Improved cardiovascular function with aminoguanidine in DOCA-salt hypertensive rats

The ability of aminoguanidine (AG), an inhibitor of collagen crosslinking, to prevent changes in cardiac and vascular structure and function has been determined in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat as a model of the cardiovascular remodelling observed in chronic human hypertension.Uninephrectomized rats (UNX) administered DOCA (25 mg every fourth 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, impaired contractility, prolongation of the action potential duration and vascular dysfunction.Treatment with AG (0.05-0.1% in drinking water; average 182+/-17 mg kg(-1) day(-1) in DOCA-salt rats) decreased blood pressure (DOCA-salt 176+/-4; +AG 144+/-5 mmHg; (*)P<0.05 vs DOCA-salt), decreased left ventricular wet weights (DOCA-salt 3.17+/-0.07; +AG 2.66+/-0.08 mg g(-1) body wt(*)), reduced diastolic stiffness constant (DOCA-salt 30.1+/-1.2; +AG 24.3+/-1.2(*) (dimensionless)), improved cardiac contractility (DOCA-salt 1610+/-130; +AG 2370+/-100 mmHg s(-1)(*)) and vascular reactivity (3.4-fold increase in maximal contractile response to noradrenaline, 3.2-fold increase in maximal relaxation response to acetylcholine, twofold increase in maximal relaxation response to sodium nitroprusside) and prolonged the action potential duration at 50% repolarization without altering collagen content or inflammatory cell infiltration.Thus, cardiovascular function in DOCA-salt hypertensive rats can be improved by AG independent of changes in collagen content. This suggests that collagen crosslinking is an important cause of cardiovascular dysfunction during cardiovascular remodelling in hypertension.     

Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats

1. This study has administered pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) or amiloride to attenuate the remodelling and associated functional changes, especially an increased cardiac stiffness, in DOCA-salt hypertensive rats. 2. In control rats, the elimination half-life of pirfenidone following a single intravenous dose of 200 mg kg(-1) was 37 min while oral bioavailability at this dose was 25.7%. Plasma pirfenidone concentrations in control rats averaged 1.9 +/- 0.1 microg ml(-1) over 24 h after 14 days' administration as a 0.4% mixture in food. 3. Pirfenidone (approximately 250-300 mg kg(-1) day(-1) as 0.4% in food) and amiloride (1 mg kg(-1) day(-1) sc) were administered for 2 weeks starting 2 weeks post-surgery. Pirfenidone but not amiloride attenuated ventricular hypertrophy (2.69 +/- 0.09, UNX 2.01 +/- 0.05. DOCA-salt 3.11 +/- 0.09 mg kg(-1) body wt) without lowering systolic blood pressure. 4. Collagen deposition was significantly increased in the interstitium after 2 weeks and further increased with scarring of the left ventricle after 4 weeks; pirfenidone and amiloride reversed the increases and prevented further increases. This accumulation of collagen was accompanied by an increase in diastolic stiffness constant; both amiloride and pirfenidone reversed this increase. 5. Noradrenaline potency (positive chronotropy) was decreased in right atria (neg log EC50: control 6.92 +/- 0.06; DOCA-salt 6.64 +/- 0.08); pirfenidone but not amiloride reversed this change. Noradrenaline was a more potent vasoconstrictor in thoracic aortic rings (neg log EC50: control 6.91 +/- 0.10; DOCA-salt 7.90 +/- 0.07); pirfenidone treatment did not change noradrenaline potency. 6. Thus, pirfenidone and amiloride reverse and prevent cardiac remodelling and the increased cardiac stiffness without reversing the increased vascular responses to noradrenaline.     

Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats

The pleiotropic effects of statins represent potential mechanisms for the treatment of end-organ damage in hypertension. This study has investigated the effects of rosuvastatin in a model of cardiovascular remodeling, the DOCA-salt hypertensive rat. Male Wistar rats weighing 300 to 330 g were uninephrectomized (UNX) or UNX and treated with DOCA (25 mg subcutaneously every fourth day) and 1% NaCl in the drinking water. Compared with UNX controls, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, inflammation with perivascular and interstitial cardiac fibrosis, endothelial dysfunction, and prolongation of ventricular action potential duration at 28 days. Rosuvastatin-treated rats received 20 mg/kg/d of the drug in 10% Tween 20 by oral gavage for 32 days commencing 4 days before uninephrectomy. UNX and DOCA-salt controls received vehicle only. Rosuvastatin therapy attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation, but did not modify hypertension or vascular dysfunction. We conclude that the pleiotropic effects of rosuvastatin include attenuation of aspects of cardiovascular remodeling in the DOCA-salt model of hypertension in rats without altering systolic blood pressure.     

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.     

Cardiac and vascular responses in deoxycorticosterone acetate-salt hypertensive rats

1. Hypertension leads to ventricular hypertrophy and, eventually, to heart failure. The present study has investigated the functional consequences of deoxycorticosterone acetate (DOCA)-salt hypertension in rats by defining the inotropic, chronotropic and vascular responses to noradrenaline (NA; beta1-adrenoceptor agonist), forskolin (adenylate cyclase activator) and theophylline (phosphodiesterase inhibitor). 2. Administration of DOCA (25 mg, s.c., every 4th day) and excess salt (1% NaCl in drinking water) to uninephrectomized rats increased left ventricular wet weight by 35 and 71% after 4 and 8 weeks, respectively. Addition of KCl (0.4%) or CaCl2 (1%) in the drinking water for 4 weeks attenuated blood pressure increases, but not ventricular weight increases (46 and 28%, respectively). 3. Positive inotropic responses in papillary muscles from uninephrectomized rats to NA (-log EC50 6.73+/-0.38; n = 7), forskolin (-log EC50 6.15+/-0.31; n = 7) and CaCl2 (-log EC50 2.40+/-0.02; n = 14) were unchanged in hypertrophied left ventricles of DOCA and DOCA-CaCl2 rats, although maximal responses to NA were decreased in DOCA-KCI rats (1.2+/-0.6 mN, n = 8; DOCA-salt 2.9+/-0.5 mN, n = 6); theophylline was less potent in DOCA-salt rats. Positive chronotropic responses to NA, forskolin and theophylline in right atria and negative inotropic responses to carbachol in papillary muscles were unchanged. 4. Maximal vasoconstrictor responses to NA in thoracic aortic rings were reduced in DOCA-KCI rats to 2.4+/-0.9 mN (n = 5), but were increased in DOCA-CaCl2 rats to 26.6+/-2.2 mN (n = 7; DOCA-salt 7.8+/-2.2 mN, n = 9). Vasorelaxant responses to forskolin and theophylline were unchanged. 5. These results show that cardiac responses are only minimally affected during the development of DOCA-salt hypertension-induced hypertrophy, despite the reported decreases in adenylate cyclase activity, in these rats. This is in contrast with the decreased responses reported in other rat models of cardiac hypertrophy and in the failing human heart. Thus, hypertrophy in hearts of DOCA-salt hypertensive rats does not produce similar changes to the failing human heart.     

The class III effect of azimilide is not associated with reverse use-dependence in open-chest dogs

Certain class III antiarrhythmic agents manifest loss of effect at short cycle lengths (CLs). This effect may limit their efficacy in the presence of tachycardia. We studied the frequency-dependent effect of azimilide (NE-10064), a new class III agent, on the right ventricular monophasic action potential (APD90) in 12 open-chest dogs. The monophasic action-potential duration at different pacing CLs (140-400 ms), during sinus rhythm, and ventricular fibrillation CL (VFCL) from left epicardial electrograms were recorded before and after increasing doses of intravenous azimilide. At pacing CL of 400 ms, APD90 was significantly prolonged after 7, 17, and 30 mg/kg of azimilide by 5.4, 7.7, and 10.7%, respectively. The extent of APD90 prolongation was independent of rate. Azimilide increased the APD90 by similar amounts at CL of 400 ms and at the fastest possible stimulation rate maintaining 1:1 capture (mean, 171 +/- 23 ms): by 2.6 +/- 8.6% and 5.6 +/- 5.9% at 2 mg/kg, 5.4 +/- 4.8% and 4.8 +/- 4.7% at 7 mg/kg, 7.7 +/- 5.6% and 9.9 +/-4.5% at 17 mg/kg, and 10.7 +/- 2.6% and 19.3 +/- 11.9% at 30 mg/kg, respectively. Azimilide caused no changes in arterial blood pressure or heart rate. Azimilide prolongs APD90 even at very short CLs. The absence of reverse use-dependence of effect on APD90 may have clinical importance.     

Effect of prolonged administration of a urinary kinase inhibitor, ebelactone B on the development of deoxycorticosterone acetate-salt hypertension in rats

The effect of prolonged administration of a carboxypeptidase Y-like kininase inhibitor, ebelactone B (EB) (2-ethyl-3, 11-dihydroxy-4, 6, 8, 10, 12-pentamethyl-9-oxo-6-tetradecenoic 1, 3-lactone), on the development of deoxycorticosterone acetate (DOCA)-salt hypertension was tested. The systolic blood pressure (SBP) of non-treated 6-week-old Sprague-Dawley strain rats was gradually increased by DOCA-salt treatment from 137+/-2 mmHg (n=11) to 195+/-7 mmHg at 10 weeks of age. With daily oral administration of lisinopril (5 mg kg(-1), twice a day), which is an inhibitor of angiotensin converting enzyme, a major kininase in plasma, the development of hypertension was not suppressed. By contrast, administration of EB (5 mg kg(-1), twice a day), completely inhibited the development of hypertension (SBP: 146+/-1 mmHg, n=5, 10 weeks old). The reduced SBP at 10 weeks of age was equal to the SBP before any treatment (142+/-1 mmHg, n=5). Direct determination of mean blood pressure (MBP) in conscious, unrestrained rats confirmed that MBP elevation was completely inhibited by EB. Continuous subcutaneous infusion (5 mg kg(-1) day(-1)) of HOE140, a bradykinin B2 receptor antagonist, restored the elevation of SBP, which was suppressed by EB. The weights of left ventricle of DOCA-salt treated rats 10-weeks-old (0.36+/-0.02 g 100 g body weight(-1), n=11) was significantly reduced by EB (0.27+/-0.01, n=5), as were the sodium levels in serum, cerebrospinal fluid and erythrocyte. These findings suggested that EB is effective in preventing salt-related hypertension presumably by eliminating sodium retention.     

Evaluation of the acute electrophysiologic effects of intravenous dronedarone, an amiodarone-like agent, with special emphasis on ventricular repolarization and acquired torsade de pointes arrhythmias

In the anesthetized dog with complete chronic AV block (CAVB), we evaluated and compared the acute electrophysiologic effects of dronedarone i.v. (Dron, 2 times 2.5 mg/kg/10 min) and amiodarone i.v. (Amio, 2 times 5 mg/kg/10 min). This canine model with a high sensitivity for acquired torsade de pointes (TdP) provides an ideal substrate to evaluate ventricular repolarization abnormalities. Six ECG leads and two endocardial monophasic action potential (MAP) recordings in the left and right ventricle (LV and RV) were simultaneously recorded to measure QT time, action-potential duration (APD), interventricular dispersion (deltaAPD = LV(APD) - RV(APD)), early afterdepolarizations (EADs), ectopic beats (EBs), and TdP. Measurements were made at the spontaneous idioventricular rhythm (IVR) and 1,000-ms steady-state pacing. To investigate its short-term, antiarrhythmic properties, Dron was given after almokalant (0.12 mg/kg)-induced TdP. Furthermore, in another set of experiments, oral Dron (20 mg/kg, b.i.d) was given for 3 weeks to conscious CAVB dogs. Dron, i.v., shortened ventricular repolarization (QT, 435 +/- 60 to 360 +/- 55; LV(APD) 395 +/- 75 to 335 +/- 60 ms; p < 0.05), whereas IVR and ventricular effective refractory period (VERP, 225 +/- 30 to 230 +/- 30 ms) remained similar. Therefore the VERP/QT ratio increased (0.55 +/- 0.04 to 0.61 +/- 0.03; p < 0.05). Similar results were obtained with Amio, i.v.. Almokalant-induced TdP was characterized by an increased repolarization duration, deltaAPD, and EADs. Dron, i.v., suppressed the EADs, EBs, and TdP by a reduction and homogenization of repolarization (LV(APD), 505 +/- 110 to 455 +/- 80 ms, and deltaAPD, 110 +/- 55 to 65 +/- 40 ms). Long-term oral Dron increased the PP interval, CL-IVR, and QT(c) time. In contrast to oral treatment, Dron i.v. shortens ventricular repolarization parameters, resulting in suppression of EAD-dependent acquired TdP. The increased VERP/QT ratio after Dron i.v. may indicate an important second antiarrhythmic property.     

Inhibition of inflammation and fibrosis by a complement C5a receptor antagonist in DOCA-salt hypertensive rats

The anaphylatoxin C5a generated by activation of the innate immunity complement system is a potent inflammatory peptide mediator through the G-protein-coupled receptor C5aR (CD88) present in immune-inflammatory cells, including monocytes, macrophages, neutrophils, T cells, and mast cells. Inflammatory cells infiltrate and initiate the development of fibrosis in the chronically hypertensive heart. In this study, we have investigated whether treatment with a selective C5aR antagonist prevents cardiovascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Control and DOCA-salt rats were treated with PMX53 (AcF-[OPdChaWR], 1 mg·kg·d oral gavage) for 32 days; structural and functional changes in cardiovascular system were determined. DOCA-salt hypertension increased leukocyte extravasation into ventricular tissue, increasing collagen deposition and ventricular stiffness; PMX53 treatment attenuated these changes, thereby improving cardiac function. Further, treatment with PMX53 suppressed an increased expression of C5aR in the left ventricle from DOCA-salt rats, consistent with the reduced infiltration of inflammatory cells. Vascular endothelial dysfunction in thoracic aortic rings was attenuated by PMX53 treatment, but systolic blood pressure was unchanged in DOCA-salt rats. In the heart, PMX53 treatment attenuated inflammatory cell infiltration, fibrosis, and ventricular stiffness, indicating that C5aR is critically involved in ventricular remodeling by regulating inflammatory responses in the hypertensive heart.     

Cardiovascular and renal effects of buspirone in several animal models

Intravenous administration (0.3 or 3 mg/kg) of buspirone to anesthetized rats elicited a transient pressor response (14 +/- 2 mmHg) and sustained bradycardia. However, oral administration (30 mg/kg) reduced the blood pressure and heart rate of conscious normotensive (-14 +/- 4 mmHg) and DOCA-salt hypertensive rats (-22 +/- 5 mmHg). Buspirone (3-100 mg/kg, p.o.) elicited increases in urinary volume and electrolyte excretion of conscious normotensive rats and decreased these parameters in conscious mice. Buspirone was observed to possess alpha 1-adrenoceptor agonist activity in ganglion-blocked anesthetized rats. Buspirone (0.3-3 mg/kg, i.v.) elicited transient elevations in the blood pressure of open-chest anesthetized dogs. There was a sustained increase in total peripheral resistance and a decrease in aortic blood flow, heart rate, right ventricular contractile force and left ventricular dp/dt max. Intravenous and oral administration to anesthetized and conscious dogs elevated urinary volume and electrolyte excretion. However, the doses used to elicit the observed alterations in hemodynamic/renal function are considerably greater than those which produce anxiolytic effects. Thus, it is doubtful that anxiolytic doses of buspirone will produce cardiovascular alterations in patients.     

Tert-butyl hydroperoxide-mediated vascular responses in DOCA-salt hypertensive rats

tert-Butyl hydroperoxide (t-BOOH), a membrane permeant oxidant, elicits enhanced vasoconstriction of perfused kidney and mesenteric arterial beds isolated from DOCA-salt-induced hypertensive rats. We hypothesize that enhanced vasoconstriction to t-BOOH during DOCA-salt hypertension involves free radical species and decreases in the expression of the endogenous antioxidant enzyme, superoxide dismutase (SOD). t-BOOH (0.01-50 micromol) dose-dependently constricted the perfused kidney and mesenteric vascular beds (MVB) of rats. Infusion of tempol (100 microM), a free radical scavenger, reduced the constrictor responses from 116.70+/-16.65% to 57.45+/-9.25% (kidneys) and from 72.91+/-3.70% to 48.10+/-0.10% (mesenteric beds). t-BOOH-induced vasoconstriction of both vascular beds were also significantly reduced in DOCA-salt rats treated chronically (15 mg/kg ip, 3 weeks) with tempol (DOCA/TEMPOL). Catalase (500 IU) did not attenuate t-BOOH-induced responses in vascular beds of DOCA/TEMPOL rats. Western blot analyses showed significant reduction in Cu/Zn-SOD expression in DOCA-salt versus sham rats of both vascular preparations; SOD expressions were protected from down-regulation in DOCA/TEMPOL vascular beds. This study suggests that free radical species is involved in both t-BOOH-induced constrictions and in the down-regulation of SOD protein expressions during DOCA-salt hypertension.     

Essential oil of Croton nepetaefolius decreases blood pressure through an action upon vascular smooth muscle: studies in DOCA-salt hypertensive rats

Experiments tested the hypothesis that hypotensive effects of intravenous (i.v.) treatment with the essential oil of Croton nepetaefolius (EOCN) result from its vasodilatory effects directly upon vascular smooth muscle. In both deoxycorticosterone-acetate (DOCA)-salt hypertensive and uninephrectomised control, conscious rats, i.v. bolus injections of EOCN (1 to 50 mg/kg) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-related manner. Treatment with DOCA-salt significantly enhanced EOCN-induced decreases in MAP without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. hexamethonium (30 mg/kg), a ganglion blocker, were significantly greater in DOCA-salt hypertensive than in control rats. In DOCA-salt hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg) reduced the bradycardia elicited by EOCN (50 mg/kg) without affecting the enhancement of EOCN-induced hypotension. In isolated thoracic aorta preparations from DOCA-salt hypertensive rats, EOCN (1-300 micrograms/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction. Arteries from DOCA rats showed increased sensitivity to EOCN, as evidenced by the significant decrease in the IC50 for EOCN-induced reduction of phenylephrine-induced contraction (16.4 +/- 3.6 vs. 112.9 +/- 23.4 micrograms/ml in uninephrectomized controls). These results show that i.v. treatment with EOCN dose-dependently decreases blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement appears to be related mainly to an increase in EOCN-induced vascular smooth muscle relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model. Thus, the hypothesis that EOCN may be a direct vasorelaxant agent is supported by the results of the present study.     

Enhanced blood pressure sensitivity to DOCA-salt treatment in endothelin ET(B) receptor-deficient rats

The role of endothelin ET(B) receptor-mediated action in the development and maintenance of deoxycorticosterone acetate (DOCA)-salt-induced hypertension was evaluated using the spotting-lethal (sl) rat which carries a naturally occurring deletion in the ET(B) receptor gene. Homozygous (sl/sl) rats treated with DOCA-salt for 1 week exhibited an earlier onset of hypertension than heterozygous (sl/+) and wild-type (+/+) rats (systolic blood pressure, SBP; 156.7+/-3.4 versus 128.8+/-5.3 and 132.9+/-3.7 mmHg, respectively). Four weeks after the start of DOCA-salt treatment, homozygous rats developed marked hypertension, with a SBP of 206. 0+/-4.5 mmHg, compared with 184.8+/-10.7 mmHg in heterozygous and 164.3+/-4.8 mmHg in wild-type rats. Cardiovascular hypertrophy and renal dysfunction observed after 4-weeks treatment with DOCA-salt were more severe in homozygous rats, compared to wild-type and heterozygous animals. These evidences support strongly the view that ET(B) receptor-mediated actions are a protective factor in the pathogenesis of DOCA-salt-induced hypertension.     

Restoration of normal ventricular electrophysiology in renovascular hypertensive rabbits after treatment with losartan

Left ventricular hypertrophy (LVH) is associated with abnormal ventricular electrophysiology. We have shown complete regression of LVH and normalization of ventricular electrophysiology in renovascular hypertensive rabbits treated with captopril. To determine if angiotensin II type 1 receptor (AT1) blockade produces the same benefit, we treated hypertensive rabbits with losartan for 3 months. LVH was evaluated by heart-to-body weight ratio (HW/BW). Vulnerability to ventricular arrhythmia was assessed by ventricular fibrillation threshold (VFT) and dispersion of effective refractory period (ERP). The electrical properties of single left ventricular myocytes were characterized by action potential duration at 90% repolarization (APD90) and inward rectifier K+ current (I(K1)) density. Hypertensive rabbits treated with vehicle (LVH/Vehicle) had higher mean arterial pressure (MAP, 81+/-2 vs. 60+/-2 mm Hg) and HW/BW (2.71+/-0.07 vs. 1.97+/-0.04 g/kg), lower VFT (20+/-1 vs. 39+/-2 mA), larger dispersion of ERP (34+/-3 vs. 14+/-3 ms), longer APD90 (187+/-6 vs. 162+/-6 ms) and lower I(K1) density compared with control rabbits. Hypertensive rabbits treated with losartan (LVH/Losartan) had HW/BW (2.36+/-0.06 g/kg) between those of LVH/Vehicle and control rabbits, whereas MAP (65+/-2 mm Hg), VFT (34+/-2 mA), dispersion of ERP (19+/-1 ms), APD90 (160+/-6 ms), and I(K1) density were significantly different from LVH/Vehicle but similar to control. We conclude that AT1 blockade in renovascular hypertensive rabbits normalizes ventricular electrophysiology.     

Is functional upregulation of the 5-HT2B receptor in deoxycorticosterone acetate salt-treated rats blood pressure dependent?

This study tests the hypothesis that the functional upregulation of the arterial 5-hydroxytryptamine (5-HT)2B receptor in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats depends on the development of high blood pressure. Wistar-Furth and Wistar rats were given sham or DOCA-salt treatment (200 mg/kg DOCA, SC; 1.0% NaCl and 0.2% KCI in drinking water). Systolic blood pressures (4 week; mm Hg) were: Wistar Sham (120+/-3), Wistar DOCA (176+/-6), Wistar-Furth Sham (112+/-3) and Wistar-Furth DOCA (136+/-4). Isolated mesenteric arteries from Wistar DOCA and Wistar-Furth DOCA rats displayed a three- to fivefold leftward shift in contraction to 5-HT that was insensitive to blockade by the 5-HT2A receptor antagonist ketanserin (10 nM) and a significantly increased maximal contraction to the 5-HT2B receptor agonist BW723C86 [Wistar DOCA = 90+/-17% phenylephrine contraction; Wistar Sham = 1+/-1%; Wistar-Furth DOCA = 33+/-8%; Wistar-Furth Sham = 0%]. Arteries from Sprague-Dawley rats receiving salt or DOCA alone displayed similar systolic blood pressures (151+/-11 mm Hg and 144+/-5 mm Hg, respectively), but only tissues from rats receiving DOCA displayed an increased contraction to BW723C86 (DOCA alone = 60.7+/-16% vs. sham = 13+/-5.3%). These data suggest that upregulation of the arterial 5-HT2B receptor is largely independent of an increase in blood pressure.     

The antiarrhythmic effects of ischaemic preconditioning in anaesthetized dogs are prevented by atropine; role of changes in baroreceptor reflex sensitivity

1. Dogs, anaesthetized with chloralose and urethane, were subjected to a 25 min occlusion of the left anterior descending coronary artery. This resulted in ventricular ectopic activity, a reduction in baroreflex sensitivity (BRS, measured following the intravenous administration of phenylephrine), elevations in the epicardial ST-segment and increases in the degree of inhomogeneity of electrical activation, both measured from the ischaemic region of the left ventricular wall. 2. These changes were markedly reduced when the 25 min occlusion was preceded, 20 min earlier, by a 5 min (preconditioning) occlusion of the same coronary artery (e.g. VF during ischaemia reduced from 40% in the controls to 0%; P<0.05; BRS increased from 1.22+/-0.23 pre-occlusion to 1.61+/-0.25 mmHg ms(-1) post-occlusion in preconditioned dogs; cf. 1.28+/-0.29 to 0.45+/-0.12 mmHg ms(-1) respectively in the controls, P<0.05). 3. These beneficial effects of preconditioning were prevented by the administration, 10 min prior to the 25 min coronary artery occlusion, of atropine (1 mg kg(-1) i.v. followed by a continuous infusion of 0.04 mg kg(-1) h(-1)). For example, VF during occlusion was increased from 0% in the preconditioned dogs to 40% (P<0.05) in the presence of atropine and BRS was again reduced during occlusion (from 1.75+/-0.29 to 0.30+/-0.08 mmHg ms(-1); P<0.05). 4. We conclude that preconditioning reduces arrhythmia severity during ischaemia by favourably modifying cardiac autonomic receptor mechanism through enhancing vagal influences.     

Modification of left ventricular hypertrophy by chronic etomixir treatment

1. Etomoxir (2[6(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), an irreversible carnitine palmitoyl-transferase 1 inhibitor, reduces the expression of the myocardial foetal gene programme and the functional deterioration during heart adaption to a pressure-overload. Etomoxir may, however, also improve the depressed myocardial function of hypertrophied ventricles after a prolonged pressure overload. 2. To test this hypothesis, we administered racemic etomoxir (15 mg kg(-1) day(-1) for 6 weeks) to rats with ascending aortic constriction beginning 6 weeks after imposing the pressure overload. 3. The right ventricular/body weight ratio increased (P<0.05) by 20% in etomoxir treated rats (n = 10) versus untreated rats with ascending aortic constriction (n = 10). Left ventricular weight was increased (P<0.05) by 8%. Etomoxir blunted the increase in left ventricular chamber volume. Etomoxir raised the proportion of V1 isomyosin (35+/-4% versus 24+/-2%; P<0.05) and decreased the percentage of V3 isomyosin (36+/-4% versus 48+/-3%; P<0.05). 4. Maximum isovolumically developed pressure was higher in etomoxir treated rats than in untreated pressure overloaded rats (371+/-22 versus 315+/-23 mmHg; P<0.05). Maximum rates of ventricular pressure development (14,800+/-1310 versus 12,340+/-1030mmHg s(-1); P<0.05) and decline (6440+/-750 versus 5040+/-710 mmHg s(-1); P<0.05) were increased as well. Transformation of pressure values to ventricular wall stress data revealed an improved myocardial function which could partially account for the enhanced function of the whole left ventricle. 5. The co-ordinated action of etomoxir on ventricular mass, geometry and myocardial phenotype enhanced thus the pressure generating capacity of hypertrophied pressure-overloaded left ventricles and delayed the deleterious dilative remodelling.     

Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats

Background and purpose:

Histone deacetylases (HDACs) silence genes by deacetylating lysine residues in histones and other proteins. HDAC inhibitors represent a new class of compounds with anti-inflammatory activity. This study investigated whether treatment with a broad spectrum HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), would prevent cardiac fibrosis, part of the cardiovascular remodelling in deoxycorticosterone acetate (DOCA)-salt rats.

Experimental approach:

Control and DOCA-salt rats were treated with SAHA (25 mg·kg⁻¹·day⁻¹ s.c.) for 32 days. Changes in cardiovascular structure and function were assessed by blood pressure in vivo and in Langendorff perfused hearts, ventricular papillary muscle and in aortic rings in vitro. Left ventricular collagen deposition was assessed by histology.

Key results:

Administration of SAHA to DOCA-salt rats attenuated the following parameters: the increased concentration of over 20 pro-inflammatory cytokines in plasma, increased inflammatory cell infiltration and interstitial collagen deposition, increased passive diastolic stiffness in perfused hearts, prolongation of action potential duration at 20% and 90% of repolarization in papillary muscle, development of left ventricular hypertrophy, systolic hypertension and changes in vascular dysfunction.

Conclusions and implications:

The HDAC inhibitor, SAHA, attenuated the cardiovascular remodelling associated with DOCA-salt hypertensive rats and improved cardiovascular structure and function, especially fibrosis, in the heart and blood vessels, possibly by suppressing inflammation. Control of cardiac histone or non-histone protein acetylation is a potential therapeutic approach to preventing cardiac remodelling, especially cardiac fibrosis.     

Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers,S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide,azimilide, d,l-sotalol and ibutilide

Inhibition of the cardiac Kv1.5 channel, the molecular base for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)), is considered a new promising atrial selective antiarrhythmic concept since this channel is presumed to contribute to atrial but not ventricular repolarization in the human heart. In a previous study in pigs we found clear baseline differences in refractoriness between left and right atrium with shorter effective refractory periods (ERPs) of the left atrium associated with a high left atrial vulnerability for tachyarrhythmias. In this newly established model we compared atrial and ventricular effects of two novel I(Kur) blockers, S9947 and S20951, with the I(Kr) blockers dofetilide, azimilide, ibutilide and d,l-sotalol. In pentobarbital anesthetized pigs (n=45) we determined ERPs in the free walls of both atria with the S1-S2-stimulus method at three basic cycle lengths (BCL 240/300/400 ms) and QTc-intervals. The incidence of atrial tachyarrhythmias triggered by the S2-extrastimulus of the left atrium was evaluated (referred to as left atrial vulnerability). In contrast to I(Kr) blockade, I(Kur) blockade had no effect on the QT-interval, but prolonged the atrial ERP. The I(Kur) blockers were significantly stronger on left atrial ERP, I(Kr) blockers on right atrial ERP (P<0.05 for all compounds tested). At 240 ms BCL the I(Kur) blocker S20951, 3 mg/kg, prolonged left vs. right atrial ERP by 28+/-5 ms vs. 12+/-3 ms and S9947, 3 mg/kg, by 45+/-7 ms vs. 19+/-6 ms. By contrast the effect of dofetilide, 10 microg/kg, was stronger on the right than left atrium (47+/-6 ms vs. 25+/-2 ms), a profile also found with azimilide (5 mg/kg, 43+/-3 ms vs. 17+/-3 ms), ibutilide (15 microg/kg, 70+/-10 ms vs. 29+/-4 ms) and d,l-sotalol (1.5 mg/kg, 57+/-6 ms vs. 36+/-4 ms). The I(Kur) blockers, S20951and S9947, significantly decreased left atrial vulnerability (-82% and -100%, respectively, P<0.01) in contrast to the selective I(Kr) blocker dofetilide (-14%; n.s.). In conclusion, I(Kur) and I(Kr) blockers showed substantial differences in their atrial and ventricular actions in pigs. I(Kr) blockers were stronger on right atrial ERP, I(Kur) blockers on left atrial ERP, suggesting interatrial differences in the expression of potassium channels. In contrast to selective I(Kr) blockade, I(Kur) blockade inhibited left atrial vulnerability and had no effect on the QT-interval. Thus, blockade of I(Kur) seems to be a promising atrial selective antiarrhythmic concept.     

Effects of sesamin on altered vascular reactivity in aortic rings of deoxycorticosterone acetate-salt-induced hypertensive rat

The effect of sesamin, a lignan from sesame oil, on altered vasodilator and vasoconstrictor responses in aortic rings from deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats, were examined. The systolic blood pressure after 5-weeks DOCA-salt treatment was 195.0+/-2.8 mmHg, which was much higher than that of sham-operated control animals (131.2+/-2.4 mmHg). Sesamin feeding significantly suppressed the development of this hypertension (167.1+/-8.6 mmHg). Acetylcholine (ACh)-induced endothelium-dependent relaxation of aortic rings was markedly decreased in the DOCA-salt hypertensive animals, compared with cases of the control (pD2, 7.0+/-0.1; maximal response, 64.8+/-3.4% versus pD2, 7.7+/-0.2; maximal response, 93.3+/-2.7%). These changes were partially but significantly improved by the sesamin feeding. This improvement seems to be related to a nitric oxide (NO)-dependent component of ACh-induced action, because sesamin feeding did not affect the responses to ACh in the presence of NO synthase inhibitor. A spontaneous NO releaser (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR 3) which exerts endothelium-independent vasodilatation, produced the same patterns of responses as those observed with ACh in cases of DOCA-salt treatment and sesamin feeding. Phenylephrine-induced vasoconstriction was enhanced by the DOCA-salt treatment, both in preparations with and without endothelium, but these enhancements were almost completely normalized by sesamin feeding. Thus, dietary sesamin could efficiently improve the abnormal vasodilator and vasoconstrictor responses in DOCA-salt hypertensive animals. These effects may contribute to the antihypertensive activity of sesamin.