Antihypertensive Effect In Patients Research Articles

The renal profile of eprosartan.

The angiotensin II (AII) receptor antagonist eprosartan is a highly selective, nonpeptide drug specific for the AT1 receptor subtype that completely inhibits pressor, aldosterone secretory, and renal vasoconstrictive effects produced by AII infusions in healthy humans. It increases effective renal plasma flow in both salt-replete and salt-restricted healthy men, and maintains glomerular filtration rates in patients with essential hypertension and those with renal insufficiency after either single or multiple doses. In healthy salt-restricted men, the drug suppresses and stimulates aldosterone and renin, respectively, in the initial few hours after administration. This feedback inhibition for renin release and suppression of aldosterone is reduced with normal sodium intake. Eprosartan is natriuretic in salt-restricted subjects and does not induce sodium retention even when it reduces blood pressure. These properties, in addition to antagonism of AII effect at the AT1 receptor, no doubt contribute to the agent's antihypertensive effect in patients with essential hypertension. Pharmacodynamic studies predict that doses of up to 400 mg are safe. Additional preliminary studies suggest that doses as high as 1200 mg are safe and well tolerated, while producing meaningful hemodynamic and neurohumoral effects in patients with essential hypertension.

Enhanced Efficacy of Nilvadipine in Hypertensives Whose Raised Ambulatory Blood Pressure Is Sustained During Sleep

This study was designed to clarify the relationship between the antihypertensive effects of the calcium antagonist nilvadipine, and circadian changes in blood pressure. Based on measurements using an ambulatory blood pressure monitoring system (ABPM), 17 outpatients with untreated essential hypertension were divided into two groups: a sustained hypertensive group (with a fall in blood pressure during sleep < 10%, n = 7) and a waking time hypertensive group (with a fall in blood pressure during sleep ≥ 10%, n = 10). During treatment with nilvadipine (8 mg/day, ≥ 2 weeks), patients were reexamined by ABPM. The antihypertensive effect of nilvadipine was significantly and negatively correlated with the night time fall in blood pressure: this effect was significantly greater in the sustained hypertensive group than in the waking time hypertensive group. These data suggest that the long acting calcium antagonist nilvadipine has more potent antihypertensive effects in patients with sustained hypertension (“nondippers”) than in those whose hypertension lessens during sleep (“dippers”).

Endothelium-derived vasoactive factors in hypertension: nitric oxide and endothelin.

ENDOTHELIUM-DERIVED NITRIC OXIDE: The endothelium is a source of vasoactive factors among which the most relevant are nitric oxide and endothelin. Nitric oxide is synthesized from L-arginine by a family of nitric oxide synthases and is a widespread biological mediator. It is implicated in many physiological and pathophysiological processes, including a variety of cardiovascular diseases like hypertension. NITRIC OXIDE AND HYPERTENSION: The release of nitric oxide seems to be modulated by changes in blood pressure. However, the role of nitric oxide in hypertension is still controversial and seems to vary depending on the stage of the disease and the model studied. In spontaneous hypertension, the production of nitric oxide is increased but inefficacious, probably because of increased inactivation or scavenging. In the heart the production of nitric oxide seems to be increased, probably as a compensatory mechanism against hypertension. In salt-induced hypertension, nitric oxide production may be impaired. In human hypertension, pharmacological experiments reveal an impaired nitric oxide dilator mechanism. In pulmonary hypertension, the use of nitric oxide gas inhalation has been proposed as a future therapy for this condition. ENDOTHELIN: Endothelin-1 is a potent vasoconstrictor peptide produced and released from endothelial cells. In isolated blood vessels, endothelin causes profound contraction. The hemodynamic effects of endothelin can be explained by the activation of two endothelin receptors, ETA and ETB. The relationship between endothelin and hypertension is not clear. Although plasma endothelin levels are normal in most patients with essential hypertension, the hypertensive blood vessel wall may contract more profoundly in response to the peptide; hence, endothelin antagonists may have antihypertensive effects in patients with hypertension.

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. Exploratory study in which active treatment was preceded by placebo. Inpatient unit of teaching hospital. Nine men with uncomplicated essential hypertension who had a normal sodium intake. Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.

Nicardipine for systemic hypertension: Effects on blood pressure and target organ function

Nicardipine has been shown to lower blood pressure in patients with uncomplicated hypertension as well as in patients with concomitant renal impairment, coronary artery disease or congestive heart failure. The decrease in blood pressure induced by nicardipine is related to a concurrent decrease in total peripheral vascular resistance. The antihypertensive actions of nicardipine are maintained during long-term administration without the development of tachyphylaxis. In patients receiving diuretics or β blockers, the addition of nicardipine has been shown to produce an additional decrease in blood pressure. The combined use of nicardipine and β blockers may be beneficial in the treatment of hypertension: the increase in peripheral vascular resistance during β blockade may be prevented by nicardipine-induced vasodilation; conversely, β blockers may prevent reflex tachycardia and other consequences of peripheral vasodilatation. Although nicardipine may increase the heart rate acutely, tachycardia does not occur during long-term therapy. Preliminary data suggest that nicardipine exerts potent antihypertensive effects in patients with renal insufficiency without altering renal parameters. In patients with normal renal function, nicardipine has been shown to cause acute natriuresis and an increase in renal blood flow and glomerular filtration rate. Nicardipine also has a favorable effect on peripheral and cerebral blood flow. Like other dihydropyridines, nicardipine appears to have an antiatherogenetic effect in the experimental model. Short-term therapy with nicardipine does not affect serum lipid levels. Results from several studies suggest that nicardipine is an effective antihypertensive agent that can be used as monotherapy or in combination with other drugs such as β blockers or diuretics. Nicardipine may also have a favorable effect on target organ function and on various circulatory parameters without causing adverse metabolic or biochemical consequences.

Clinical significance of beta 1-selectivity and intrinsic sympathomimetic activity in a beta-adrenergic blocking drug

Almost all β-adrenergic blockers, regardless of their pharmacologic characteristics, appear to have blood pressure-lowering activity in hypertensive patients. Comparisons between nonselective β-blocking agents, such as propanolol and nadolol, with β 1-selective drugs, such as metoprolol, atenolol and acebutolol, have demonstrated close similarities in their antihypertensive effects in patients. Similarly, β blockers with and without intrinsic sympathomimetic activity (ISA) have comparable antihypertensive effects. However, β-selective agents may offer some advantages over conventional β blockers in hypertensive patients with concurrent conditions such as chronic obstructive airways disease, peripheral vascular disease, diabetes and hyperlipidemia. β 1-selective drugs are also preferred in diabetic patients receiving hypoglycemic agents because they do not interfere with glycogenolysis. Agents lacking ISA, such as propranolol, acutely increase peripheral resistance. β blockers with ISA usually lower resistance. ISA may also minimize the bradycardia frequently found in elderly patients. Agents with ISA may protect against the decrease in high density lipoprotein cholesterol and the modest increase in triglycerides noted with some β blockers that do not have ISA. Thus, in a large number of clinical situations in which hypertension is found, the properties of β 1 selectivity and ISA allow β blockers to be used with greater safety. Therefore, agents possessing both of these properties may be particularly valuable.

Esmolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Esmolol is a relatively cardioselective beta-adrenoceptor antagonist. Since esmolol is rapidly metabolised by blood-borne esterases, it has a very short half-life (about 9 mins) and a short duration of action. In this respect esmolol is unique amongst currently available beta-adrenoceptor antagonists, and it is anticipated that it will be particularly useful in critical care situations where administration by continuous intravenous infusion should permit a level of control over beta-adrenoceptor antagonism that has previously been unattainable. In perioperative settings, esmolol attenuates tachycardia induced by a variety of surgical stimuli such as endotracheal intubation, sternotomy and aortic dissection, suggesting a clinical use of the drug to prevent potentially serious complications in surgical patients with cardiovascular disease. Additionally, clinical studies have shown that titrated dosages of esmolol achieved therapeutic response rates of 66 to 79% in patients with supraventricular tachyarrhythmias, which favourably compared with response rates achieved with propranolol. In most of these patients esmolol produced a reduction in ventricular rate which was well maintained during infusion but disappeared within 30 minutes following esmolol withdrawal. Preliminary studies involving small numbers of patients have reported that esmolol exerts significant antihypertensive effects in patients with postoperative hypertension, and beneficial effects in patients with myocardial ischaemia and infarction, but support for these results is required from additional large, well-controlled studies. Esmolol has been generally well tolerated, and although hypotension has occurred in up to 44% of patients it resolved during or soon after the infusion of esmolol. Thus, esmolol is the first titratable beta-adrenoceptor antagonist able to be rapidly 'switched on' and 'off', a property that is expected to offer a major contribution to safety in critical care patients requiring beta-adrenoceptor antagonism for short durations.

Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension

The treatment response to beta-adrenoceptor blocking drugs was compared in two groups of patients with primary (essential) hypertension and different renin levels. Each group consisted of 25 patients and was equally distributed regarding age, severity and stage of hypertension. In the first group (group 1), the mean upright plasma renin activity was 0.8 ng ml −1h −1 (range 0.3 to 1.5) and the patients were considered to have tow renin hypertension. In the other group (group 2) the patients had a mean plasma renin activity of 2.1 ng ml −1h −1 (range 1.1 to 5.1) and were considered to have normal to high renin hypertension. In both groups the patients were initially treated with beta-blocking drugs; in group 1 with a beta-blocker corresponding to an average dose of 311 mg propranolol a day for at least eight weeks and in group 2 with propranolol 320 mg a day in a fixed dose for eight weeks. The hypotensive response differed significantly between the two groups (p < 0.001). In group 1 the pretreatment blood pressure was 197 117 mm Hg supine and 198 120 mm Hg standing. During treatment blood pressure decreased only 5 3 mm Hg supine and 9 5 mm Hg standing. The pretreatment blood pressure in group 2 was 187 114 mm Hg supine and 186 117 mm Hg standing. Beta-blocking therapy reduced blood pressure 36 23 and 34 18 mm Hg , respectively (both p < 0.001). Pulse rates fell significantly in the two groups, both in the lying and standing positions. In 17 patients with low renln hypertension (group 1), a volume-depleting drug was added (splronolactone, 14 patients; thiazides, 3 patients) and this achieved a marked fall in blood pressure levels of 38 16 mm Hg supine and 37 19 mm Hg standing (both p < 0.001). These results suggest the following: (1) Most patients with normal to high plasma renin activity respond well to moderate doses of propranolol. (2) Propranolol given in the same doses is almost without antihypertensive effect in patients with low renin hypertension. (3) A volume factor may be operating in patients with low renin hypertension since a hypotensive effect is demonstrated after the addition of volume-depleting drugs. (4) Determination of plasma renin activity with adequate methods can predict the treatment response to hypotensive agents.