Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We conducted pharmacodynamic studies with a new vasodilator, MDL-899. Following initial dose-ranging studies we studied eight male normotensive volunteers, each of whom received, orally, 10 mg MDL-899 or placebo in double-blind random order. MDL-899 significantly lowered standing blood pressure, the maximal effect occurring 3-6 h following drug administration. There was a significant increase in heart rate in both supine and standing positions, maximal 6-8 h postdose. Supine plasma noradrenaline concentrations were greater following MDL-899, with the greatest difference present 4 h after drug administration. Plasma renin concentrations were greater following MDL-899. Six of our subjects were also given 10 mg MDL-899 together with 100 mg atenolol, in an additional study. Atenolol increased the hypotensive effect and attenuated the tachycardia following MDL-899 alone. Side effects following MDL-899 administration included headache, lightheadedness, and tachycardia. These were reduced following atenolol coadministration. The haemodynamic profile of MDL-899 suggests that this drug acts as a direct arteriolar vasodilator in man. The observed increase in heart rate is likely mediated by reflex activation of the sympathetic nervous system.
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PMID:Pharmacodynamic studies in normal volunteers with MDL-899, a new arteriolar vasodilator. 619 50

Isoprenaline bitartrate (0.5 microgram/kg/min i.v.) increased the rate of noradrenaline release into the circulation of pentobarbitone-anesthetized rabbits. This increase was much greater than that produced by an equi-hypotensive dose of the vasodilator hydralazine (0.2 mg/kg i.v.), suggesting that it was only partly due to baro-reflex activation of sympathetic nerves. This facilitatory effect of isoprenaline was also observed in the nephrectomized, pithed rabbit, with electrically stimulated sympathetic outflow, ruling out central nervous system and renin-angiotensin effects. ICI 118,551 HCl (0.3 mg/kg + 0.1 mg/kg/h i.v.) blocked the isoprenaline-induced hypotension, but did not affect the isoprenaline-induced tachycardia, suggesting that it selectively blocked beta 2-adrenoceptors. ICI 118,551 totally abolished the isoprenaline-induced increase in noradrenaline release, suggesting a beta 2-effect. Atenolol (0.3 mg/kg + 0.1 mg/kg/h) blocked the isoprenaline-induced tachycardia, a beta 1-effect, but only slightly attenuated the isoprenaline-induced increase in noradrenaline release. Atenolol by itself decreased heart rate and arterial pressure, but there was no reflex rise in the noradrenaline release rate, which suggests that atenolol impairs baroreceptor activation of sympathetic nerves. In another series of experiments, also in the pentobarbitone-anesthetized rabbit, adrenaline was released into the circulation by splanchnic nerve stimulation. This resulted in prolonged increases of adrenaline levels in heart tissue. After the plasma adrenaline levels had returned to prestimulation values, the rate of noradrenaline release into the plasma was enhanced. This increase was not observed in rabbits treated with either desipramine HCl (1 mg/kg i.v.) or propranolol HCl (2 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Local modulation of noradrenaline release in vivo: presynaptic beta 2-adrenoceptors and endogenous adrenaline. 620 19

The relationship between the oral dosage and plasma concentration of the long-acting cardioselective beta-adrenoceptor blocker atenolol and the antihypertensive response to the the degree of beta-adrenoceptor blockade and change in plasma renin activity (PRA) was evaluated in patients with mild-to-moderate essential hypertension in a double-blind, randomized, between-patient, dose-ranging (25, 50 or 100 mg once daily for 4 weeks) study. The optimum, or minimum, daily dose of atenolol to treat patients with mild-to-moderate hypertension was not clearly identified in this study. A between-treatment comparison did not demonstrate that all blood pressure falls were always less in the 25 mg group than in the other two groups. Calculation of beta-error or the power for the negative results between doses suggested that a large sample size is required to draw a conclusion that no dose-antihypertensive relationship of atenolol exists in the treatment of mild-to-moderate hypertension. A relatively flat plasma concentration-antihypertensive response relationship was observed. Steady-state plasma concentrations of atenolol were dose-related and renal drug clearance was well correlated with individual creatinine clearance. beta-adrenoceptor blockade was better correlated with plasma atenolol concentration. Correlations which were less strong were between plasma drug concentration and change in various blood pressures and between blood pressure falls and beta-adrenoceptor blockade. There was no relationship between the fall in blood pressure and change in PRA. Atenolol appeared to suppress PRA in an all-or-none fashion.
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PMID:A dose ranging study of atenolol in hypertension: fall in blood pressure and plasma renin activity, beta-blockade and steady-state pharmacokinetics. 634 68

Combinations of a beta-blocker and a diuretic often produce a greater fall in blood pressure than does either drug alone. Furthermore, beta-blockers prevent an increase in plasma renin activity, thereby attenuating diuretic-induced potassium excretion and also the reduction in hypotensive response to the diuretic. This study was designed to compare the effects of the two fixed-dose combinations atenolol 100 mg plus chlorthalidone 25 mg (Tenoretic; ICI) and sotalol 320 mg plus hydrochlorothiazide 50 mg (Sotazide; B-M) on the pattern of diuresis and the biochemical composition of the urine in normal subjects. These preparations differ mainly in that the plasma half-lives of chlorthalidone and hydrochlorothiazide are 60 hours and 6 hours respectively; the former therefore accumulates when given once daily while the latter does not. These two preparations were found to have similar effects on the pattern of diuresis and the biochemical values. It is therefore concluded that the relationship between the serum chlorthalidone level and the fall in serum potassium level is in keeping with the flat dose-response curves for the thiazide and phthalimide diuretics.
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PMID:The effects of two combinations of a beta-blocker and a diuretic on diuresis in normal subjects. 636 98

A new beta-blocking agent, atenolol was studied on the supposition that it was a beta-blocker without any action on central nervous system. Atenolol was orally given to 10 patients with essential hypertension once a day and changes in various parameters were observed through 24 hours. As the results, hypotensive effect was accompanied by marked reduction of heart rate, systemic vascular resistance, plasma renin activity and blood aldosterone level over 24 hours. It was a decrease in systemic vascular resistance that showed best correlation with hypotensive effect.
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PMID:Acute effect of atenolol on hemodynamic, plasma renin activity and plasma aldosterone concentration in the once daily oral administration. 638 68

The cardiovascular effects of YM-16151-4 were evaluated in rats and dogs. In conscious rats, YM-16151-4 (3-30 mg/kg p.o.) produced a dose-dependent hypotensive effect without increasing heart rate (HR) and plasma renin activity (PRA). Nifedipine (3-10 mg/kg p.o.) produced a dose-dependent hypotensive effect but significantly increased HR and PRA. Atenolol (30 mg/kg p.o.) decreased PRA but did not decrease blood pressure and HR. The cardiovascular effects of the combination of nifedipine and atenolol were similar to those of YM-16151-4. It is interesting that the time course of the hypotensive effect of YM-16151-4 was similar to that of its beta 1-adrenoceptor blocking effect, although the time courses of these effects of the combination of nifedipine and atenolol were different. In conscious dogs, YM-16151-4 (0.3-10 mg/kg p.o.) also produced a long-lasting hypotensive effect with almost no effect on HR and PQ-interval. The time course of the beta 1-adrenoceptor blocking effect was similar to that of its hypotensive effect. Furthermore, during 10-day repeated oral administration, neither tolerance nor augmentation was observed in the hypotensive and beta 1-adrenoceptor-blocking effects. In conclusion, the present results indicate that YM-16151-4 is an effective and long-lasting hypotensive agent that does not increase HR and PRA. These effects of YM-16151-4 may be attributable to its calcium-entry-blocking and beta 1-adrenoceptor-blocking activities, and the ratio of two activities was constant after single and repeated oral administrations.
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PMID:Cardiovascular effects of YM-16151-4: a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent in rats and dogs. 769 65

The objective of this study was to evaluate the mechanisms of the renin secretion response to the angiotensin II (AII) receptor type 1 (AT1) antagonist losartan (DuP 753) in anesthetized rabbits. All receptor blockade with losartan (4 mg/kg bolus and 2 mg/kg/hr i.v.) decreased blood pressure (BP) and increased plasma renin activity (PRA) and heart rate (HR) significantly, whereas the beta-1 adrenoceptor antagonist atenolol (0.02 mg/kg/min i.v.) caused significant reductions in these parameters. Atenolol blocked HR and PRA responses but not the effect of losartan on BP. Cyclooxygenase inhibition with indomethacin (5 mg/kg bolus and 40 micrograms/kg/min i.v.) did not result in significant effects, and the coadministration of indomethacin and losartan resulted in a greater PRA effect than with losartan alone. These results preclude the involvement of prostaglandins, such as PGE2 and PGI2, in the renin response to losartan. The PRA response to atenolol alone suggests that renin release in anesthetized rabbits is under tonic control by beta adrenergic receptors. Furthermore, the discrepancy in the PRA responses to equipotent hypotensive doses of hydralazine and losartan indicates that beta adrenoceptor activation in the kidney, probably the result of blockade of AII-mediated inhibition of renin secretion, contributes to the renin-releasing effect of the AT1 receptor antagonist losartan.
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PMID:Beta adrenoceptor blockade in rabbit inhibits the renin-releasing effect of AT1 receptor antagonist losartan. 790 89

The present study investigated the hypothesis that the increase in plasma angiotensinogen after nephrectomy is mediated by endogenous renin and angiotensin (ANG) II. Rats were divided into control, nephrectomy, or nephrectomy plus adrenalectomy groups. In addition, similar cohorts were divided as just mentioned and then given either atenolol (selective beta 1-adrenoceptor inhibitor that prevents renin release) or Dup-753 [ANG II (AT1) receptor antagonist]. The plasma angiotensinogen levels increase approximately fivefold after 24 h in nephrectomized rats. Pretreatment with atenolol blunted this increase. A significant reduction was observed 4 h (P < 0.05) and 8 h (P < 0.005) after surgery. Dup-753 nearly abolished the increase in angiotensinogen plasma levels. After pretreatment with Dup-753, significantly higher angiotensinogen levels (P < 0.005) were found only after 24 h. Nephrectomy plus adrenalectomy also blunted the rise in plasma angiotensinogen. A significant increase in angiotensinogen plasma levels could only be observed after 8 h (P < 0.005) and 12 h (P < 0.005) but not after 24 h. Atenolol further reduced this increase. After atenolol pretreatment, significantly higher angiotensinogen levels could only be observed after 12 h (P < 0.05). Dup-753 completely abolished the increase of plasma angiotensinogen after nephrectomy plus adrenalectomy. In anesthetized control rats at time 0 the plasma ANG I levels were 0.7 nM. Pretreatment with atenolol decreased the ANG I values by 30%, whereas Dup-753 caused a sixfold increase in plasma ANG I levels in the control rats at time 0.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II is the mediator of the increase in hepatic angiotensinogen synthesis after bilateral nephrectomy. 821 50

We undertook this study to investigate the regulatory mechanism of cardiac gene expression in spontaneously hypertensive rats (SHR) during development. We measured cardiac mRNAs by Northern blot analysis. In 9-week-old SHR at the very early stage of cardiac hypertrophy, the expression of various cardiac genes related to the regulation of cardiac contraction and relaxation was already significantly changed compared with control Wistar-Kyoto rats, indicating that cardiac molecular changes are responsible for cardiac remodeling or the modulation of cardiac performance in SHR. We gave various types of antihypertensive drugs, at oral doses causing a mild and comparable hypotensive effect, to 27-week-old SHR to examine the effects on the altered cardiac gene expression. Imidapril, an angiotensin-converting enzyme inhibitor, normalized the increased gene expression of atrial natriuretic polypeptide and collagen types I and III and the decreased expression of alpha-myosin heavy chain in SHR heart. Atenolol (a beta 1-blocker) combined with doxazosin did not affect cardiac ANP and alpha-myosin heavy chain expression of SHR but normalized the increased collagen expression. In contrast, despite a hypotensive effect comparable to these two drug treatments, doxazosin (an alpha 1-blocker) alone or manidipine (a calcium antagonist) did not normalize these altered gene expressions of SHR. These results show that the cardiac renin-angiotensin system is involved in the altered cardiac gene expression in SHR. The beta 1- but not alpha 1-adrenergic receptor is also responsible for the increased cardiac collagen expression in SHR.
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PMID:Role of angiotensin-converting enzyme, adrenergic receptors, and blood pressure in cardiac gene expression of spontaneously hypertensive rats during development. 884 89

The antihypertensive effects of an angiotensin II antagonist, candesartan cilexetil (TCV-116), and other classes of antihypertensive drugs (including a calcium antagonist, manidipine; a diuretic, hydrochlorothiazide (HCTZ); an alpha-blocker, prazosin; and a beta-blocker, atenolol) administered in combination were examined in spontaneously hypertensive rats by oral administration daily for 2 wk. TCV-116 at 1 mg/kg lowered the blood pressure by about 50 and 30 mmHg, 5 and 24 h after dosing, respectively. The blood pressure was slightly lowered by HCTZ at 10 mg/kg, but it was synergistically reduced when HCTZ was given in combination with TCV-116. Manidipine at 3 mg/kg lowered the blood pressure by about 50 mmHg 1 h after administration. When manidipine was given in combination with TCV-116, blood pressure was reduced additively. Prazosin at 1 mg/kg lowered the blood pressure by 40 to 50 mmHg 1 h after dosing. When prazosin was given in combination with TCV-116, the reduction was intensified more than additively, to about 100 mmHg. Atenolol at 50 mg/kg lowered the blood pressure by 10 to 20 mmHg 5 h after dosing. Even when atenolol was administered in combination with TCV-116, the reduction in blood pressure was virtually the same as that observed when TCV-116 was given alone. TCV-116 and HCTZ had no effect on the pulse rate, whereas manidipine and prazosin both increased it, owing to reflex tachycardia, and atenolol decreased it. TCV-116 had no effect on the change in the pulse rate induced by these antihypertensive drugs and no effect on HCTZ-induced diuresis. TCV-116 and HCTZ each caused a significant increase in plasma renin concentration (PRC), and prazosin caused a slight elevation. Manidipine had no effect on the PRC, whereas atenolol reduced it. Given in combination with TCV-116, these antihypertensive drugs had the same effect on the elevated PRC induced by TCV-116 as they did on the basal PRC when administered alone. These results suggest that antihypertensive drugs that cause compensatory activation of the renin-angiotensin system have more marked antihypertensive activity when given in combination with TCV-116, but that there will is no combined effect on the pulse rate.
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PMID:Combined effects of the angiotensin II antagonist candesartan cilexetil (TCV-116) and other classes of antihypertensive drugs in spontaneously hypertensive rats. 898 55


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