Labedipinedilol‐A: A vanilloid‐based α/β‐adrenoceptor blocker with calcium entry blocking and long‐acting antihypertensive properties

The combination of β‐adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol‐A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol‐A (0.1–1.0 mg/kg) produced dose‐dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)‐induced hypotensive and reflex tachycardia activities in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐A also inhibited phenylephrine (20 μg/kg, i.v.)‐induced hypertensive and (‐)isoprenaline (0.5 μg/kg, i.v.)‐induced tachycardia effects. Oral administration of labedipinedilol‐A (5–50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol‐A (10^–7–10^–5 M) competitively antagonized (‐)isoprenaline (10^–10–10^–4M)‐induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol‐A also prevented the rate‐increasing effects of increased extracellular Ca²⁺ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐A competitively antagonized CaCl₂ and norepinephrine‐induced contractions with pKCa^–1 and pA₂ values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K⁺‐induced vasocontraction. Furthermore, labedipinedilol‐A, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐A (10^–9–10^–6 M). The binding characteristics of labedipinedilol‐A were evaluated in [³H]CGP‐12177 binding to ventricle and lung and [³H]nitrendipine and [³H]prazosin binding to brain membranes in rats. The ‐logIC₅₀ values of labedipinedilol‐A for β₁‐, β₂‐, and α₁‐adrenoceptor and calcium channel, were 8.17 × 10^–7 M, 8.20 × 10^–7 M, 2.20 × 10^–8 M, and 2.46 × 10^–8 M, respectively. Labedipinedilol‐A‐induced sustained depressor effect was mainly attributed to its calcium entry and α‐adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β‐adrenoceptor and calcium entry blocking, which deleted the sympathetic activation‐associated reflex tachycardia in the heart. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley‐Liss, Inc.     

Third‐generation dihydropyridine‐type calcium channel blocker labedipinedilol‐B displays α/β‐adrenoceptor blocking activities

The pharmacological properties of labedipinedilol‐B {N‐[4‐[2‐hydroxy‐3‐(2‐methoxy‐1‐oxyethylaminobenzene) propoxy]‐benzyl]‐2,6‐dimethyl‐3,5‐dicarbomethoxy‐1,4‐dihydropyridine} were investigated in vivo and in vitro in comparison with labedipinedilol‐A. Intravenous labedipinedilol‐B (0.5, 1.0, and 3.0 mg kg^–1), produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐B (1.0 mg kg^–1, iv) also inhibited phenylephrine (10 μg kg^–1)‐induced hypertensive and (–)isoproterenol (0.5 μg kg^–1)‐induced tachycardia effects. In the isolated Wistar rat right and left atria and guinea pigs tracheal strips experiments, labedipinedilol‐B (10^–7, 10^–6, and 10^–5 M) competitively antagonized the (–)isoproterenol‐induced positive chronotropic and inotropic effects and tracheal relaxation responses in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curve of (–)isoproterenol suggested that labedipinedilol‐B was a β₁/β₂‐adrenoceptor competitive antagonist. Labedipinedilol‐B (10^–7, 10^–6, and 10^–5 M) also prevented the rate‐increasing effects of increased extracellular Ca²⁺ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐B (10^–7, 10^–6, and 10^–5 M) competitively antagonized the CaCl₂ and norepinephrine‐induced contractions with pKCa^–1 and pA₂ values of 8.02 ± 0.04 and 7.55 ± 0.05 in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curves of norepinephrine suggested that labedipinedilol‐B was an α‐adrenoceptor competitive antagonist. Furthermore, labedipinedilol‐B, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the isolated rat aorta, labedipinedilol‐B also competitively antagonized CaCl₂‐induced contractions and made the parallel shift to the right of the concentration–response curve of CaCl₂. In cultured blood vessel smooth muscle cells (A7r5 cell lines), Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐B, suggesting that the compound was a calcium channel blocker. The binding characteristics of labedipinedilol‐B were evaluated in [³H]CGP‐12177 binding to ventricle and lung and [³H]prazosin binding to brain membranes in rats. Labedipinedilol‐B also was evaluated in [³H]nitrendipine binding to brain membranes in rats. These results indicated that labedipinedilol‐B, similar to labedipinedilol‐A, has α‐adrenoceptor blocking, β‐adrenoceptor blocking, and calcium entry blocking activities in a single compound. We suggest that these two compounds represent a new generation of 1,4‐dihydropyridine‐type calcium channel blockers. Drug Dev. Res. 52:462–474, 2001. © 2001 Wiley‐Liss, Inc.     

Effects of labedipinedilol‐A,third‐generation dihydropyridine‐type calcium blocker,on ouabain‐induced arrhythmia

Labedipinedilol‐A, a novel dihydropyridine‐type calcium antagonist with α/β‐adrenoceptor blocking properties, has been reported to produce a cardioprotective effect against ischemia reperfusion injury in rats. We investigated the protective effects of labedipinedilol‐A on ouabain‐induced tonotropy and arrhythmias in isolated whole atria, and using patch‐clamp techniques to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. Labedipinedilol‐A (10 µM) suppressed the tonotropic effect of ouabain significantly and prolonged the onset time of extra‐systole (arrhythmia) induced by ouabain in isolate atria. In the voltage‐clamp study, labedipinedilol‐A (1–100 µM) reduced the peak amplitude of sodium inward current (I_Na) and L‐type calcium current (I_Ca‐L), and shifted the current‐voltage (I‐V) curve upward in a concentration‐dependent manner. In contrast, the addition of labedipinedilol‐A increased transient outward potassium current (I_to) and inward rectifier potassium current (I_K1) significantly. Labedipinedilol‐A (10 µM) also effectively depressed the isoproterenol‐induced increase in the Ca²⁺ current. These results show that labedipinedilol‐A blocks I_Ca‐L and I_Na, and increases I_to and I_K1. These findings indicate that labedipinedilol‐A produces direct cardiac action, probably due to the inhibition of cardiac Na⁺ and Ca²⁺ channels. Our results suggest that labedipinedilol‐A may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain‐induced arrhythmia. Drug Dev Res 69:26–33, 2008 © 2008 Wiley‐Liss, Inc.     

Autonomic and antihypertensive activity of oral amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor blocking agent in conscious rats

The autonomic and antihypertensive activities of amosulalol (YM-09538) were studied in conscious rats. Single oral administration of amosulalol antagonized the phenylephrine-induced pressor and isoproterenol-induced positive chronotropic responses with DR10 values of 11.5 and 13.6 mg/kg in pithed rats, respectively, indicating that the compound inhibits both alpha 1- and beta 1-adrenoceptors to almost the same extent in agreement with previously reported results in vitro. Amosulalol was approximately 50 times less potent than prazosin and 12 times more potent than labetalol at alpha 1-adrenoceptors, and it was approximately as effective as labetalol and 2 times more potent than propranolol at beta 1-adrenoceptors. In spontaneously hypertensive rats (SHR), renal hypertensive rats and DOCA/salt hypertensive rats, a single oral administration of amosulalol (3-30 mg/kg) lowered acutely systolic blood pressure with a duration of over 6 hr and was found to be approximately 50 times less potent than prazosin and 3 times more potent than labetalol in lowering blood pressure. Propranolol did not cause such an immediate hypotensive effect. Amosulalol and labetalol did not increase heart rate, whereas prazosin induced a tachycardia in the hypertensive rats. Repeated oral administrations of amosulalol and labetalol (50 mg/kg/day, b.i.d., for 12 weeks) produced not only an antihypertensive effect without evidence of tolerance, but also reductions in plasma renin activity (PRA) and heart rate in SHR with established hypertension. We conclude that alpha-adrenoceptor blockade by amosulalol might account for its antihypertensive activity and that its beta-adrenoceptor blockade might inhibit reflexogenic increases in heart rate and PRA due to the reduction in blood pressure.     

Effects of nine antihypertensive drugs on blood pressure variability in sinoaortic-denervated rats

AIM: The present work was designed to investigate the effects of nine commonly used antihypertensive drugs on blood pressure (BP) and blood pressure variability (BPV) in conscious sinoaortic-denervated (SAD) rats. METHODS: Seventy-two SAD rats were randomly divided into nine groups. They were respectively given nifedipine 3 mg/kg, nitrendipine 5 mg/kg, amlodipine 1 mg/kg, clonidine 10 mug/kg, prazosin 0.5 mg/kg, atenolol 20 mg/kg, telmisartan 20 mg/kg, hydrochlorothiazide 40 mg/kg or captopril 50 mg/kg. The drugs were given via a catheter previously implanted into the stomach. BP was recorded for 5 h from 1 h before drug administration to 4 h after drug administration in conscious, freely moving rats. RESULTS: It was found that all these nine drugs significantly decreased BP in SAD rats. Six of these drugs (nifedipine, nitrendipine, amlodipine, clonidine, prazosin and atenolol) significantly decreased BPV in SAD rats, but the remaining three drugs did not. Clonidine and atenolol increased the heart period and the others did not. No drugs affected the heart period variability. CONCLUSION: Among nine antihypertensive drugs from different classes, calcium antagonists and sympathetic inhibitors decreased BPV in SAD rats.     

Angiotensin‐(1–7) treatment ameliorates angiotensin II‐induced apoptosis of human umbilical vein endothelial cells

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2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure influence the expression of glutamate transporter GLT‐1 in C6 glioma cells via the Ca2+/protein kinase C pathway

The widespread environmental contaminant, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), is considered one of the most toxic dioxin‐like compounds. Although epidemiological studies have shown that TCDD exposure is linked to some neurological and neurophysiological disorders, the underlying mechanism of TCDD‐mediated neurotoxicity has remained unclear. Astrocytes are the most abundant cells in the nervous systems, and are recognized as the important mediators of normal brain functions as well as neurological, neurodevelopmental and neurodegenerative brain diseases. In this study, we investigated the role of TCDD in regulating the expression of glutamate transporter GLT‐1 in astrocytes. TCDD, at concentrations of 0.1–100 nm , had no significantly harmful effect on the viability of C6 glioma cells. However, the expression of GLT‐1 in C6 glioma cells was downregulated in a dose‐ and time‐dependent manner. TCDD also caused activation of protein kinase C (PKC), as TCDD induced translocation of the PKC from the cytoplasm or perinuclear to the membrane. The translocation of PKC was inhibited by one Ca²⁺ blocker, nifedipine, suggesting that the effects are triggered by the initial elevated intracellular concentration of free Ca²⁺. Finally, we showed that inhibition of the PKC activity reverses the TCDD‐triggered reduction of GLT‐1. In summary, our results suggested that TCDD exposure could downregulate the expression of GLT‐1 in C6 via Ca²⁺/PKC pathway. The downregulation of GLT‐1 might participate in TCDD‐mediated neurotoxicity. Copyright © 2016 John Wiley & Sons, Ltd.     

Synergism of simvastatin with losartan prevents angiotensin II‐induced cardiomyocyte apoptosis in vitro

Objectives Increasing evidence suggests that cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodelling to heart failure. The synergistic effect of statins (3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors) and angiotensin II (Ang II) type 1 receptor antagonists reduces the incidence of cardiovascular events. However, the anti‐apoptotic potential of the synergism between losartan and simvastatin in heart failure remains unexplored. Here, we demonstrate that Ang II‐induced apoptosis is prevented by losartan and simvastatin in neonatal cardiomyocytes. Methods The in‐vitro cardiomyocyte apoptosis model was established by co‐culturing neonate rat cardiomyocytes with Ang II. Cell viability was analysed by the MTT assay. Cell apoptosis was evaluated using fluorescence microscopy and flow cytometry. Apoptosis‐related proteins Bax and Bcl‐2 expressions were measured by flow cytometry detection. Key findings Incubation with 10^?7 m Ang II for 48 h increased cardiomyocyte apoptosis and decreased cell viability. Losartan (10^?5 m ) and simvastatin (10^?5 m ), either alone or in combination, significantly decreased Ang II‐induced cardiomyocyte apoptosis and increased cell viability. The q values calculated by the probability sum test were 1.31 for cardiomyocyte apoptosis and 1.21 for cell viability. Ang II induced a significant increase in Bax protein expression, whereas Bcl‐2 protein expression was decreased. Losartan alone or in combination with simvastatin blocked the increased Bax expression and increased Bcl‐2 expression. However, simvastatin had no such effect. Conclusions Our data provide the first evidence that synergism of simvastatin with losartan prevents angiotensin II‐induced cardiomyocyte apoptosis in vitro. Synergism between simvastatin and losartan may provide a new therapeutic approach to the prevention of cardiac remodelling.     

Role of α1D‐adrenoceptors in vascular wall hypertrophy during angiotensin II‐induced hypertension

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Effect of antihypertensive drug therapy on short‐term heart rate variability in newly diagnosed essential hypertension

1. Abnormalities of cardiac autonomic regulation are a potential mechanism for morbidity despite blood pressure (BP) lowering in hypertension. Analysis of short‐term (5 min) heart rate variability (HRV) provides a non‐invasive probe of autonomic regulation of sino‐atrial (SA) node automaticity. 2. We hypothesized that antihypertensive drug therapy would be associated with an increase in 5 min overall HRV, along with a decrease in blood pressure (BP), at 8 weeks follow up in subjects with newly diagnosed, never‐treated essential hypertension. 3. One hundred and fifty patients (84 men and 66 women; mean (±SD) age 48 ± 10 years) with newly diagnosed essential hypertension were divided to five groups of 30 patients each to receive one of the following antihypertensive drugs (or drug combinations): 5 mg/day amlodipine; 50 mg/day atenolol; 5 mg/day enalapril; 25 mg/day hydrochlorothiazide; or a combination of 5 mg/day amlodipine and 50 mg/day atenolol. 4. The only significant change in HRV indices was an increase in total variability of RR intervals and an increase in high‐frequency (HF) RR interval spectral power in the amlodipine + atenolol‐treated group (P < 0.05). 5. The results indicate that there is a dissociation between changes in short‐term HRV and mean RR interval and BP lowering in patients with newly diagnosed hypertension. 6. We interpret the increase in HF RR interval spectral power in the amlodipine + atenolol‐treated group as being due to an increase in vagal modulation of RR intervals and/or diminution in sympathetic restraint of respiratory sinus arrhythmia.     

Combined effects of AT(1) and ET(A) receptor antagonists, candesartan, and A-127722 in DOCA-salt hypertensive rats

Several recent studies have provided evidence that many of the hemodynamic and mitogenic actions of angiotensin II (Ang II) are mediated by endothelin-1 (ET-1). We hypothesized that Ang II and ET-1 act synergistically to promote a decline in renal function and the development of renal fibrosis in the deoxycorticosterone acetate (DOCA)-salt model of malignant hypertension and renal dysfunction. Experiments were conducted to determine the effects of ET(A) receptor antagonism (A-127722) and AT(1) receptor antagonism (candesartan cilexetil) on the development of renal fibrosis and the decline of renal function. Surgery was conducted on male, Sprague-Dawley rats to remove the right kidney and implant subcutaneously a time-release pellet containing DOCA. DOCA-treated rats were also given 0.9% NaCl to drink. After recovery from surgery, rats received one of four treatments via the drinking solution: (1) candesartan cilexetil (10 mg/kg/day), (2) A-127722 (10 mg/kg/day), (3) candesartan cilexetil plus A-127722, or (4) untreated controls. Over the course of a 3-week treatment period, systolic arterial pressure in all groups were elevated. However, this increase was significantly attenuated in the group given combined A-127722 and candesartan, but not with candesartan alone. Creatinine clearance, used as a measure of GFR, was significantly higher in rats treated with either or both drugs. At the end of the study, renal medullary tissue was harvested for determination of TGF-beta and fibronectin content (ELISA). TGF-beta levels were not reduced by either ET(A), AT(1), or combined ET(A) and AT(1) receptor blockade. Likewise, fibronectin content was similar among groups. These studies indicate that combined ET(A) and AT(1) receptor blockade may produce some improvement on hemodynamics, but have no effect on progression of renal damage in this non-renin-dependent model of hypertension.     

Clinical effectiveness of low-dose chlorthalidone (6.25 mg) + atenolol combination in stage I hypertensive patients: a multicenter,randomized, controlled study

ABSTRACT

Objective: To compare the efficacy and safety of low-dose chlorthalidone + atenolol combination with atenolol and atenolol + amlodipine combination in stage I hypertensive patients uncontrolled on active run-in monotherapy.

Methods: Newly diagnosed stage I hypertensive patients were randomized to active run-in monotherapy either with atenolol 25?mg (98/300) or chlorthalidone 6.25?mg (100/300) or amlodipine 2.5?mg (102/300). A total of 282/300 patients (atenolol 92, chlorthalidone 91, amlodipine 99) completed the active run-in phase successfully. Patients uncontrolled on active run-in monotherapy (atenolol 33, chlorthalidone 45, amlodipine 47) received the study treatment, namely atenolol 50?mg alone, chlorthalidone 6.25?mg + atenolol 25?mg and atenolol 25?mg + amlodipine 2.5?mg, respectively. Efficacy of the therapy was evaluated by BP measurement at weeks 12 and 20 post-therapy.

Results: Post-active run-in monotherapies, the study treatment groups showed a significant fall in mean SBP and DBP from baseline (p?<?0.05). The mean fall in SBP and DBP was comparable for study treatments (atenolol 50?mg, atenolol 25?mg + chlorthalidone 6.25?mg and atenolol 25?mg + amlodipine 2.5?mg) (p = 0.337 for SBP and p = 0.054 for DBP) at week 12 and (p = 0.744 for SBP and p = 0.855 for DBP) at week 20; also, the percentage of responders was comparable for the three study treatment groups (p = 0.799) indicating that the low-dose chlorthalidone + atenolol combination is non-inferior to the high-dose atenolol alone and atenolol + amlodipine combination. No serious laboratory/clinical adverse events were reported in this study.

Conclusion: Chlorthalidone 6.25?mg in combination with atenolol 25?mg is effective and safe in stage I (JNC 7) essential hypertensive patients. This low dose of chlorthalidone could reduce dose-related concerns over metabolic adverse effects and may lead to wider usage of this proven antihypertensive agent in combination therapy.     

KMUP 880708: A vanyllilamide‐based β1‐adrenoceptor antagonist with α‐adrenoceptor blocking and potassium channel opening activities

A vanillylamide‐based propanolamine derivative, KMUP 880708, was first investigated both in vivo and in vitro. KMUP 880708 (0.1, 0.5, 1.0, and 2.0 mg kg^–1, iv) produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. KMUP 880708 (0.1, 0.5, and 1.0 mg kg^–1, iv) also markedly inhibited both the tachycardia effects induced by (–)isoproterenol and arterial pressor responses induced by phenylephrine. KMUP 880708 competitively antagonized (–)isoproterenol‐induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses on isolated guinea pig tissues. The apparent pA₂ values for KMUP 880708 was 7.82 ± 0.06 in the right atria, 7.51 ± 0.13 in the left atria, and 6.31 ± 0.07 in the trachea, respectively, indicating that KMUP 880708 was selective β₁‐adrenoceptor blocker. In thoracic aorta experiments, KMUP 880708 also produced a competitive antagonism of norepinephrine‐induced contraction with pA₂ value of 7.92 ± 0.52, indicating that KMUP 880708 was α‐adrenoceptor antagonist. In isolated rat thoracic aorta, KMUP 880708 more potently relaxed the contractions induced by phenylephrine (10^–5 M) than those by high K⁺ (75 mM). KMUP 880708‐induced relaxation was significantly reduced by endothelium removal and by exposure to L‐N^G‐nitro arginine methyl ester (L‐NAME, 1 and 3 × 10^–4 M), indomethacin (3 × 10^–5 M), methylene blue (10^–5 M) and 1H‐[1,2,4]oxadiazolol[4,3,‐a]quinoxalin‐1‐one (ODQ, 10^–6 M). The vasorelaxant effect of KMUP 880708 on phenylephrine‐induced contraction was attenuated by the pretreatment with tetraethylammonium (TEA), glibenclamide, charybdotoxin, and apamin, but not by 4‐aminopyridine (4‐AP). In addition, KMUP 880708 inhibited phenylephrine‐induced biphasic contraction and affected the fast‐twitch phase more significantly than the slow tonic phase. In the radioligand‐binding assay, the K_i values of [³H]CGP‐12177 binding to rat ventricle and lung membranes were 15.14 and 524.81 nM, respectively, and the value of [³H]prazosin binding to rat brain membrane was 3.89 nM. The ranking order of inhibition for [³H]CGP‐12177 binding on β‐adrenoceptor was propranolol > labetalol > KMUP 880708 > atenolol, and that for [³H]prazosin binding to α‐adrenoceptor was KMUP 880708 > labetalol. In conclusion, KMUP 880708 was found to be a new generation α/β‐adrenoceptor blocker with selective β₁‐adrenoceptor blocking and vascular smooth muscle relaxation activities. Furthermore, the vasodilator effect of KMUP 880708 is attributed to the release of NO or NO‐related substance from vascular endothelium. While the endothelium‐independent mechanism involved in the relaxation of KMUP 880708 is probably linked to K⁺ channel activation in these vessels. Drug Dev. Res. 55:104–117, 2002. © 2002 Wiley‐Liss, Inc.     

Immunosuppression with mycophenolate mofetil attenuates the development of hypertension and albuminuria in deoxycorticosterone acetate‐salt hypertensive rats

1. The interplay between the immune and renin–angiotensin systems is emerging as a crucial factor in the development and progression of hypertension. The aim of the present study was to determine the involvement of immune cells in the hypertension and renal injury produced by a non‐angiotensin II‐dependent form of hypertension, namely deoxycorticosterone acetate (DOCA)‐salt‐induced hypertension, in rats. 2. Male Sprague‐Dawley rats underwent uninephrectomy and received either a sustained‐release pellet of DOCA s.c. and 0.9% NaCl (saline) to drink for 21 days or a placebo pellet and water to drink for 21 days. Additional groups of DOCA‐salt‐ and placebo‐treated rats were treated concurrently with the immune suppressant mycophenolate mofetil (MMF; 30 mg/kg per day). Rats were placed in metabolic cages for 24 h urine collection prior to and at weekly intervals during the 21 day experimental period. 3. Mycophenolate mofetil significantly attenuated the development of hypertension in DOCA‐salt rats compared with untreated DOCA‐salt hypertensive rats (mean arterial pressure by telemetry on Day 18 146 ± 7 vs 180 ± 3 mmHg, respectively; P < 0.001), as well as proteinuria (87 ± 27 vs 305 ± 63 mg/day, respectively, on Day 21) and albuminuria (51 ± 15 vs 247 ± 73 mg/day, respectively, on Day 21). Creatinine clearance was better preserved in MMF‐treated DOCA‐salt rats compared with untreated DOCA‐salt rats (0.74 ± 0.07 vs 0.49 ± 0.09 mL/min, respectively; P < 0.05), but was still significantly reduced compared with that in the placebo group (1.15 ± 0.12 mL/min; P < 0.05). Finally, MMF treatment significantly attenuated the DOCA‐salt‐induced rise in renal cortical T‐lymphocyte and macrophage infiltration (P < 0.05). 4. These data indicate that immune cells play a deleterious role in both the hypertension and renal injury associated with DOCA‐salt hypertension.     

Effects of P5, a novel oxazolo(3,2‐a)pyridine derivative with a long‐acting antihypertensive activity,on different agonist‐mediated pressor responses in pithed rats

1 An oxazolo(3,2‐a)pyridine derivative P5, described chemically as (±)‐ethyl‐7‐(3‐nitrophenyl)‐5,8a‐dimethyl‐6‐methoxycarbonyl‐2,3,8,8a‐tetrahydro‐7H‐oxazolo[3,2‐a]pyridin‐8‐carboxylate, is a novel compound that has been synthesized as a possible antihypertensive prodrug of the 1,4‐dihydropyridine type. Its antihypertensive activity was described in a previous study by the authors ( 22 ). 2 The aim of this work was to establish in vivo, the possible mechanisms participating in this antihypertensive action. Accordingly, we examined the effect of P5 on the pressor responses induced in pithed rats by noradrenaline (an α₁‐, α₂‐ and β‐adrenoceptor agonist), xylazine (an α₂‐adrenoceptor agonist), methoxamine (an α₁‐adrenoceptor agonist), angiotensin I, angiotensin II, L‐NAME (a nitric oxide synthase inhibitor) and BayK 8644 (a calcium channel agonist) and compared them with those of nifedipine, used as the reference drug. 3 Intravenous (i.v.) administration of P5 (2.5–10 mg kg^–1) inhibited the pressor responses to noradrenaline (1 μg kg^–1), xylazine (80 μg kg^–1), angiotensin I (0.5 μg kg^–1), angiotensin II (0.5 μg kg^–1), BayK 8644 (30 μg kg^–1) and L‐NAME (10 mg kg^–1). Nifedipine (10 μg kg^–1, i.v.) reduced the pressor responses to all these agonists and also to methoxamine (2 μg kg^–1). 4 However, P5 was more effective than nifedipine in inhibiting these responses and its inhibitory effect lasted longer. Intravenous infusion of calcium gluconate (1 ml kg^–1 min^–1) reversed the reduction in the pressor responses as a result of nifedipine. The effects of P5 were only reversed at 2–3 h after administration. 5 These results suggest that P5 has a strong capacity to inhibit the pressor responses to several agonists after its i.v. administration and that such effects are related to its potent antihypertensive activity.     

A comparison of labetalol and prazosin combined with atenolol in non-responders to atenolol plus hydrochlorothiazide in uncomplicated hypertension

Summary After screening two local populations in the northern part of The Netherlands for hypertension, patients with a diastolic pressure (DP) between 95 and 120 mmHg were treated daily either with 50 mg hydrochlorothiazide or 100 mg atenolol. Non-responders were given the combination and if necessary the dose of atenolol was increased to 200 mg. Non-responders to the latter combination were randomized and treated either with 50 mg hydrochlorothiazide and labetalol or with 50 mg hydrochlorothiazide, 200 mg atenolol and prazosin. If after 1 month a DP90 mmHg had been reached the patient was reassessed after a further 3 months. If a DP>90 mmHg was found the dose of labetalol or prazosin was increased and the patient was re-examined after 1 month.This protocol was followed until the maximum dose was reached or adverse reactions prevented a further increase in dosage.During 6 months of treatment there was a further drop in systolic and diastolic blood pressures under both regimens of, respectively, 8.6 and 2.4 mmHg for labetalol, and 7.7 and 5.0 mmHg for the prazosin group. At the end of the period the average daily doses of labetalol and prazosin were 1256 mg and 4.3 mg, respectively. There was no significant difference in the average number of complaints between the labetalol and the prazosin group.     

Treatment of mild-to-moderate hypertension with calcium channel blockers: a multicentre comparison of once-daily nifedipine GITS with once-daily amlodipine

SUMMARY

Background: Hypertension is one of the most important causes of cardiovascular disease, and treatment of hypertension leads to a significant reduction in cardiovascular mortality and morbidity. Although calcium channel blockers are regarded as an important part of the therapeutic armamentarium against cardiovascular diseases, and are among the most frequently prescribed antihypertensive medications, concern has been aroused about these drugs, particularly the short-acting dihydropyridine derivatives. However, the value of nifedipine GITS (Adalat-Crono), the long-acting dihydropyridine, is in need of being re-established.

Objective:To compare the effectiveness, safety and tolerability of once-daily nifedipine and amlodipine treatment in patients with mild-to-moderate essential hypertension.

Design: Randomised multicentre trial with an open comparison of treatments for 12 weeks, with a preceding placebo run-in period of 2 weeks (patients on beta-blockers at the time of enrolment entered a mandatory 2-week wash-out period before being allowed in the placebo run-in period; this wash-out period was one week for patients using any antihypertensive medication other than beta-blockers).

Setting: Nine centres (all university hospitals) in Turkey.

Patients: 155 patients with essential hypertension (diastolicblood pressure 95-109?mmHg).

Interventions: Initial treatment (step 1) consisted of 30mg nifedipine GITS (n?=?76; (Adalat-Crono tablets), or 5mg amlodipine (n?=?79; Norvasc* 5-mg tablets), either administered once daily, as a morning dose, or if the blood pressure was not below 140/90?mmHg, or the reduction in diastolic blood pressure was lower than 10?mmHg after a treatment period of 6 weeks, the dose was increased (Step 2) to 60?mg once daily in the nifedipine group, or 10?mg once daily in the amlodipine group.

Main efficacy parameter: Diastolic blood pressure at trough after 12 weeks of active compound therapy adjusted to baseline.

Results: After 12 weeks of treatment, the mean diastolic blood pressure was 83.1 and 81.9?mmHg, in the nifedipine and amlodipine groups, respectively (p?=?0.436). The mean decrease in systolic blood pressure (28.5?±?11.9 and 28.2?±?11.2?mmHg in the nifedipine and amlodipine groups, respectively) and the mean decrease in diastolic blood pressure (16.4?±?7.0 and 17.5?±?6.9?mmHg in the nifedipine and amlodipine groups, respectively), as well as the responder rates (88.1% and 92.1%, in the nifedipine and amlodipine groups, respectively) were comparable at the end of the study. No significant differences between groups were detected in the efficacy parameters assessed in this study. Both drugs were well tolerated. The overall incidence of adverse events was 7.9% in the nifedipine group and 10.1% in the amlodipine group. However, more patients discontinued treatment prematurely in the amlodipine group (13 patients; 19.7%), than in the nifedipine group (four patients; 5.6%).

Conclusions: The results of this study demonstrated that once-daily nifedipine in GITS formulation and amlodipine are comparably safe and effective treatment options in patients with mild-to-moderate essential hypertensi on.     

l‐Carnitine Attenuates Cardiac Remodelling rather than Vascular Remodelling in Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: l ‐Carnitine is an important co‐factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of l ‐carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (n = 6–12; #p < 0.05 versus DOCA‐salt). Uninephrectomized rats administered DOCA (25 mg every 4th day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness and vascular dysfunction with increased plasma malondialdehyde concentrations. Treatment with l ‐carnitine (1.2% in food; 0.9 mg/g/day in DOCA‐salt rats) decreased blood pressure (DOCA‐salt 169 ± 2; + l ‐carnitine 148 ± 6# mmHg), decreased left ventricular wet weights (DOCA‐salt 3.02 ± 0.07; + l ‐carnitine 2.72 ± 0.06# mg/g body‐wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA‐salt 14.4 ± 0.2; + l ‐carnitine 8.7 ± 0.5# % area), reduced diastolic stiffness constant (DOCA‐salt 26.9 ± 0.5; + l ‐carnitine 23.8 ± 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA‐salt 26.9 ± 0.8; + l ‐carnitine 21.2 ± 0.4# μmol/l) without preventing endothelial dysfunction. l ‐carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA‐salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA‐salt rats, underlying the relatively selective cardiac responses to l ‐carnitine treatment.     

Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II‐infused rats

Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II‐dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague–Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II‐induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II‐mediated increase in plasma and heart aldosterone 2.3‐ and 1.8‐fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1‐mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4‐hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress‐associated cardiovascular damage in Ang II‐dependent hypertension.