Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twelve essential hypertensive patients were entered into a prospective study assessing the effect of losartan, a non-peptide specific angiotensin II receptor antagonist, on blood pressure, the renin-angiotensin-aldosterone axis and renal function. Specifically monitored prior to and following 12 weeks of therapy at 6 (peak) and 24 (trough) h after dosing, were blood pressure, plasma renin activity (PRA), plasma aldosterone, and plasma angiotensin II (Ang II), creatinine clearance and urinary albumin excretion (UAE). In this small sample of hypertensive patients, losartan monotherapy and losartan-hydrochlorothiazide (HCTZ) combination therapy were associated with modest reductions in systolic, diastolic and mean arterial BPs; significant changes were observed only at the peak dosing interval. Losartan, given as either monotherapy or combination therapy, was associated with an increase in the 'trough' values of PRA; significant changes in the 'trough' values of plasma Ang II and plasma aldosterone were not observed. In contrast, PRA and plasma Ang II were stimulated, and plasma aldosterone was depressed, 6 h after dosing. There were significant negative correlations between both PRA and plasma Ang II reactivity (difference between PRA or plasma Ang II values obtained 6 h after placebo dosing and 6 h after drug dosing) and the change in systolic, diastolic and mean arterial BPs. Of interest, losartan/HCTZ combination therapy was associated with a decrease in the creatinine clearance; UAE was not significantly altered. Losartan appears to be an effective anti-hypertensive agent in patients with mild to moderate hypertension. Its peak BP effect appears to be at the dosing interval corresponding to pharmacological blockade of angiotensin II receptors. Furthermore, this anti-hypertensive agent may be more efficacious in patients with a reactive renin-angiotensin system.
 ...
PMID:Effects of losartan on the renin-angiotensin-aldosterone axis in essential hypertension. 759 5

Genetic approaches are setting the stage for a new understanding of the biological mechanisms underlying blood pressure regulation and hypertension. Recently, substantial progress has been made in elucidating the molecular mechanisms that cause several rare forms of hypertension, including hypertension arising from mutations in the 11 beta-hydroxylase gene, Liddle's syndrome, and glucocorticoid-suppressible aldosteronism. New results have been obtained on the possible role of the angiotensinogen gene, and other candidate genes, such as the angiotensin II receptor Type I gene and the Sa gene, in human hypertension. Investigation of experimental models of hereditary hypertension have also been important in unravelling the genetic complexity of the disease.
 ...
PMID:The genetic basis of hypertension. 760 49

The purpose of this multicenter trial was to compare the antihypertensive efficacy and safety of losartan potassium (losartan), a selective angiotensin II receptor antagonist, when added to hydrochlorothiazide in hypertensive patients whose blood pressure was not adequately controlled by 25 mg hydrochlorothiazide monotherapy. After a 4-week monotherapy period of 25 mg hydrochlorothiazide, 304 patients with trough (22 to 26 hours postdose) sitting diastolic pressure between 93 and 120 mm Hg were maintained on 25 mg hydrochlorothiazide and randomized double-blind into treatment arms consisting of either 25, 50, or 100 mg losartan or placebo once daily for 12 weeks. The reductions in sitting diastolic pressure for patients treated with 25, 50, or 100 mg losartan concomitantly administered with 25 mg hydrochlorothiazide were significantly greater (P < or = .05) than the reductions observed in the 25 mg hydrochlorothiazide plus placebo group beginning 1 week after randomization. The antihypertensive response in all groups was greater at week 3 than week 1, with some additional decrease in blood pressure in some groups at later times. Sitting systolic pressures were also significantly reduced in each group over time. Standing blood pressures at week 12 were similar to sitting blood pressures. A dose-response relationship to losartan was observed in this patient population. The percentages of the total drug-related clinical adverse experiences as assessed by the investigator were generally similar in the 25, 50, and 100 mg losartan plus 25 mg hydrochlorothiazide groups (10.3%, 24.4%, and 20.0%, respectively) compared with the placebo plus 25 mg hydrochlorothiazide group (24.7%).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Jul
PMID:Effects of losartan on a background of hydrochlorothiazide in patients with hypertension. 760 13

The renin-angiotensin system (RAS) participates in both cardiovascular homeostasis and diseases. Angiotensin converting enzyme (ACE) inhibitors have been used very successfully in the treatment of hypertension and heart failure. The therapeutic effectiveness of these drugs has been ascribed to their action in limiting the activity of the RAS and suggests that other pharmacological mechanisms that block this system, such as angiotensin II receptor inhibitors, could also be of benefit. Some properties of angiotensin II receptor inhibitors offer potential advantages over ACE-inhibitors. ACE acts on other substrates in addition to angiotensin I (i.e. bradykinin) so that more specific inhibition of the RAS can be achieved with selective angiotensin II antagonists. Data on the existence of both circulating and tissue RAS have been reported, and non-ACE pathways for angiotensin II production have also been described. So, by inhibiting the interaction of the biological active peptide at its receptor level, an angiotensin II receptor antagonist will inhibit the RAS independently of the source or route of angiotensin II synthesis. Peptide angiotensin II antagonists were first reported 20 years ago and the best studied was saralasine; they are potent and selective blockers of angiotensin II responses, but their lack of oral activity, short duration of action and the concomitant partial agonistic activity limited their clinical use. Now are available nonpeptide angiotensin II antagonists with attributes appropriate for clinical development. The preliminary evaluation of these new selective nonpeptide angiotensin II antagonists show their potential therapeutic role in many cardiovascular diseases in which the RAS is involved.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Clinical pharmacology of angiotensin II antagonists]. 763 4

We investigated the role of endogenous nitric oxide, kinins, and prostaglandins in the vasodepressor and renal excretory effects of the angiotensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor ramipril administered for 1 week to spontaneously hypertensive rats. To this end, either losartan (10 mg/kg per day) or ramipril (2.5 mg/kg per day) was administered in drinking water with or without simultaneous administration of (1) the nitric oxide synthesis inhibitor Ng-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg per day), (2) the cyclooxygenase inhibitor indomethacin (5 mg/kg per day), (3) the bradykinin B2 receptor antagonist Hoe 140 (0.5 mg/kg per day SC), or (4) L-NAME plus indomethacin. Both losartan and ramipril significantly reduced blood pressure as measured by the tail-cuff method. L-NAME increased blood pressure when administered solely or in combination with losartan. However, L-NAME attenuated the hypotensive effect of ramipril. Indomethacin did not affect blood pressure but it reduced the antihypertensive action of losartan and ramipril. Indomethacin administration did not potentiate the increase in blood pressure induced by L-NAME. However, the concurrent administration of both inhibitors almost totally blunted the vasodepressor action of ramipril. By contrast, losartan administration in the presence of L-NAME and indomethacin increased blood pressure to a level similar to that after losartan plus L-NAME. Hoe 140 did not modify either blood pressure or the hypotensive effects of losartan or ramipril. Increases in diuresis and water intake were observed during ramipril administration. Both effects were blunted only with the concurrent administration of L-NAME and indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Aug
PMID:Nitric oxide and prostaglandins in the prolonged effects of losartan and ramipril in hypertension. 763 31

The pressure-natriuresis curve of transgenic rats harboring an extra mouse renin gene [TGR(mRen-2)27] is shifted rightward compared with controls; however, whether intrarenal angiotensin II effects are responsible for the rightward shift is unknown. To clarify this issue we infused the converting enzyme inhibitor captopril or the angiotensin II receptor blocker CV 11974 into transgenic and normotensive Sprague-Dawley Hannover control rats. We eliminated any other neural or endocrine regulatory differences between transgenic and control rats by renal denervation and infusion of vasopressin, aldosterone, corticosterone, and norepinephrine in sufficient quantities to occupy all receptors. Sodium excretion increased from 3.4 +/- 1.2 to 10.1 +/- 0.5 mumol/min per gram kidney weight in transgenic rats when renal perfusion pressure was increased from 158 to 201 mm Hg. Captopril (4 mg/kg) and CV 11974 (0.1 mg/kg) shifted the pressure-natriuresis curve of transgenic rats leftward, so that sodium excretion was threefold higher at similar renal perfusion pressures (150 to 160 mm Hg). Similarly, fractional sodium and water excretion curves were shifted leftward, so that values for transgenic and control rats were no longer different. Over the pressure range, renal blood flow in transgenic rats ranged from 3.1 +/- 0.7 to 4.4 +/- 0.5 mL/min per gram kidney weight and increased (P < .05) with both captopril and CV 11974 to ranges from 4.8 +/- 0.9 to 6.8 +/- 0.6 or from 4.5 +/- 0.7 to 6.9 +/- 1.0 mL/min per gram kidney weight, respectively. Glomerular filtration rate in transgenic rats, on the other hand, was not increased. Transgenic kidneys showed severe hypertension-induced nephrosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Sep
PMID:Effect of captopril and angiotensin II receptor blockade on pressure natriuresis in transgenic TGR(mRen-2)27 rats. 764 84

As the AT1 receptor is the primary angiotensin II receptor in the myocardium and vasculature, we assessed the acute myocardial and vascular response to the AT1 angiotensin II antagonist losartan in the spontaneously hypertensive rat (SHR) to determine the contribution of angiotensin II in this genetic form of hypertension. In a preliminary dose response study, which evaluated losartan at 1.0, 3.0, and 10 mg/kg, 10 mg/kg uniformly lowered blood pressure. In a second group of experiments, 10 mg/kg also completely attenuated the pressor effects of angiotensin II administration. In nine adult SHR, intravenous losartan, 10 mg/kg, was given, with hemodynamics measured immediately and at steady-state intervals to delineate the hemodynamic response to angiotensin II antagonism. Losartan significantly lowered systolic, diastolic, and mean blood pressures, yet heart rate was unchanged. Cardiac function, as assessed by cardiac output and blood flow acceleration, demonstrated only transient increases which were not sustained during steady-state blood pressure reduction. Significant increases of peak blood flow and pulse pressure were sustained throughout the blood pressure response. At immediate and steady-state determinations, system vascular resistance and characteristic aortic impedance were significantly reduced with losartan (both P < .01). In addition, concomitant reduction of the wave reflectance index also occurred, achieving significance at steady state (P < .05). These changes demonstrate that the AT1 angiotensin II receptor contributes to both central and peripheral vasoconstriction in the spontaneously hypertensive rat. Absence of sustained increase of cardiac output and blood flow acceleration are consistent with inhibition of the previously reported positive inotropic effect of angiotensin II.
 ...
PMID:Acute myocardial and vascular responses to specific angiotensin II antagonism in the spontaneously hypertensive rat. 766 27

Although many in vitro gene transfer methods already exist, such as calcium phosphate precipitation, electroporation, or cationic liposomes, these methods cause significant cell injury and cell death. The study of the biology of endogenous autocrine-paracrine vasoactive systems such as the renin-angiotensin system in vascular cells is limited by the lack of a suitable gene transfer method with high efficiency of transfection and expression that will permit cell biology studies. Recently, the Sendai virus (hemagglutinating virus of Japan, HVJ)-liposome-mediated gene transfer method has been shown to be an efficient and nontoxic method of gene transfer. In this study, we characterized the efficiency and suitability of the HVJ method for vascular biology research. Using SV40 T-antigen complementary DNA (cDNA), we initially compared the efficiency of the HVJ method and lipofection for transfection of cultured vascular smooth muscle cells (VSMCs). We observed that after 35 minutes of incubation, the HVJ method exhibited a 10-fold higher efficiency of transfection than lipofection. We used this method to study vascular angiotensin converting enzyme (ACE) expression in cultured VSMCs and cultured rat carotid arteries in vitro. The HVJ method of transfection of human ACE cDNA into VSMCs and COS cells was significantly more efficient than lipofection. Using this method, we demonstrated that transfection of ACE cDNA resulted in increased DNA synthesis, which was inhibited by the specific angiotensin II receptor antagonist DuP 753 (10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Jun
PMID:Novel in vitro gene transfer method for study of local modulators in vascular smooth muscle cells. 768 4

To investigate the effects of renal transplantation on the plasma and local kidney renin-angiotensin systems of the recipients the left kidneys of 13 adult male Wistar-Kyoto rats (WKY) and 13 stroke-prone spontaneously hypertensive rats (SHRSP) were transplanted to bilaterally nephrectomized (WKYxSHRSP)-F1 hybrids. Nine unilaterally nephrectomized WKY and nine SHRSP served as controls. Four weeks after surgery recipients of an SHRSP kidney but not recipients of a WKY kidney had significant post-transplantation hypertension. Plasma renin activity (PRA) was higher in SHRSP than in WKY. Transplanted rats had lower PRAs than nontransplanted controls. Plasma ACE activity was lowest in SHRSP, intermediate in transplanted F1 hybrids and highest in WKY. Plasma Ang I and Ang II concentrations closely paralleled each other. They were not significantly different between WKY and SHRSP and lower in transplanted than in nontransplanted rats. ACE and renin mRNA were lower in transplanted than in nontransplanted kidneys. Glomerular angiotensin II receptor density was higher in transplanted than in nontransplanted kidneys with no significant differences between strains. We conclude that renal transplantation has profound long-term effects on the recipients' plasma and local kidney renin-angiotensin systems. These do not appear to be involved in the pathogenesis of post-transplantation hypertension in recipients of an SHRSP kidney, but may reflect a role for the intrarenal renin-angiotensin system in long-term renal adaptation and repair processes after transplantation.
 ...
PMID:Effects of kidney transplantation on the renin-angiotensin systems of the recipients. 769 99

It is difficult to establish dose-response relationships for ACE inhibitors in patients with hypertension or congestive heart failure. This has led to the widely held opinion that the effects of ACE inhibitors are hardly dose dependent. The purpose of this short discussion is to demonstrate that this class of compounds, as well as the more recent angiotensin II receptor antagonists, exhibit some very clear dose-response relationships when these are evaluated in normal volunteers based on the mechanisms for which they were designed. Characterization of these dose-response curves is important in order to use these drugs at their optimal dose and to obtain the maximal therapeutic benefit.
 ...
PMID:Dose-response relationships of ACE inhibitors and angiotensin II blockers. 771 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>