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12th May 2008 @ 2:43am |
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Volume 1, Number 2, June 2000POPULAR There is increasing evidence to suggest endothelial dysfunction as a critical factor in vascular diseases. Genetically predisposed spontaneously hypertensive rats (SHR) treated with inhibitors of nitric oxide (NO) synthase, develop a severe hypertensive nephrosclerosis without the necessity for surgical reduction in renal mass, nephrectomy, renal infarction or nephrotoxic drugs. In these animals, endothelial dysfunction is considered a valid model for assessment of the efficacy of cardiovascular therapy. SHR were treated with either the angiotensin-converting enzyme inhibitor enalapril or the angiotensin II (Ang II) AT1-receptor antagonist (AIIA) valsartan at sub-hypotensive doses and the effects on survival rates, cardiac and renal changes were monitored. Rats treated with valsartan, alone or in combination with enalapril, showed markedly higher survival rates (67–85%, respectively) than untreated animals (37%) or those treated with enalapril alone (55%). Valsartan at a dose which attenuated blood pressure increase led to even greater survival rates (95%). Despite these improved survival rates, at non-hypotensive doses the drugs had no effect on histological appearance, nor was kidney function improved. Plasma creatinine levels were reduced by valsartan, alone or in combination with enalapril, but proteinuria persisted with all treatments over the 12 weeks of the study. Aldosterone levels were significantly reduced by all treatments. The results suggest a beneficial role for endothelium in hypertension. Reduced renal perfusion pressure probably underlies the beneficial renal effects of high-dose valsartan. JRAAS 2000;1:151-158. PAPERBinding characteristics of [3H]-irbesartan to human recombinant angiotensin type 1 receptors The aim of the present work was to investigate the binding properties of the selective AT1-receptor antagonist irbesartan to human AT1-receptors by direct radioligand binding. For this purpose the specific binding of [3H]-irbesartan to intact Chinese Hamster Ovary (CHO) cells expressing human recombinant AT1-receptors was determined. Specific binding of [3H]-irbesartan rapidly reached equilibrium and was saturable with a KD of 1.94 ± 0.12 to a homogeneous class of binding sites. Its binding was inhibited by other AT1 antagonists (AIIAs) with the same potency order as previous results from [3H]-angiotensin II and [3H]-candesartan binding to human AT1-receptors. Whereas the dissociation rate of [3H]-irbesartan was essentially independent of the radioligand concentration, it was much slower at 12°C when compared with 37°C. Moreover, the dissociation rate was similar, as determined in washout experiments in the absence or presence of unlabelled AT1 antagonists. At 37°C the dissociation rate constant corresponded to a half-life of approximately seven minutes, which is sufficient to explain the partially insurmountable inhibition by irbesartan in previous studies. In contrast, other phenomena such as the plasma half life and tissue-related factors are necessary to explain its sustained in vivo antihypertensive effect. JRAAS 2000;1:159-165. PAPERMolecular mechanism(s) of insulin action on the expression of the angiotensinogen gene in kidney proximal tubular cells To investigate the molecular mechanism(s) of insulin action on the expression of the angiotensinogen (ANG) gene in kidney proximal tubular cells, we constructed a fusion gene, pOGH (hANG N-1064/+27), containing the 5'-flanking regulatory sequence of the human ANG gene fused with the human growth hormone (hGH) gene as a reporter and stably integrated the fusion gene into the opossum kidney (OK) cell genomes. The level of expression of pOGH (hANG N-1064/+27) was quantified by the amount of immunoreactive hGH secreted into the medium. The addition of a high level of D(+)-glucose (25 mM) or phorbol 12-myristate 13-acetate (PMA, 10-7 M) stimulated the expression of the fusion gene in OK cells. The stimulatory effect of glucose (25 mM) was blocked by insulin and tolrestat (an inhibitor of aldose reductase). Tolrestat also inhibited the increase of cellular DAG and PKC activity stimulated by 25 mM glucose. While insulin did not affect the cellular DAG and PKC activity, it did block the stimulatory effect of high glucose (25 mM) and PMA on the expression of the fusion gene. Finally, PD98059 (an inhibitor of mitogen-activated protein kinase kinase (MEK)) enhanced the stimulatory effect of high levels of glucose and blocked the inhibitory effect of insulin on the expression of the fusion gene as well as on the phosphorylation of MEK and mitogen-activated protein kinase (MAPK). In contrast, Wortmannin (an inhibitor of phosphatidylinositol-3-kinase) did not block the inhibitory effect of insulin on the ANG gene expression. These studies demonstrate that the action of insulin, blocking the stimulatory effect of a high level of D(+)-glucose (25 mM) on the ANG gene expression is mediated, at least in part, via the 5'-flanking region of the ANG gene and MAPK signal transduction pathway. JRAAS 2000;1:166-174. POPULAR A recent study has shown that losartan, an AT1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of the present study was to analyse the ability of different angiotensin II (Ang II) AT1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers and were stimulated with the thromboxane A2 analogue, U46619 (10-6 mol/L). U46619-stimulated platelet activation was significantly reduced by losartan in a dose-dependent manner. Only maximal doses of valsartan (5x10-6 mol/L), reduced U46619-induced platelet activation. The active form of candesartan cilexetil, candesartan (CV-11974), failed to modify platelet activation. Losartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed to a lesser extent with valsartan but not with CV-11974. These results suggest that, whilst some AT1-receptor antagonists reduce TxA2-dependent human platelet activation, it is not a feature common to all AT1 antagonists. JRAAS 2000;1:175-179. PAPERNitric oxide mediates inhibitory effect of losartan on angiotensin-induced contractions in hamster but not rat aorta We investigated a possible contribution of nitric oxide (NO) and prostaglandins to the inhibitory effect of losartan on contractions to Ang I (10-6 M) and Ang II (10-7 M) with or without L-NAME (10-4 M) or indomethacin (10-5 M) in the aorta of WKY, SHR and hamster (n=7 each). Rings of thoracic aorta (2-mm long) were placed in a myograph (5 ml). Endothelium-dependent vasodilations were evaluated with acetylcholine (10-8 ~ 10-6 M). After a 45-minute incubation with L-NAME under a resting tension of 2 g, only hamster aorta contracted (p<0.01). The SHR aorta showed impaired relaxations to acetylcholine compared with the WKY and hamster aorta (p<0.05). Despite the difference in the stimulated NO release, losartan completely abolished the responses to Ang I and Ang II both in WKY and SHR vessels irrespective of the presence of L-NAME. In contrast to the rat aorta, the inhibitory effect of losartan was attenuated in the presence of L-NAME in the hamster aorta (78% vs 99% inhibition, p<0.05). Indomethacin did not alter the effect of losartan in any vessels. Our results suggest that the presence of NO, particularly a basal secretion of NO, is necessary for the full expression of the inhibitory effect of losartan in the hamster, but not in WKY or SHR, aorta. Unlike NO, prostaglandins do not appear to play a role in the effect of losartan. JRAAS 2000;1:180-183. POPULAR To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT1) receptor blockade involves Ang II type 2 (AT2) receptor expression and protein kinase C-ε (PKCε) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT1/AT2-receptor expression, IP3R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKCε proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT1-receptor blockade with oral losartan or UP269-6. The animals were randomised to sham; sham + losartan or UP269-6; MI alone; MI + losartan; MI + UP269-6. More marked AT1-receptor blockade with UP269-6 (greater inhibition of Ang II pressor responses) was associated with a smaller increase in preload, less systolic and diastolic dysfunction, less infarct expansion, and smaller LV diastolic and systolic volumes. However, both AT1-receptor antagonists decreased infarct size. Importantly, MI decreased AT1-receptor and AT2-receptor expression while MI after AT1-receptor antagonism increased AT1-receptor (mRNA, not protein) and AT2-receptor (mRNA and protein) expression as well as IP3R and PKCε proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT1-receptor antagonism involves enhanced AT2-receptor expression and possibly downstream signalling through IP3R, PKCε and cGMP. JRAAS 2000;1:184-195. PAPERAngiotensin II does not mediate the pressor response to PGD2 (icv) The objective of the present studies was to examine the interaction between brain-derived angiotensin II (Ang II) and prostaglandins in order to identify the mechanisms mediating the pressor response produced by these neuroregulators. Inhibiting synthesis of prostaglandins with indomethacin [indocin, 200 μg/ 5 μl artificial cerebrospinal fluid (aCSF)], administered intracerebroventricularly (icv) to conscious adult male Sprague-Dawley rats, reduced blood pressure to values below basal levels. When injected prior to Ang II (50 ng/5 μl aCSF; icv), indomethacin completely abolished the pressor response induced by the octapeptide. The increase in blood pressure produced by prostaglandin D2 (PGD2, 20 μg/5 μl; icv), the most prominent prostaglandin in the rat brain, however, was not prevented by losartan (25 μg/5 μl; icv), an Ang II AT1-receptor antagonist. Collectively, these results indicate that prostaglandins produced tonically in the brain maintain resting arterial blood pressure and that the pressor action of Ang II is dependent on de novo synthesis of a prostaglandin. JRAAS 2000;1:196-201. POPULAR Sympathetic nervous system (SNS) activity, measured
by norepinephrine (NE) turnover rate, was greater in the posterior hypothalamic
(PH) nuclei, the paraventricular nuclei (PVN), and the locus coeruleus
(LC) of 5/6 nephrectomised (CRF) rats than of control rats. NE secretion from the PH was also greater
in CRF than in control rats. These findings demonstrate that SNS activity plays
an important role in the genesis of hypertension associated with CRF. The increase
in central SNS activity was mitigated by increased local expression of nitric oxide
synthase (NOS)-mRNA and nitric oxide (NOx) production. Because angiotensin II may
stimulate the central SNS, we tested the hypothesis that losartan, a specific angiotensin
II AT1-receptor antagonist, may lower blood pressure (BP), at least in part, by central
noradrenergic inhibition. To this end, we studied two groups of CRF rats. One group received losartan (10 mg/kg body weight) in drinking
water between the 3rd and 4th week after nephrectomy, the second group received
drinking water without losartan. SNS activity was measured by NE secretion from
the PH using the microdialysis technique. NOS-mRNA gene expression was also measured
by RT-PCR in the PH, PVN, and LC of CRF and control rats. Losartan reduced systolic
BP from 184±3.7 to 152±3.1 mmHg and NE secretion from the PH from 340±9.7
to 247±4.8 pg/ml. CRF rats treated with losartan manifested a significant (p<0.01) increase in
the expression of nNOS-mRNA in the PH (from 84±1.2 to 99±2.6), the PVN
(from 44±1.5 to 63±2.1), and the LC (from 59±6.7 to 76±2.1).
CRF rats also manifested a significant increase (p<0.01) in
the expression of IL-1β in the PH (from 41.6±2.8 to 54.3±1.4), PVN
(from 44±1.9 to 54±1.5), and LC (from 35.5±1.6 to 53.5±1.9). JRAAS 2000;1:202-208. EDITORIAL REVIEWACE inhibitors in hypertension: Still a shortage of evidence Two studies have recently been reported comparing angiotensin-converting enzyme inhibitor (ACE-I)-based treatment with older drugs in hypertensive patients. The hypothesis being tested was that newer drugs would confer a benefit (25% relative risk reduction in total cardiovascular events) compared with other drugs. In retrospect, these objectives were unrealistic based on observations from earlier meta-analyses. JRAAS 2000;1:117-118. EDITORIAL REVIEWACE inhibition and the kidney: species variation in the mechanisms responsible for the renal haemodynamic response The mechanisms by which angiotensin-converting enzyme inhibitors (ACE-I) reduce the progression of renal injury in diabetes mellitus and other forms of nephropathy remains unclear, in particular whether the major influence is by inhibition of angiotensin II (Ang II) formation, or by inhibition of kininase II and the consequent potentiation of bradykinin (BK), prostaglandin (PG) and nitric oxide (NO) vasodilatory pathways. In addition, the possibility of important species differences in the pathways by which ACE-I affect the kidneys has been suggested. The current paper makes a systematic review of the published literature. Studies were categorised according to their method of assessing the mechanisms of ACE-I action; some studies measured plasma levels of the relevant hormones after ACE-I administration, whereas others measured haemodynamic responses when ACE-I were administered in conjunction with other drugs, including angiotensin receptor blockers (ARBs) and agents which block BK, PG and NO pathways. Experiments in rat, dog and rabbit were analysed separately and compared with the limited data available in humans. As the analysis proceeded, it became clear that there were obvious similarities between rat and dog and so the results from these species are discussed together in this review. JRAAS 2000;1:119-124. POPULAR Angiotensin II activates multiple signalling pathways in vascular smooth muscle. The precise pattern of signals and their relative importance to a particular functional response depends on both cell type and differentiation state. Although the contractile and trophic effects of Ang II are often thought of as distinct responses it is increasingly difficult to differentiate them in terms of signalling pathways. Since vasoconstriction and abnormal growth are both features of circulatory diseases such as hypertension and atherosclerosis a better understanding of the signalling pathways responsible for the vasoconstrictor and trophic actions of this peptide may help define novel therapeutic targets in cardiovascular disease. JRAAS 2000;1:125-130. EDITORIAL REVIEWOngoing Clinical trials with angiotensin II receptor antagonists in chronic heart failure and myocardial infarction A number of large scale landmark trials have shown that angiotensin-converting enzyme inhibitors (ACE-I) reduce mortality and morbidity in patients with chronic heart failure (CHF). Recently it has been shown that the use of high doses of ACE-I are more effective in this respect than low doses and moreover, that blocking the renin-angiotensin-aldosterone system (RAAS) with an aldosterone antagonist in addition to an ACE-I is also more effective than ACE inhibition alone. With the introduction of angiotensin receptor blockers (ARBs) into clinical practice, the question arises as to whether these will have a role in the management of CHF and acute myocardial infarction (AMI). JRAAS 2000;1:131-136. EDITORIAL REVIEWInsights derived from ACE knockout mice The evaluation of ACE knockout mice has illustrated the tremendous physiologic importance of the RAAS. We have discussed how interruption of this system influences blood pressure, renal function, renal development, serum and urine electrolyte composition, haematocrit and male reproductive capacity. This body of data underlines the modelling of the RAAS as a type of biological machine that is positioned to respond to environmental insult and to maintain a homeostasis of blood pressure, blood volume and electrolyte composition. These data also emphasise Harry Goldblatt's seminal observation that the kidney and the RAAS are intimately linked in the regulation of normal blood pressure. JRAAS 2000;1:137-141. POPULAR The HOPE study has provided important
new data with regard to cardiovascular protection for patients at high risk of cardiovascular
disease. Its results demonstrate that ACE-inhibition and the associated blood pressure
reduction are unequivocally beneficial in high risk patients and any strategy that
imparts benefit in a high risk group, whatever the mechanism, should be deployed.
Nevertheless, the pathophysiological basis for this benefit is not unimportant.
If there is a benefit that is independent of blood pressure reduction, related to
blockade of the RAAS or potentiation of bradykinin by ACE-inhibition, then this
represents a key advance and should prompt further study into the pathophysiological
basis of this effect in order that it may be optimised. It also raises important
questions. For instance, what is the dose of ACE-inhibition required for maximal
benefit? Is bradykinin important in this response? If so, would the benefit be reproduced
by angiotensin II receptor antagonists? JRAAS 2000;1:142-146. EDITORIAL REVIEWPersistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure Plasma levels of Angiotensin II (Ang II) rise during long-term administration of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). The rise in Ang II plasma levels indicate that, despite ACE inhibition, the renin-angiotensin-aldosterone system (RAAS) remains persistently elevated in these patients. The added benefits of Ang II type I (AT1)-receptor antagonists in patients with CHF who are already treated with ACE inhibitors (ACE-I) also point to persistent activation of RAAS. JRAAS 2000;1:147-150. |
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