a activation, which results in reduced plasma renin activity and BP. It provides BP reductions comparable to an ACE inhibitor, ARB, or CCB. It also has additive antihypertensive effects when used in combination with thiazides, ACE inhibitors, ARBs, or CCBs. It is approved for monotherapy or in combination with other agents. 

Reserpine has a long half-life that allows for once-daily dosing, but it may take 2 to 6 weeks before the maximal antihypertensive effect is seen. 

Noncydic nitrosohydrazines have been reported to function as NO-sources and to exhibit antithrombotic and antihypertensive effects in animal models that were similar to their corresponding cydized compounds [139, 150]. 

A series of 1-substituted 3-phenylbenzazepines have been evaluated. It was found that the aminopropyl derivative (6, n = 3 R1 = R2 = Et) counteracted amphetamine toxicity, and that the piperazinyl derivative (6) (n = 2 NR R2 = N(CH2CH2)2 = NCH2CH2OH) gave protection against maximal electroshock seizures (MES) [12]. None of the other derivatives such as the 2-oxo derivatives showed any significant effects on the central nervous or cardiovascular system, nor did any of them exhibit any diuretic or hypo-glycaemic activity [12]. Several similar compounds possess antiarrhythmic and antihypertensive effects this will be mentioned in a later section. 

Some optically active compounds have been studied [54], The benzazepinone diacid (CGS 12831, 27) was found to have the best in vitro inhibitor potency in a series of lactam compounds, but it showed only marginal biological activity following oral administration, presumably because of poor absorption. The corresponding monoethyl ester (CGS 14824A, 28) was much more potent in vivo [54, 56]. This compound (28) was found to produce dose-dependent antihypertensive effects in conscious normotensive and spontaneous hypertensive rats, generally similar to those produced by enalapril. Evaluation of (28) in healthy volunteers [57, 58] shows that it is an effective,... 

Despite their successful use for at least 20 years, the mechanisms by which they lower the blood pressure remain uncertain. Theories to explain the antihypertensive effectiveness of the diuretic agents have included a) alteration of sodium and water content on arterial smooth muscle, b) the induction of a decreased vascular response to catecholamines, c) a decrease in blood volume and total extracellular fluid volume, and d) a direct vasodilator action independent from the diuretic effect(12). 

Maruyama, H., Sumitou, Y., Sakamoto, T., Araki, Y. and Hara, H. (2009) Biol. Pharm. Bull., Antihypertensive effects of flavonoids isolated from Brazilian green propolis in spontaneously hypertensive rats, 32(7), 1244-1250. 

Rauwolfia derivatives became available in the 1950s in western medicine for the treatment of hypertension. The antihypertensive effects of rauwolfia alkaloids occur from their depletion of monoamines in adrenal chromaffin cells and sympathetic ganglia, and perhaps central neurons as well (Oates 1996). 

Oxdralazine (67) is characterized by a bis(2-hydroxyethyl)amino group attached to position 6 of 3-hydrazinopyridazine. The antihypertensive effect of (67) has been studied in rats (spontaneous, desoxycorticosteron-induced, and renal hypertension) [223]. Its effect in the long-term treatment of hypertensive rats on plasma and kidney renin activities has been reported [224]. The effects of (67) on the general and cardiac haemodynamics of anaesthe-... 

Several peptides possessing antihypertensive effect proved to play a promising role in regnlating vascnlar fnnctions as described in the past researches. The present chapter is aimed to offer an overview of a new functionality of small peptides in preventing hypertension and vessel dysfunctions including atherosclerosis. 

Table 1 summarizes the antihypertensive effects of ACE inhibitory small peptides. Information of dosage is also listed. It is clear that small peptides can exert an antihypertensive action following oral administration to mild hypertensive subjects, similar to therapeutic ACE inhibitory drugs, despite their poor potency on ACE inhibitory activity. It seems likely that ca. 20-fold higher doses of small peptides than drugs are required to... 

Kawasaki T, Seki E, Osajima K, Yoshida M, Asada K, Matsui T, Osajima Y. (2000) Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects. 

Sekiya S, Kobayashi Y, Kita E, Imamura Y, Toyama S. (1992) Antihypertensive effects of tryptic hydrolysate of casein on normotensive and hypertensive volunteers. J Jpn Soc Nutr Food Sci 45 513-517. 

Kajimoto O, Maruyama H, Tokunaga K, Yoshida C, Suzuki K, Araki Y, Mishima S, Sakamoto A, Kajimoto Y, Hirata H. (2004) Antihypertensive effect of protease-treated royal jelly in subjects with high-normal or mild hypertension. J Nutr Food 7 53-71. 

Lee SH, Qian ZJ, Kim SK. (2010) A novel angiotensin 1 converting enzyme inhibitory peptide from tuna frame protein hydrolysate and its antihypertensive effect in spontaneously hypertensive rats. Food Chem 118 96-102. 

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