Cardiac mass in glucocorticoid-hypertensive rats with and without circulating adrenaline.

There is evidence that catecholamines may promote the development of cardiac hypertrophy in hypertension. To test the hypothesis that adrenaline directly determines left ventricular mass, normotensive Wistar rats were made adrenaline-deficient by adrenalectomy and hypertensive by administration of glucocorticoid. Blood pressure, heart rate, and body weight of the adrenalectomised group were not significantly different from a glucocorticoid treated control group with intact adrenals. Heart weight was significantly lower in the adrenalectomised rats, but this difference disappeared when heart weight was adjusted for body weight. It appears therefore that the presence or absence of adrenaline does not significantly affect cardiac mass in the presence of hypertension in this animal model

The new angiotensin II receptor antagonist, irbesartan: pharmacokinetic and pharmacodynamic considerations.

This article reviews the pharmacokinetics and pharmacodynamics of angiotensin II (AII) receptor antagonists (AIIRA), with particular focus on the novel compound irbesartan. Irbesartan has the highest oral bioavailability in its class (60% to 80%) and, unlike valsartan, its absorption is not affected by food. Irbesartan displays linear, dose related pharmacokinetics and, with the exception of tasosartan's active metabolite, has the longest elimination half-life of the AIIRA (11 to 15 h). Irbesartan exhibits the lowest amount of protein binding, limiting its potential for drug interactions. No drug interactions with irbesartan have been identified. Unlike losartan, candesartan, and tasosartan, irbesartan does not require biotransformation for AII blockade. The pharmacokinetics of irbesartan are not altered in renally or hepatically impaired patients, probably owing to excretion characteristic by both biliary and renal routes, or by differences in gender or age. Within its therapeutic dose range (150 to 300 mg), irbesartan shows sustained, dose related blockade 24 h after dosing. Irbesartan lowers blood pressure in a dose related manner up to 300 mg daily. Some clear differences in pharmacokinetics and pharmacodynamics exist among the AIIRA, which may have clinical implications

Combination antihypertensive therapy: does it have a role in rational therapy?

The pharmacological treatment of hypertension allows one to reduce substantially the risk of developing a cardiovascular complication. It appears more and more important to bring blood pressure to normal values in order to get the maximal benefit from antihypertensive therapy. Blood pressure lowering drugs make it possible to control blood pressure in about half of the patients when administered as monotherapy. The fraction of patients with a normal blood pressure can be markedly increased by combining drugs acting by different mechanisms. Low doses of antihypertensive agents are generally enough when coadministered. This helps to keep the incidence of side effects minimal and facilitates the patient's compliance with long-term treatment. Low-dose, fixed-dose combination therapy may therefore represent a valuable option not only to treat hypertensive patients unresponsive to drugs given as monotherapy, but also to initiate the treatment

The renin-angiotensin system in refractory heart failure: clinical, hemodynamic and hormonal effects of captopril and enalapril.

Studies using a competitive inhibitor of angiotensin II (saralasin) or converting enzyme inhibitors (teprotide, captopril, enalapril) have established that the renin-angiotensin system participates in the control of vascular tone in congestive heart failure both in experimental settings and in patients. In man, the marked decrease in left ventricular filling pressure and the variable increase in stroke volume induced by renin-angiotensin blockade suggests that angiotensin II actively constricts venous as well as arteriolar vascular beds. Captopril, in doses of 25 to 150 mg p.o. TID, maintains its efficacy during chronic administration with persistent clinical and hemodynamic improvement as well as increased exercise tolerance. In our experience, enalapril, 10 mg p.o., improves cardiac function within 4 to 6 h as reflected by a 30% decrease in left ventricular filling pressure, a 28% increase in stroke volume in the face of unchanged heart rate. Clinical improvement, enhanced exercise tolerance and characteristic hormonal responses suggest that enalapril also maintains its efficacy during long-term treatment. Chronic angiotensin II converting enzyme inhibition appears to be a major advance in the treatment of patients with severe congestive heart failure, refractory to digitalis and diuretics

Dose-Response Relationships Following Oral Administration of DuP 753 to Normal Humans

We assessed the inhibitory effect of DuP 753, an orally active angiotensin II receptor antagonist, on the pressor action of exogenous angiotensin I and II in healthy volunteers. In a single dose study, doses of 2.5, 5, 10, 20, and 40 mg of DuP 753 or placebo were tested serially at one week intervals. In the multiple dose study, the administration of placebo or DuP 753 (5, 10, 20, or 40 mg, per os once daily) for eight consecutive days was evaluated. The blood pressure response to angiotensin I and II was inhibited in a dose-dependent fashion with a blocking effect still present 24 h post drug. DuP 753 also induced a dose-dependent compensatory rise in plasma renin. This new compound was well tolerated by these normal volunteers. Thus, DuP 753 appears to be a well tolerated, orally active, potent and long-lasting antagonist of angiotensin II in humans. Am J Hypertens 1991;4:350S-354

Vascular acetylcholine response during chronic NO synthase inhibition: in vivo versus in vitro.

OBJECTIVE: The aim of this study was to compare the response to NO-mediated vasodilators in vivo and in vitro during chronic NO synthase inhibition. METHODS: NG-Nitro-L-arginine-methyl ester (L-NAME, 0.4 g/l) or vehicle was administered in the drinking water for 6 weeks to male Wistar rats weighing 220-240 g. The effect of acetylcholine and sodium nitroprusside was examined in vivo, on systemic blood pressure and heart rate and in vitro, on the precontracted isolated mesenteric artery. The in vivo response to both vasodilators was examined in awake rats monitored by an indwelling catheter in the femoral artery. Isolated segments of the third-generation mesenteric artery were examined in vitro with a Mulvany dual myograph after precontraction with noradrenaline. RESULTS: In isolated mesenteric arteries obtained from rats chronically treated with L-NAME, the initial relaxant response to acetylcholine was significantly decreased whereas that to sodium nitroprusside was enhanced. A late acetylcholine-induced contractile response was present and abolished by indomethacin. In vivo, the hypotensive action of sodium nitroprusside was also enhanced in the L-NAME-treated rats. Acetylcholine reduced blood pressure in the L-NAME-treated hypertensive animals more than in normotensive controls, but less than in control rats infused intravenously with noradrenaline at a dose increasing their blood pressure to hypertensive levels. CONCLUSIONS: The NO-mediated vasodilation induced by acetylcholine is attenuated during chronic NO synthase inhibition, both in vivo and in vitro. The blunted hypotensive response to acetylcholine can be demonstrated only if blood pressure of control rats is acutely increased to hypertensive levels

Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients.

The new renin inhibitor CGP 38560A has been shown to block angiotensin (ANG) production in healthy volunteers. In order to determine its potential antihypertensive effect, the compound was administered in a 30-min infusion, in 12 hypertensive patients (mean blood pressure (BP): 112.8 +/- 3.5 mm Hg). These patients were selected for their sensitivity to captopril: a single oral dose of 50 mg captopril lowered their mean BP by 8.8 +/- 2.2 mm Hg after 30 min and by 15.3 +/- 1.5 mm Hg after 90 min. At the end of the renin inhibitor infusion, mean blood pressure decreased by 5.7 +/- 2.2 mm Hg in the six patients infused with the dose of 0.125 mg/kg and by 6.0 +/- 1.8 mm Hg in the six patients infused with 0.250 mg/kg. The fall in blood pressure was correlated to the initial plasma renin activity (PRA) (r = 0.61, P less than .05). A dose-dependent effect was observed on plasma ANG I which fell by 74% with 0.125 mg/kg and by 94% with 0.250 mg/kg. Identical falls were found for plasma ANG II (72% and 94%, respectively) and ANG I and ANG II were well correlated (r = 0.91, P less than .001). The fall in BP was correlated to the fall in plasma ANG I (r = 0.77, P less than .01). The time-course of the BP changes was parallel to the changes in plasma angiotensins, as were the slightly delayed rise and fall in active renin measured by a direct immunoradiometric assay. When measured by the conventional ANG I radioimmunoassay, PRA values indicated a long-lasting inhibition.(ABSTRACT TRUNCATED AT 250 WORDS

Measurement of plasma endothelin-1 in experimental hypertension and in healthy subjects.

BACKGROUND: Endothelin-1 is an endothelium-derived potent vasoconstrictor peptide of 21 amino acids. To establish reference values in different models of hypertension and in human subjects an assay for plasma immunoreactive endothelin-1 (ET-1) was optimized. METHODS: ET-1 is extracted by acetone from 1 mL of plasma and subjected to a sensitive enzyme-linked immunosorbent assay. RESULTS: The detection limit for plasma ET-1 is 0.05 fmol/mL. Mean recoveries of the 1, 2, 5, and 10 fmol of ET-1 added to 1 mL of plasma were 66%, 75%, 85%, and 92%, respectively. Within- and between-assay coefficients of variation were < or =12% and < or =10%, respectively. Assay accuracy was demonstrated by consistent recoveries of added ET-1 over the entire physiologic range of plasma concentrations and by the linearity of ET-1 concentrations measured in serially diluted plasma extracts (r = 0.99). No ET-1 was detected when albumin buffer was extracted instead of plasma. Using this method, we found increased ET-1 levels in plasma of three experimental rat models of hypertension: stroke prone spontaneously hypertensive rats (SP-SHR), deoxycorticosterone acetate-salt hypertensive rats, and one kidney-one clip hypertensive rats. In contrast, plasma ET-1 levels of SHR were half those of normotensive Wistar rats. In two kidney-one clip hypertensive rats, plasma ET-1 concentrations were not different from those found in sham-operated control rats. Plasma ET-1 concentrations of 37 healthy men were 0.85 +/- 0.26 fmol/ml (mean +/- SD). CONCLUSIONS: The present assay reliably measures ET-1 levels in rat and human plasma. It allows to discriminate between different forms of hypertension with high or low circulating levels of ET-1

Blood sampling methodology is crucial for precise measurement of plasma catecholamines concentrations in mice.

Epinephrine (E) and norepinephrine (NE) play a major role in regulating metabolism and cardiovascular physiology. Both are secreted in response to stress and their measurement in plasma allows the study of sympathoadrenal function. Several studies investigating sympathoadrenal physiology are conducted using mice. Review of the literature revealed that basal mouse NE and E plasma concentrations range within 4-140 nM depending on the blood sampling method. Such variability doesn't allow study comparison and may conceal catecholamine variations in response to stress. Therefore, our aim was to determine a reliable sampling method to measure mouse plasma catecholamine concentrations. Results showed that arterial catheterization is the most accurate sampling method: E and NE basal levels were similar to those found in humans (1.1+/-0.3 nM and 4.1+/-0.5 nM, respectively). Retro-orbital bleeding led to analogous results. On the contrary, decapitation was stressful for mice and consequently NE and E concentrations were high (24.6+/-2.7 nM and 27.3+/-3.8 nM, respectively). These different bleeding methods were compared in terms of their ability to detect sympathoadrenal system stimulation (cold-pressure test). With catheter and retro-orbital samplings the expected increase in NE and E levels was easily perceived. In contrast, with decapitation no significant change in E was detected. In conclusion, arterial-catheter and retro-orbital blood sampling methods appear to be the most accurate procedures for studying the sympathetic nervous system in mice in both unstressed and stressed conditions