Biomedical subjects

Peter Dominiak

Publications and source records attributed to Peter Dominiak.

At least 19 recordsLinked to original sources

PubMed2006

Non-hypoxic induction of HIF-3alpha by 2-deoxy-D-glucose and insulin.

Hypoxia-inducible factors (HIFs) are key mediators of cellular adaptation to hypoxia, but also respond to non-hypoxic stimuli. To clarify involvement in metabolic disturbances, HIFs were characterised in rats subjected to insulin-induced hypoglycaemia or cellular glucoprivation provoked by 2-deoxy-D-glucose (2-DG). Using real-time qPCR, organ-specific expression of HIF-1alpha, -2alpha, -3alpha, -1beta, and of the target gene GLUT-1 was determined. Distribution of HIF-3alpha proteins was examined by immunohistochemistry. Both, insulin and 2-DG resulted in a widespread increase in HIF-3alpha mRNA. HIF-2alpha mRNA increased in lung and heart after 2-DG only, whereas other HIFs remained unaffected. A pronounced increase of protein levels in cerebral cortex was observed for HIF-3alpha. Functional significance of HIF induction was reflected in enhancement of GLUT-1 mRNA. Transcriptional up-regulation of HIF-3alpha represents a typical response to in vivo hypoglycaemia and glucoprivation. These data suggest an involvement of the HIF system in metabolic derangements as for instance caused by diabetes.

Animals↗

PubMed2006

Adrenal expression of orexin receptor subtypes is differentially regulated in experimental streptozotocin induced type-1 diabetes.

Orexins (hypocretins) are involved in the regulation of energy homeostasis and sleeping behavior. Orexins were also implicated in the regulation of neuroendocrine and autonomic functions. Recent data show the expression of orexin receptors within the hypothalamic-pituitary-adrenal (HPA) axis and suggest specific actions of orexins at the pituitary and adrenal glands. To further evaluate the role of orexin in the HPA axis, we investigated the mRNA expression of prepro-orexin (PPO) and orexin receptors within the HPA axis of streptozotocin-injected (STZ) rats showing type-1 like diabetes. PPO, as well as OX(1) and OX(2) receptor levels were analyzed by quantitative real-time PCR (qPCR). STZ rats were characterized by decreased body weight, plasma insulin, and leptin levels and by increased plasma glucose. Hypothalamic PPO mRNA levels were significantly reduced in STZ compared to non-diabetic control rats. No differences were found in the mRNA levels of hypothalamic or pituitary OX(1) and OX(2) receptors between control and STZ rats. In adrenals, OX(1) receptor mRNA levels were significantly elevated in STZ rats while OX(2) receptors were significantly reduced. Our results imply distinct functions of adrenal orexin receptor subtypes during type-1 like diabetes.

Adrenal Glands↗

PubMed2006

Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats.

Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

Angiotensin II↗

PubMed2006

Microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension: final results of a prospective long-term study (MARPLE Study)*.

OBJECTIVE: To evaluate the impact of microalbuminuria (MAU) or tubular proteinuria (TPU) on cardiovascular and cerebrovascular events and all-cause mortality, and to assess whether a normalization of MAU and/or TPU induced by angiotensin-converting enzyme-inhibitor-based antihypertensive treatment with ramipril improves cerebrovascular prognosis in essential hypertensive patients without diabetes mellitus. METHOD: A prospective, controlled, multicenter study was performed involving 3529 hypertensive participants (average follow-up 42.5 months). Ramipril was the basic antihypertensive medication. Proteinuria analysis (albumin, alpha 1-microglobulin, SDS electrophoresis) was performed by quantitative measurement every year. Ambulatory blood pressure monitoring was performed once yearly. The main outcome determined was cardiovascular and cerebrovascular events and all-cause mortality. RESULTS: In patients with TPU and/or MAU, the risk for endpoints increased significantly compared with normal (TPU, 30.0%; MAU, 54.7%; MAU + TPU, 64.0%; macroproteinuria, 74.4%). A change of protein excretion either from pathologic to normal or from normal to pathologic showed a clear trend to correlate with cerebrovascular endpoints (P = 0.056 and P = 0.055). Normal protein excretion at baseline and during follow-up indicated a significantly better prognosis than pathologic proteinuria at baseline and during follow-up. (P < 0.0001). TPU normalized in 31.9%, MAU in 30.6%, MAU + TPU in 29.3%, and macroproteinuria in 10.2% of patients. A total of 445 (25.4%) patients with normal protein excretion developed pathologic proteinuria during follow-up. CONCLUSIONS: In non-diabetic hypertensive patients, MAU as well as TPU increases the incidence of cardiovascular events. Normalization of MAU, TPU or macroproteinuria during angiotensin-converting enzyme-inhibitor-based treatment correlates with a reduction of cardiovascular events. Beyond blood pressure control, normalization of MAU and TPU should be considered as a further therapeutic goal. There is a need for further studies to optimize treatment if proteinuria is unresponsive to angiotensin-converting enzyme inhibitors.

Aged↗

PubMed2006

Inhibition of nonexocytotic norepinephrine release by desipramine reduces myocardial infarction size.

During myocardial ischemia, a substantial accumulation of norepinephrine occurs in the ischemic zone due to a local nonexocytotic release of norepinephrine. Norepinephrine release is driven by the neuronal monoamine transporter (NET), which reverses its usual transmembrane transport direction. We investigated whether this local accumulation of norepinephrine contributes to irreversible myocardial injury in an in vivo model of myocardial infarction. Male, anaesthetized Wistar rats were subjected to 30 min coronary occlusion and subsequent 120 min reperfusion. Five minutes prior to coronary occlusion, the NET inhibitor desipramine was administered intravenously. Infarct size (IS) was determined by TTC-staining and was related to the area at risk (AAR). The influence of desipramine on cardiac norepinephrine release was investigated in isolated perfused hearts with 30 min of regional ischemia. Norepinephrine was measured in the effluent from the hearts by HPLC and electrochemical detection. Desipramine (0.1-0.8 mg/kg) dose-dependently reduced infarct size (IS/AAR) from 0.54 to 0.21 and suppressed postischemic norepinephrine release from 245 to 108 pg/mL. In summary, the data indicate that nonexocytotic release of norepinephrine in myocardial ischemia exaggerates acute ischemic damage, because suppression of ischemia-induced release of norepinephrine by the tricyclic antidepressant desipramine effectively reduces infarct size in an in vivo model of myocardial ischemia.

Adrenergic Uptake Inhibitors↗

PubMed2005

Expression of nitric oxide synthase isoforms in hypothalamo-pituitary-adrenal axis during the development of spontaneous hypertension in rats.

This study was performed to investigate the expression of the major isoforms of nitric oxide synthase mRNA and protein in the hypothalamo-pituitary-adrenal axis (HPA axis) of spontaneously hypertensive rats (SHR) at two different postnatal ages corresponding to the development of genetic hypertension. Using RT-PCR and Western blot techniques, the mRNA and protein levels of neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) isoforms were measured in 3- to 4-week-old (prehypertensive phase) and 12- to 13-week-old (established hypertension phase) SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. nNOS but not eNOS mRNA levels were increased at prehypertensive and hypertensive phases in SHR HPA axis. Compared to age-matched WKY rats, significantly higher levels of nNOS protein were found in the hypothalamus, lower levels in the adrenal glands and no changes were observed in the pituitary gland. At both ages tested, there was no significant change in eNOS protein expression in SHR HPA axis. The expression of iNOS mRNA and protein was under detection limit. In the HPA axis, the expression of nNOS isoform appears to be differentially controlled at the transcriptional and translational levels in SHR. Increased mRNA levels and differential nNOS protein expression from birth in SHR HPA axis may contribute in the pathogenesis of genetic hypertension.

Animals↗

PubMed2005

Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES).

BACKGROUND AND PURPOSE: In hypertensive stroke patients, for the same level of blood pressure control, eprosartan will be more effective than nitrendipine in reducing cerebrovascular and cardiovascular morbidity and mortality. METHODS: A total of 1405 well-defined, high-risk hypertensives with cerebral event during the last 24 months (proven by cerebral computed tomography scan or nuclear magnetic resonance) were randomized to eprosartan or nitrendipine (mean follow-up 2.5 years). Primary end point was the composite of total mortality and all cardiovascular and cerebrovascular events, including all recurrent events. RESULTS: Randomization was successful without significant differences in the baseline characteristics. Blood pressure was reduced to a comparable extent without any significant differences between the 2 groups during the whole study period (150.7/84 mm Hg and 152.0/87.2 mm Hg with eprosartan and nitrendipine therapy to 137.5/80.8 mm Hg and 136.0/80.2 mm Hg, respectively, confirmed by ambulatory blood pressure monitoring). Moreover, already after 3 months, normotensive mean values were achieved, and 75.5% reached values <140/90 mm Hg with the eprosartan regimen and 77.7% with the nitrendipine regimen. During follow-up, in total, 461 primary events occurred: 206 eprosartan and 255 nitrendipine (incidence density ratio [IDR], 0.79; 95% CI, 0.66 to 0.96; P=0.014). Cardiovascular events were: 77 eprosartan and 101 nitrendipine (IDR, 0.75; 95% CI, 0.55 to 1.02; P=0.06); cerebrovascular events: 102 eprosartan and134 nitrendipine (IDR, 0.75; 95% CI, 0.58 to 0.97; P=0.03). CONCLUSIONS: The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study was the first to compare an angiotensin II type 1 receptor antagonist with a calcium antagonist in secondary stroke prevention. In these high-risk hypertensive stroke patients, an early normotensive and comparable blood pressure was achieved. The combined primary end point was significantly lower in the eprosartan group.

Acrylates↗

PubMed2005

Calcitonin gene related peptide mediates cardioprotection by remote preconditioning.

Excitation of sensory nerves and activation of myocardial protein kinase C (PKC) epsilon contribute to the transduction of remote preconditioning (RPC) to the heart. Since calcitonin gene related peptide (CGRP) is an important mediator of sensory neurons we tried to delineate whether CGRP a) protects the heart from ischemic injury, b) is involved in cardioprotection after RPC, and c) leads to an activation of myocardial PKCepsilon. RPC was achieved by brief mesenteric artery occlusion followed by reperfusion. Myocardial infarct size (IS) was measured by TTC staining after temporary coronary artery occlusion (CAO) in rats. CGRP plasma levels were determined by radioimmunoassay and PKCepsilon was measured by quantitative immunoblotting. CGRP infusion reduced infarct size by 57%, an action that was abolished after co-treatment with the PKC inhibitor chelerythrine. RPC significantly increased CGRP plasma levels, reduced infarct size, and activated myocardial PKCepsilon. Infarct size reduction was abolished and PKCepsilon activation was significantly attenuated by CGRP(8-37), a specific CGRP receptor antagonist. Ganglion blockade with hexamethonium did not influence CGRP release by RPC but abolished CGRP mediated myocardial PKCepsilon activation. In conclusion, CGRP protects the heart from ischemic injury and is involved in RPC, presumably by activating myocardial PKCepsilon.

Animals↗

PubMed2005

Deferoxamine induces prolonged cardiac preconditioning via accumulation of oxygen radicals.

Iron chelation by deferoxamine (DFO) blocks the Fenton reaction, but also inhibits prolyl hydroxylases and thereby activates certain hypoxia-inducible transcription factors (HIFs) that trigger cellular adaptation to hypoxia. Because both mechanisms may alleviate tissue damage in ischemia and reperfusion, we tried to differentiate their contribution to DFO-induced cardioprotection. Myocardial ischemia and reperfusion were induced in anesthetized Wistar rats. Infarct size was related to the ischemic area. Myocardial mRNA expression was determined by real-time PCR. Radical reactivity was probed in myocardial tissue slices with the redox-sensitive dye CM-H(2)DCFDA. Single ip applications of DFO (200 mg/kg) administered 2 h to 3 days before infarction reduced infarct size from 55 +/- 7% to 22-26%. Protection was abolished by the radical scavenger N-(2-mercaptopropionyl)glycine and the protein kinase C inhibitor chelerythrine when either was given 30 min before DFO, whereas subsequent application was ineffective. DFO did not alter the expression of various HIF target genes, whereas mRNAs of HIF-independent genes, aldose reductase and glucose transporter-4, were increased in infarcted myocardium 2 days after DFO treatment. Enhancement of superoxide activity by DFO could be demonstrated in vitro. Acute and prolonged myocardial preconditioning is triggered by DFO in response to accumulation of oxygen radicals and activation of protein kinase C.

Aldehyde Reductase↗

PubMed2005

Angiotensin I-converting enzyme-dependent and neutral endopeptidase-dependent generation and degradation of angiotensin II contrarily modulate noradrenaline release: implications for vasopeptidase-inhibitor therapy?

OBJECTIVES: Vasopeptidase inhibitors inhibit neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE). Since angiotensin (ANG) II availability is decreased by ACE inhibition but is increased by NEP inhibition, we evaluated the influence of the vasopeptidase inhibitor omapatrilat on ANG II-dependent noradrenaline (NA) release. DESIGN: The functional relevance of ACE-dependent and NEP-dependent generation and degradation of ANG II on NA overflow was determined in pithed rats by applications of ANG I (0.1-100 microg/kg) or ANG II (0.01-10 microg/kg) after single injections of ramipril (1 mg/kg), the NEP inhibitor candoxatril (100 mg/kg), or the vasopeptidase inhibitor omapatrilat (30 mg/kg). RESULTS: Blood pressure was equipotently decreased by ramipril and omapatrilat, but not by candoxatril. NA overflow was increased after ANG I infusions in controls (EC50 = 9.0 microg/kgANG I, Emax = 5680 pg/ml), but almost completely suppressed by ramipril and omapatrilat. Candoxatril decreased EC50 (4.1 microg/kg) and increased Emax (7259 pg/ml). NA overflow after ANG II infusions was enhanced by candoxatril or omapatrilat. Ex vivo ACE activity was extensively inhibited by ramipril or omapatrilat, whereas ex vivo NEP activity was reduced by omapatrilat and candoxatril only. In vitro, omapatrilat inhibited NEP and ACE with similar potencies (IC50 NEP/IC50 ACE = 0.4). CONCLUSIONS: Vasopeptidase inhibitors influence ANG II-related NA release depending on their ability to modulate the availability of ANG II via ACE or NEP. After acute application, the vasopeptidase inhibitor suppresses NA release in response to ANG I due to a predominant reduction of ANG II formation. These results indicate that the ratio of ACE-inhibitory and NEP-inhibitory potencies of vasopeptidase inhibitors may be relevant for sympathetic activation in chronic therapy.

Angiotensin II↗

PubMed2005

Peripheral sympatholytic actions of four AT1 antagonists: are they relevant for long-term antihypertensive efficacy?

BACKGROUND: Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities. OBJECTIVE: The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists. DESIGN: Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan. METHODS: In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II. RESULTS: Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (-42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity. CONCLUSION: AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

Acrylates↗

PubMed2004

Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection.

OBJECTIVE: Rho-kinase activity is increased in cardiovascular diseases and in patients with cardiovascular risk factors. However, it is not known whether inhibition of Rho-kinase could lead to cardiovascular protection and, if so, by what mechanism. METHODS AND RESULTS: In human endothelial cells, the Rho-kinase inhibitor, hydroxyfasudil (HF) (1 to 100 micromol/L), increased Akt serine-473 phosphorylation within 15 minutes, leading to a 2.2-fold and 4.0-fold increase in Akt kinase activity and nitric oxide (NO) release, respectively. Activation of Akt and eNOS by HF was completely blocked by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002 (10 micromol/L). To determine the physiological relevance of this pathway, we used 2 models of ischemia-reperfusion (I/R) injury. Acute administration of fasudil (10 mg/kg, intraperitoneal, 1 hour before ischemia) decreased leukocyte recruitment and adhesion to the mesenteric endothelium after I/R injury in wild-type but not eNOS-/- mice. Similarly, treatment with fasudil decreased myocardial infarct size by 38% in rats subjected to transient coronary artery occlusion. Cotreatment with 2 PI3-kinase inhibitors, wortmannin and LY294002, or the eNOS inhibitor, L-NAME, blocked the cardiovascular protective effects of fasudil. CONCLUSIONS: Inhibition of Rho-kinase leads to the activation of the PI3-kinase/Akt/eNOS pathway and cardiovascular protection. These findings suggest that Rho-kinase may play an important role in mediating the inflammatory response to I/R injury.

Animals↗

PubMed2004

Reduction of vascular noradrenaline sensitivity by AT1 antagonists depends on functional sympathetic innervation.

Blockade of angiotensin II type-1 (AT1) receptors has been shown to reduce the magnitude of the blood pressure response to noradrenaline in pithed rats via an unidentified mechanism. Dose-response curves were established for the noradrenaline-induced (10(-12) to 10(-7) mol/kg) increase of diastolic blood pressure in pithed rats treated with tubocurarine, propranolol, and atropine. Candesartan (1 mg/kg) increased the ED50 of the noradrenaline response (1.3+/-0.1 nmol/kg) up to 20-fold. Vasopressor responsiveness to noradrenaline was attenuated specifically, whereas the vasopressin-induced increase in diastolic blood pressure was maintained. Specific involvement of AT1 receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or alpha2-adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the ED50 values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and alpha2-adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity (ED50 5.5+/-1.3 versus 5.6+/-1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine (ED50 7.1+/-0.8 versus 7.8+/-0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT1 blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic alpha2-mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT1 blockers.

Adrenergic alpha-Antagonists↗

PubMed2004

Cardiovascular and renal function of angiotensin II type-2 receptors.

While all of the well-known cardiovascular and renal effects of angiotensin II (ANG) are attributed to the ANG type-1 (AT(1)) receptor, much less is known about the function of ANG type-2 (AT(2)) receptors. This review focuses on progress made in AT(2) receptor research over the past 10 years mainly enabled by the availability of AT(2) receptor-deficient mice. Two general mechanisms regarding AT(2) receptor-mediated actions emerge from recent experiments. Firstly, AT(2) receptor stimulation inhibits growth and promotes apoptosis, an important mechanism during development and tissue remodeling. Secondly, ANG stimulates the release of nitric oxide (NO)/cGMP via AT(2) receptor activation, as described in the aorta, heart, and kidney. This effect appears to be indirectly mediated by the modulation of bradykinin release. Thus, activation of AT(2) receptors may be potentially protective and appears to oppose the effects mediated by AT(1) receptors. The question whether AT(2) receptors are activated in patients with elevated ANG levels when treated with AT(1) receptor antagonists and whether these effects are relevant awaits further clarification.

Angiotensin II↗

PubMed2004

Expression of kinin receptor mRNA in the HPA axis of type 1 and type 2 diabetic rats.

mRNA levels of kinin B1 and B2 receptors were determined in HPA axis of type 1 (STZ-induced) and type 2 diabetic rats (ZDF and obese Zucker rats). B2 mRNA levels were elevated in hypothalamus of STZ-induced diabetic (STZ-D) and ZDF rats. Pituitary B2 mRNA levels were elevated in ZDF and obese rats. Adrenal B2 mRNA level was attenuated in STZ-D rats. Kinin B1 receptor may not play a role in HPA axis in diabetes since its expression was unchanged. Enhanced mRNA expression of B2 receptors in hypothalamus of STZ-D and ZDF rats parallels a rise in plasma glucose and reflect a functional relationship. Enhanced pituitary B2 mRNA in type 2 and reduced adrenal in type 1 diabetes account for a differential pattern in release of transmitters.

Animals↗

PubMed2004

Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR.

OBJECTIVES AND DESIGN: To check whether antihypertensive effects are additive or synergistic upon blockade of both angiotensin (AT1)-receptors and angiotensin-converting enzyme (ACE), spontaneously hypertensive rats (SHR) were treated with candesartan-cilexetil (0.1-30 mg/kg per day), ramipril (0.03-10 mg/kg per day), the calcium-antagonist mibefradil (1-150 mg/kg per day) or combinations thereof. Systolic blood pressure (SBP), left ventricular weight (LVW) and the cardiac activity/mRNA levels of ACE were determined. RESULTS: SBP was decreased by candesartan-cilexetil [inhibitory concentration (IC50) (mg/kg): 2.47], ramipril (1.97), mibefradil (4.41), candesartan-cilexetil/ramipril (0.68), and candesartan-cilexetil/mibefradil (5.68). Combining candesartan-cilexetil with ramipril increased SBP reduction synergistically rather than additively, since the dose-response curve was shifted 6.6-fold leftwards compared to a hypothetically generated additive curve, calculated by summing up the doses and corresponding effects of the ramipril and candesartan-cilexetil monotreatment regimes. A total threshold dose < 5.14 mg/kg (derived from dose-response curves) was found to exert synergistic effects when candesartan-cilexetil was combined with ramipril. Antihypertensive effects of mibefradil can not be increased when combined with candesartan-cilexetil. When LVW was correlated with SBP reduction, regression lines of candesartan-cilexetil, ramipril and their combination were congruent, while that for mibefradil was significantly flatter and became steeper under candesartan-cilexetil co-administration. Cardiac ACE activity was greatly reduced by ramipril independently of SBP reduction and dosage. With SBP-ineffective doses of ramipril, cardiac ACE mRNA levels were doubled, indicating a positive feedback mechanism. The increase in ACE mRNA was renormalized when SPB-effective ramipril doses were applied, suggesting a blood pressure-dependent regulation of cardiac ACE expression. CONCLUSIONS: Since synergy was observed only after combining low doses of ramipril and candesartan-cilexetil, prospective clinical trials should be performed on a low-dose combination, revealing the antihypertensive/antiproliferative benefits.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2004

Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway.

Long-term pretreatment with statins reduces myocardial injury after acute ischemia and reperfusion by increasing the expression of endothelial nitric oxide synthase (eNOS). We hypothesized that statins may act rapidly enough to protect the myocardium from ischemia/reperfusion injury when given right at the beginning of the reperfusion period and tried to delineate the role of PI 3-kinase/Akt pathway in early eNOS activation. Activated simvastatin was given intravenously 3 minutes before starting the reperfusion after temporary coronary artery occlusion (CAO) in anaesthetized rats. Simvastatin significantly increased myocardial PI 3-kinase activity, AktSer473, and eNOSSer1177 phosphorylation and reduced infarct size by 42%. Infarct size reduction as well as activation of PI 3-kinase/Akt/eNOS pathway were not observed in rats co-treated with the PI 3-kinase inhibitor wortmannin. Contribution of eNOS was further delineated using the NOS inhibitor L-NAME, which could completely block cardioprotection by the statin. In summary, simvastatin acutely reduces the extent of myocardial necrosis in normocholesterolemic rats in an NO- dependent manner by activating the PI 3-kinase/Akt pathway. This is the first study demonstrating short-term cardioprotective effects of simvastatin in an in vivo model of ischemia/reperfusion.

Androstadienes↗

PubMed2003

The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors.

BACKGROUND AND PURPOSE: The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke. The study was also designed to provide an estimate of the number of cases required to perform a larger phase III efficacy study. METHODS: Five hundred patients were recruited in a prospective, double-blind, placebo-controlled, randomized, multicenter phase II study. RESULTS: This safety trial was stopped prematurely when 342 patients (339 valid) had been randomized because of an imbalance in end points. Demographic data, cardiovascular risk factors, and blood pressure on admission, on study onset, and within the whole study period were not significantly different between the 2 groups. However, the cumulative 12-month mortality and the number of vascular events differed significantly in favor of the candesartan cilexetil group (odds ratio, 0.475; 95% CI, 0.252 to 0.895). There were no significant differences in concomitant medication and in number or type of side effects. CONCLUSIONS: Although the mechanisms by which angiotensin type 1 (AT1) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar beneficial effects in cerebral and in myocardial ischemia. The fact that no cardiovascular or cerebrovascular event occurred as a result of hypotension is of significant clinical importance. When there is need for or no contraindication against early antihypertensive therapy, candesartan cilexetil is a safe therapeutic option according to the ACCESS results.

Acute Disease↗