Biomedical subjects

F H Leenen

Publications and source records attributed to F H Leenen.

At least 19 recordsLinked to original sources

PubMed2001

Central sympathoinhibitory effects of calcium channel blockers.

It is generally assumed that the arterial vasodilation induced by inhibition of Ca(2+) influx into vascular smooth muscle cells represents the main mechanism for the hypotensive effect of dihydropyridine calcium channel blockers. Increases in sympathetic tone have been related to activation of the arterial baroreflex by rapid lowering of blood pressure. This review highlights new findings in two areas. First, in animal studies, direct central administration of dihydropyridines such as nifedipine or amlodipine lowers sympathetic nerve activity and thereby blood pressure. Peripheral administration of nifedipine or amlodipine at low rates appears to result in gradual accumulation of drug in the central nervous system, and also causes lowering of sympathetic nerve activity and thereby lowering of blood pressure (rather than by arterial vasodilation). Second, in hypertensive humans treated with long-acting dihydropyridines and presumably little activation of the arterial baroreflex, some studies have demonstrated lowering of sympathetic activity (as assessed by plasma norepinephrine), but others reported increases (as assessed by plasma norepinephrine or microneurography). This sympathoexcitatory response may be due to activation of the renin-angiotensin system, particularly at higher doses.

Animals↗

PubMed2001

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): clinical center recruitment experience.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trial's recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

Antihypertensive Agents↗

PubMed2001

High salt intake and the brain renin--angiotensin system in Dahl salt-sensitive rats.

OBJECTIVES: To assess changes in the activity of the brain renin-angiotensin system during (i) the development of salt-sensitive hypertension; and (ii) the prevention of salt-sensitive hypertension by blocking brain 'ouabain'. METHODS: In protocol I, angiotensin converting enzyme (ACE) mRNA and activity and angiotensin I and II levels were assessed in the hypothalamus and pons of Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on regular (120 micromol Na+ per g) or high (1370 micromol Na+ per g) salt diet from 4-6 weeks or 4-9 weeks of age. In protocol II, ACE mRNA and activity were assessed in the hypothalamus and pons in Dahl S on regular or high salt treated with intracerebroventricular (i.c.v.) Fab fragments blocking brain 'ouabain' or gamma-globulins, and in Dahl R on high or regular salt ACE mRNA was assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay and angiotensin I and II by radioimmunoassay after high-performance liquid chromatography. In protocol III, effects of i.c.v. angiotensin I and i.c.v. bradykinin on renal sympathetic nerve activity (RSNA), heart rate and blood pressure before and after i.c.v. captopril were assessed in Dahl S and R rats on regular or high salt intake from 4-8 weeks of age. RESULTS: High salt diet caused a gradual, but marked increase in blood pressure in Dahl S but not Dahl R rats. Dahl S rats showed small but significant increases in ACE mRNA in the hypothalamus on regular salt diet. In Dahl S rats on high salt diet for 2 or 5 weeks ACE mRNA levels significantly increased in both hypothalamus and pons, compared with Dahl R rats on either diet or Dahl S rats on regular diet. After 5 weeks of high salt diet, ACE mRNA levels in the hypothalamus in Dahl S rats were almost three-fold higher and in the pons two-fold higher than in Dahl R rats on either diet or Dahl S on regular salt diet. High salt diet also increased ACE activity of the hypothalamus and pons in Dahl S but not Dahl R. Consistent with this increased ACE activity, central responses to angiotensin I were clearly enhanced and to bradykinin markedly diminished in Dahl S on high salt intake. Chronic blockade of brain 'ouabain' by i.c.v. Fab fragments prevented the increases in blood pressure, ACE mRNA and activity in the hypothalamus and pons by high salt intake in Dahl S rats. Angiotensin I levels in the hypothalamus and pons were similar in both groups of rats and there were no significant changes caused by high salt diet in Dahl S and R rats. On regular salt intake angiotensin II levels in the hypothalamus of Dahl S rats showed a significant decrease as compared with Dahl R rats on regular salt diet, and were similar in the pons of the two strains. High salt intake did not affect angiotensin II levels in either hypothalamus or pons in Dahl S and R rats. CONCLUSIONS: These results indicate that high salt intake increases blood pressure, ACE expression and activity in the hypothalamus and pons of Dahl S rats without a parallel increase in angiotensin II levels. Effects of high salt intake on ACE mRNA and activity appear to be secondary to activation of brain 'ouabain'.

Angiotensin I↗

PubMed2001

AT(1) receptor blockers prevent sympathetic hyperactivity and hypertension by chronic ouabain and hypertonic saline.

Sympathetic hyperactivity and hypertension caused by chronic treatment with ouabain or sodium-rich artificial cerebrospinal fluid (aCSF) can be prevented by central administration of an angiotensin type 1 (AT(1)) receptor blocker. In the present study, we assessed whether, in Wistar rats, chronic peripheral treatment with the AT(1) receptor blockers losartan and embusartan can exert sufficient central effects to prevent these central effects of ouabain and sodium. Losartan or embusartan (both at 100 mg x kg(-1) x day(-1)) were given subcutaneously once daily. Ouabain (50 microg/day) was infused subcutaneously, and sodium-rich aCSF (1.2 M Na(+), 5 microl/h) was infused intracerebroventricularly, both by osmotic minipump for 13-14 days. The mean arterial pressure (MAP) at rest and in response to air stress and intracerebroventricularly injection of guanabenz (75 microg/7.5 microl), ANG II (30 ng/3 microl), and ouabain (0.5 microg/2 microl) were then measured. In control rats, chronic treatment with ouabain subcutaneously and hypertonic saline intracerebroventricularly both increased baseline MAP by 20-25 mmHg and enhanced twofold the pressor responses to air stress and depressor responses to the alpha(2)-adrenoceptor agonist guanabenz. Simultaneous treatment with losartan or embusartan fully prevented hypertension, maintained normal responses to air stress and guanabenz, and attenuated pressor responses to acute intracerebroventricular injection of ANG II and ouabain. We concluded that peripheral administration of losartan as well as embusartan can cause sufficient central effects to prevent the sympathetic hyperactivity and hypertension induced by chronic peripheral ouabain and central sodium.

Air Movements↗

PubMed2001

ANG II in median preoptic nucleus and pressor responses to CSF sodium and high sodium intake in SHR.

Pressor responses to increases in cerebrospinal fluid (CSF) sodium in Wistar rats and to high salt intake in spontaneously hypertensive rats (SHR) involve both brain ouabainlike activity ("ouabain") and the brain renin-angiotensin system (RAS). Because some of the effects of "ouabain" are mediated by the median preoptic nucleus (MnPO) and this nucleus contains all elements of the RAS, the present study assessed possible interactions of "ouabain" and ANG II in this nucleus. In conscious Wistar rats, injection of ANG II into the MnPO significantly increased mean arterial pressure (MAP) and heart rate (HR). This response was not affected by pretreatment with a subpressor dose of ouabain. MAP and HR increases by ouabain in the MnPO were significantly attenuated by MnPO pretreatment with losartan. In Wistar rats, losartan in the MnPO also abolished pressor and HR responses to intracerebroventricular 0.3 M NaCl and attenuated MAP and HR responses to intracerebroventricular ouabain. Five weeks of a high-salt diet in SHRs resulted in exacerbation of hypertension and increased responses to air-jet stress and intracerebroventricular guanabenz. Losartan injected into the MnPO reversed the salt-sensitive component of the hypertension and normalized the depressor response to guanabenz but did not change responses to air-jet stress. We conclude that in the MnPO, ANG II via AT(1) receptors mediates cardiovascular responses to an acute increase in CSF sodium as well as the chronic pressor responses to high sodium intake in SHR.

Angiotensin II↗

PubMed2001

Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats.

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+ were evaluated. In conscious young (5-6 wk old) and adult (10-11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2-0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 microl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular alpha2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus "ouabain" significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain "ouabain" is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.

Adrenergic alpha-Agonists↗

PubMed2001

Isoproterenol-induced cardiac hypertrophy: role of circulatory versus cardiac renin-angiotensin system.

To assess the possible contribution of the circulatory and cardiac renin-angiotensin system (RAS) to the cardiac hypertrophy induced by a beta-agonist, the present study evaluated the effects of isoproterenol, alone or combined with an angiotensin I-converting enzyme inhibitor or AT(1) receptor blocker, on plasma and LV renin activity, ANG I, and ANG II, as well as left ventricular (LV) and right ventricular (RV) weight. Male Wistar rats received isoproterenol by osmotic minipump subcutaneously and quinapril or losartan once daily by gavage. Plasma and LV ANGs were measured by radioimmunoassay after separation by HPLC. Isoproterenol alone decreased blood pressure, more markedly when combined with losartan or quinapril. Isoproterenol significantly increased LV and RV weight and total collagen. Neither losartan nor quinapril inhibited the increases in LV or RV weight. Losartan prevented the increase in RV collagen but enhanced the increase in LV collagen. Isoproterenol increased plasma renin, ANG I, and ANG II three- to fourfold. Isoproterenol combined with losartan or quinapril, caused marked further increases except for a significant decrease in plasma ANG II with quinapril. Isoproterenol alone did not increase LV ANG II and, combined with losartan or quinapril, actually decreased LV ANG II. These results indicate that isoproterenol-induced cardiac hypertrophy is associated with clear increases in plasma ANG II, but not in LV ANG II. Both losartan and quinapril lower LV ANG II below control levels, but do not prevent the isoproterenol-induced cardiac hypertrophy. These findings do not support a role for the circulatory or cardiac RAS in the cardiac trophic responses to beta-receptor stimulation.

Adrenergic beta-Agonists↗

PubMed2001

Mortality after coronary artery occlusion in different models of cardiac hypertrophy in rats.

Chronic treatment with minoxidil induces cardiac trophic and sympathetic responses, which may increase the propensity for lethal arrhythmias. To test this hypothesis, acute coronary artery occlusion was performed in conscious normotensive rats treated for 2 or 5 weeks with minoxidil with the use of a 2-stage approach to cause a myocardial infarction. For comparison, rats with aortocaval (A-V) shunts and spontaneously hypertensive rats (SHR) were studied. Minoxidil increased left ventricular and right ventricular weights by 15% to 20%, and the A-V shunt increased these weights by 30% to 40%. In SHR, left ventricular weight was increased by 50%, and right ventricular weight was increased by 25%. In rats treated with minoxidil for 5 weeks, coronary artery occlusion caused a rapid and marked mortality, and 4 hours after myocardial infarction, only 18% of these rats were alive versus 61% of the control rats. In rats with the A-V shunt, coronary artery occlusion was also associated with increased mortality, and after 6 hours, 33% were still alive compared with 59% of the control rats. In contrast, SHR with marked hypertension and cardiac hypertrophy showed only a minor increase in mortality (survival rates were 53% versus 60% in SHR versus Wistar-Kyoto rats, respectively). Mortality was preceded by high arrhythmia scores, and ventricular fibrillation was the cause of death. Discontinuation of minoxidil for 1 week, sympathetic blockade with nadolol or clonidine, or blockade of the renin-angiotensin system with enalapril or losartan did not improve minoxidil-induced excess mortality. We conclude that ventricular stretch and other mechanisms (eg, cardiac vagal activity) in rats appear to be more potent than hypertension-induced left ventricular hypertrophy in predisposing for lethal arrhythmias in the setting of acute ischemia.

Animals↗

PubMed2001

Responses to central Na(+) and ouabain are attenuated in transgenic rats deficient in brain angiotensinogen.

Studies with angiotensin (Ang) II type 1 receptor blockers suggest that the brain renin-angiotensin system contributes to sodium-induced sympathoexcitation and hypertension. To provide more specific evidence for the involvement of Ang II, locally produced in the brain, transgenic rats were used, which express an antisense RNA against angiotensinogen mRNA specifically in the brain, reducing angiotensinogen levels in the brain by >90%. In freely moving transgenic rats and Sprague-Dawley rats as control animals, blood pressure and heart rate responses to intracerebroventricular infusion (3.8 microL/min for 10 minutes) of artificial cerebrospinal fluid and Na(+)-rich artificial cerebrospinal fluid (containing 0.2, 0.3, and 0.45 mol/L Na(+)) as well as intracerebroventricular injection of ouabain (0.3 and 0.6 microgram/2 microL) were assessed. Central infusion of Na(+)-rich artificial cerebrospinal fluid increased blood pressure and heart rate in a dose-related manner. However, the peak increases by each dose of Na(+) were attenuated by 50% to 70% in the transgenic versus Sprague-Dawley rats. Increases in blood pressure and heart rate in response to ouabain at both doses were attenuated by 55% to 70% in the transgenic versus Sprague-Dawley rats. In the hypothalamus, Ang I level was markedly lower (31+/-9 versus 76+/-13 pg/g, P<0.05) and Ang II level tended to be lower in the transgenic versus Sprague-Dawley rats. These results indicate that the production of angiotensins in the brain is decreased in transgenic rats. The attenuated sympathoexcitatory and pressor responses to ouabain and Na(+)-rich artificial cerebrospinal fluid in transgenic rats support the concept that the local brain renin-angiotensin system, that is, locally produced Ang II, plays an important role in the sympathoexcitatory effects of ouabain and sodium.

Angiotensin I↗

PubMed2001

Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade.

Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT(1)) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT(1) receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT(1) receptor blockade that is induced. Dahl S rats received a high-salt (1370 micromol Na(+)/g) or regular (101 micromol Na(+)/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 microg. kg(-1). d(-1), oral treatment with control versus irbesartan at 125 or 500 mg. kg(-1). d(-1) once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg. kg(-1). d(-1) by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to approximately 160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT(1) receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT(1) receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT(1) receptor blockade.

Administration, Oral↗

PubMed2001

Monotherapy versus combination therapy as first line treatment of uncomplicated arterial hypertension.

Mild to moderate hypertension still remains poorly controlled. This relates to multiple factors including low antihypertensive efficacy of single drug therapies reluctance of primary care physicians to modify/titrate initially chosen therapy to obtain target blood pressure, and poor compliance with medication. Several guidelines for the treatment of high blood pressure now include combination therapy with low doses of 2 drugs as one of the strategies for the initial management of mild/moderate arterial hypertension. Evidence discussed in this article points to superior control of blood pressure by combinations of low doses of 2 drugs as compared with monotherapy in regular doses. This superior effectiveness of combined therapy relates to a better antihypertensive efficacy and higher response rates in the low range of doses as the result of complementary mechanisms of antihypertensive effects, better tolerance as a result of a lower rate of adverse effects in the low dose range, improved compliance from better tolerance and simple drug regimen, and lower cost. Whether increased use of fixed low dose combination therapies would translate to better control of arterial hypertension in the population and thereby further reduction of cardiovascular/cerebrovascular morbidity and mortality caused by hypertension remains to be assessed.

Antihypertensive Agents↗

PubMed2001

Effects of centrally administered losartan on deoxycorticosterone-salt hypertension rats.

To investigate whether brain AT1 receptor stimulation contributes as a hypertensive mechanism to deoxycorticosterone acetate (DOCA)-salt hypertension, losartan (1 mg/4 microL) or artificial cerebrospinal fluid (aCSF) was injected into the lateral cerebral ventricle in conscious control uninephrectomized Wistar rats or rats with DOCA-salt for 2 or 4 weeks, and mean arterial pressure (MAP) and heart rates (HR) were recorded. In rats with DOCA-salt treatment, resting MAP increased to 144+/-6 mmHg after 2 weeks and to 170+/-5 mmHg after 4 weeks versus 115- 120 mmHg in controls. In rats with 2 week DOCA-salt treatment, MAP started declining at 4 hr after intracerebroventricular (icv) injection of losartan, and significant decreases in MAP were found at 18 and 24 hr. In rats with 4 week DOCA-salt treatment, MAP was significantly decreased at 4, 18 and 24 hr. In both groups MAP decreased to that of control rats. In control rats, icv losartan had no effect on MAP and HR. Icv aCSF did not significantly change MAP and HR in either DOCA-salt hypertensive rats or control rats. Normalization of MAP after icv administration of the AT1 receptor antagonist suggests a significant role for brain AT1 receptor stimulation in the development and maintenance of hypertension in the DOCA-salt hypertensive rat model.

Animals↗

PubMed2001

Peripheral administration of AT1 receptor blockers and pressor responses to central angiotensin II and sodium.

Central administration of AT1 receptor blockers prevents salt-sensitive hypertension and inhibits progression of CHF. We investigated in Wistar rats the effectiveness of peripheral administration of two AT1 receptor blockers, losartan and embusartan, in exerting central AT1 receptor blockade. Losartan or embusartan at doses of 30 and 100 mg/kg were administered subcutaneously (s.c.) as a single dose, or one dose daily for 6 days. The BP responses to intracerebroventricular (i.c.v.) injection of Ang II, i.c.v. infusion of Na+-rich aCSF (0.3 M NaCl), and intravenous (i.v.) injection of Ang II were then measured. Losartan or embusartan at 30 and 100 mg/kg both inhibited the BP increases induced by i.c.v. Ang II and, to a lesser extent, by Na+-rich aCSF. After a single dose, this inhibition was more pronounced for losartan. However, after 6 days of treatment, there were no significant differences between the effects of losartan and embusartan. Losartan and embusartan blocked responses to Ang II i.v. to a similar extent. These results indicate that results from single-dose studies may not reflect the chronic steady-state, and that during chronic treatment both AT1 receptor blockers are similarly effective in inhibiting AT1 receptors in the central nervous system, when assessed by pressor responses to acute increases in CSF Na+ or CSF Ang II.

Angiotensin II↗

PubMed2000

Neuronal Fos-like immunoreactivity in ouabain-induced hypertension.

In normotensive Wistar rats, systemic administration of exogenous ouabain for 10 days or more induces hypertension, presumably through central mechanisms. To identify which neuronal populations may be involved, we assessed Fos-like immunoreactivity (FLI) using an antibody that recognizes the protein products of the fos family comprising Fos, Fos B, Fra 1 and Fra 2, thus enabling detection of chronic neuronal activation. Young Wistar rats received s.c. infusions of either ouabain (50 microg/day) or saline for 7 or 14 days. At the end of the experimental period, mean arterial pressure (MAP) was assessed. In a separate set of rats FLI was detected immunohistochemically and quantified in cardiovascular and osmo-regulating centers. Resting MAP in ouabain-treated rats was significantly higher than in control rats at 14 but not at 7 days (125+/-4 vs. 101+/-6, P<0.05 and 102+/-4 vs. 98+/-6 (not significant), respectively). Within the supraoptic nucleus, ouabain induced significant increases in FLI compared with control rats at 14 days (9+/-2 vs. 2+/-2, P<0.05) but not at 7 days. Within the locus ceruleus, FLI was only detectable in rats that received ouabain infusions for 14 days but not in other groups of rats. Ouabain treatment did not induce significant changes in FLI within other areas. These results demonstrate that chronic s.c. ouabain infusion only increases neuronal FLI in the supraoptic nucleus and locus ceruleus where increases in FLI parallel the increase in blood pressure.

Animals↗

PubMed2000

Stimulation of Na+,K+-ATPase activity, increase in potassium uptake, and enhanced production of ouabain-like compounds in ammonia-treated mouse astrocytes.

Active potassium (K+) uptake and Na+,K+-ATPase activity were measured in primary cultures of mouse astrocytes. Both parameters were virtually unaffected by acute ammonia treatment but increased after chronic exposure to pathophysiologically relevant concentrations of ammonia (0.3 or 3 mM) for 1-4 days. The increased Na+,K+-ATPase activity after chronic treatment with ammonia was further enhanced in the acute presence of 12 mM K+. Based on these observations and literature data it was hypothesized that the direct effect of ammonia is formation of easily diffusible compound(s) with ouabain-like effect, that upregulation occurs of Na+,K+-ATPase activity and K+ uptake in response to the resulting ATPase inhibition, and that the washing procedure preceding the uptake experiments and the determination of Na+,K+-ATPase activity unmasks the upregulation. To test this hypothesis, the content of compounds with ouabain-like action was measured in media in which astrocytes had been incubated in the presence of 3 mM ammonia for 4 days and in controls to which an additional 3 mM NaCl had been added instead of ammonia. An endogenous, compound with ouabain-like activity was demonstrated both under control conditions and in the ammonia-treated cultures, and the content of this compound was increased by 50% in the ammonia-treated cultures. Preliminary experiments showed that at least part of the released ouabain-like compounds cross-react with authentic ouabain.

Ammonia↗

PubMed2000

Antihypertensive efficacy of the ACE-inhibitor perindopril in the elderly.

To assess the antihypertensive efficacy of the angiotensin-converting enzyme (ACE)-inhibitor, perindopril, in the elderly, patients >65 years of age with supine diastolic blood pressure (BP) > or =90 and < or =110 mm Hg at the end of a 4-week placebo washout period were treated with perindopril 4-8 mg/daily vs placebo using a multicentre, randomised, double-blind, parallel group design. Of the 191 patients entered, 183 completed 8 weeks of double-blind therapy. Average age was 72-73 years. Supine and standing BP at the end of the placebo run-in period were 173/96 vs 168/96 mm Hg. BPs were measured in the morning, 20-25 h after the previous day's dose (ie, at the end of the dosing interval). In the placebo group, supine and standing diastolic BP decreased by 3-4 mm Hg, and systolic BP by 6-7 mm Hg. In the perindopril-group, diastolic BP decreased by 6-7 mm Hg and systolic BP by 10-13 mm Hg (both P < 0.01 vs placebo). These data indicate a substantial placebo response of particularly systolic BP in older hypertensives and indicate the importance of a parallel placebo-group to assess the extent of the actual drug's effect. Perindopril caused additional decreases in diastolic BP by about 2 mm Hg, and in systolic BP by 4-5 mm Hg. The extent of this drug-effect may be less in older vs middle-aged hypertensives.

Aged↗

PubMed2000

Fixed low-dose combination therapy in hypertension--a dose response study of perindopril and indapamide.

OBJECTIVE: To establish the optimal dose of the perindopril/indapamide combination (Per/Ind) in the treatment of mild or moderate hypertension. DESIGN: This was a randomized, double-blind, placebo-controlled, seven-way parallel-group, dose-ranging study, set in multicenter, outpatient offices/clinics in Europe and Canada. PATIENTS: A total of 438 patients aged between 18 and 75 years whose supine diastolic blood pressure was between 95 and 114 mmHg were randomly assigned to an 8-week double-blind treatment with either placebo, Per 2/Ind 0.625, Per 4/Ind 1.25, Per 8/Ind 2.5, Per 0/Ind 1.25, Per 2/Ind 1.25 or Per 8/Ind 1.25 mg. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure measured in the clinic approximately 24 h after dosing. RESULTS: There was a linear dose-response relationship (P<0.001) for doubling the dose of Per 2/Ind 0.625 mg up to Per 8/Ind 2.5 mg with a progressive fall in supine diastolic blood pressure (-9.3 to -15.0 mmHg). Combining 1.25 mg Ind with increasing doses of Per (0, 2, 4 and 8 mg) also showed a linear dose-response relationship (P<0.001), with supine diastolic blood pressure falling by -8.0 to -12.0 mmHg compared with a fall of -5.2 mmHg for the placebo group. Similar findings were noted for supine systolic blood pressure, standing blood pressure and ambulatory blood pressure. Hypokalemia was more common (9.7%) in the Per 8/Ind 2.5 mg group than in the groups receiving other doses (0-4.6%). CONCLUSION: The combinations of Per 2/Ind 0.625 mg and Per 4/Ind 1.25 mg were effective in reducing blood pressure without producing clinically important side effects.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Cardiac hypertrophy and cardiac renin-angiotensin system in Dahl rats on high salt intake.

OBJECTIVE: On high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin-angiotensin system (RAS). METHODS: Cardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 micromol/g food) or regular salt (120 micromol/g food) diet for 2-5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension. RESULTS: In Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4-5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet Chronic intra-cerebroventricular treatment with Fab fragments blocking brain 'ouabain' prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II. CONCLUSIONS: These data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.

Angiotensin I↗