Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers.

OBJECTIVE: To examine the associations between postmortem Alzheimer disease (AD) neuropathology and autopsy-verified cardiovascular disease. METHODS: The authors examined 99 subjects (mean age at death = 87.6; SD = 8.7) from the Mount Sinai School of Medicine Department of Psychiatry Brain Bank who were devoid of cerebrovascular disease-associated lesions or of non-AD-related neuropathology. Density of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) as well as coronary artery and aortic atherosclerosis, left ventricular wall thickness, and heart weight were measured. Partial correlations were used to assess the associations of the four cardiovascular variables with NPs and NFTs in the hippocampus, entorhinal cortex, and multiple regions of the cerebral cortex after controlling for age at death, sex, dementia severity, body mass index, and ApoE genotype. These analyses were also repeated separately for ApoE4 carriers and noncarriers. RESULTS: The extent of coronary artery disease and to a lesser extent atherosclerosis were significantly associated with the density of cardinal neuropathologic lesions of AD in this autopsy sample (significant correlations between 0.22 and 0.29). These associations were more pronounced for the ApoE4 allele carriers (n = 42; significant correlations between 0.34 and 0.47). CONCLUSIONS: The degree of coronary artery disease is independently associated with the cardinal neuropathological lesions of Alzheimer disease. These associations are primarily attributable to individuals with the ApoE4 allele.

Effects of LDL cholesterol on vascular function.

Oxidised low-density lipoprotein (LDL) cholesterol is vasoconstrictor, mitogenic, pro-inflammatory and thrombogenic. This review summarises the evidence for its vasoconstrictor properties. LDL cholesterol potentiates noradrenaline vasoconstriction in the peripheral vasculature, and in the coronary, cerebral and renal vascular beds. There is also blunting of endothelium-dependent vasodilator responses to acetylcholine. These effects are reversed, or at least reduced, by lipid-lowering agents and (because LDL cholesterol down-regulates endothelial nitric oxide synthase) by the administration of L-arginine, the substrate for nitric oxide (NO) formation. Anti-oxidants also improve endothelial function in hypercholesterolaemic animals and human patients. More research is needed to assess the possible beneficial effects of lipid lowering on vascular structure and function, and on cardiovascular morbidity and mortality, in normocholesterolaemic individuals.

Vascular hypertrophy in hypertension: role of the renin-angiotensin system.

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.

Efficacy and tolerability of nisoldipine coat-core formulation in the treatment of essential hypertension: The South African Multicenter ANCHOR Study. Ambulatory Nisoldipine Coat-Core Hypertension Outpatient Response (ANCHOR) Investigators.

A double-blind, placebo-controlled, multicenter trial was undertaken to assess the antihypertensive efficacy and tolerability of a controlled-release (Coat-Core [CC] tablet) formulation of the second-generation dihydropyridine calcium channel antagonist, nisoldipine. Of the 208 patients with mild-to-moderate essential hypertension, two were excluded from the main efficacy analysis, and the rest randomized into one of four treatment groups, to receive either placebo, or nisoldipine CC at doses of 10, 20, or 30 mg once daily for 6 weeks, following a 4-week placebo run-in period. Blood pressure measurements (supine, standing, diastolic, and systolic) were taken at trough plasma levels, 24 h after previous dosing at 2-week intervals throughout the study. Adverse events and laboratory parameters (plasma lipid and glucose levels, and thyroid function) were monitored. All three doses of nisoldipine CC lowered blood pressure, as compared with placebo, 24 h after dosing. At endpoint (after 6 weeks) mean changes in supine blood pressure from baseline were (systolic/diastolic) 0.9/-2.3, -8.0/-5.5, -16.9/-9.0, and -15.0/-10.3 mm Hg for the groups assigned to placebo and nisoldipine CC 10, 20, and 30 mg, respectively. The response rates were 35%, 47%, and 63% for nisoldipine CC 10, 20, and 30 mg, respectively. Twenty-four-hour ambulatory blood pressure monitoring showed that nisoldipine CC effectively controlled blood pressure throughout the dosing interval. No change in heart rate was seen for all three doses of nisoldipine CC over the 24-h dosing interval. Nisoldipine CC was at least as effective in black patients as in whites. Generally adverse events were not increased, except for peripheral edema, with rates of 7% in placebo, and 6%, 9%, and 19%, respectively, in those receiving nisoldipine CC 10, 20, or 30 mg daily. There were no clinically significant changes in blood lipids, blood glucose, or thyroid function. In conclusion, once-daily nisoldipine CC at doses of 10 to 30 mg was an effective and well tolerated antihypertensive agent, providing 24-h control of blood pressure without any increase in heart rate.

Endothelin, vascular hypertrophy, and hypertension.

The endothelins (ET-1, 2, and 3) constitute a family of 21 amino-acid peptides with potent biological activities. They are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. The production and release of endothelin is stimulated by many factors, hormonal and metabolic, and by growth factors, hypoxia, and shear stress. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release. The ETA receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) causes vasoconstriction and stimulation of vascular smooth muscle cell growth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angiotensin II, alpha-adrenergic agonists, Ca2+, and other growth factors. In animal models of hypertension, endothelin causes vascular hypertrophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat than in the spontaneously hypertensive rate. In humans there is an increase in the plasma concentration of endothelin in severe atherosclerotic disease, but not consistently in hypertension. Evidence for the role of endothelin in the vascular hypertrophy of human hypertension is scanty, but the development of nonpeptide and receptor subtype-selective antagonists will permit meaningful studies, including clinical trials of a new class of antihypertensive agents.

The renin-angiotensin system and vascular hypertrophy.

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.

Beta-blocking agents with vasodilator activity.

Use of non-selective beta-blockers: Non-selective beta-blockers reduce blood pressure by reducing cardiac output. They have a proven record of efficacy, alone or in combination with other drug classes, in the treatment of hypertension, ischemic heart disease and some tachyarrhythmias. They have also proved effective in the primary and secondary prevention of myocardial infarction. However, adverse effects include increased peripheral resistance, limitation of exercise tolerance, and bradyarrhythmia, cold extremities and bronchoconstriction in susceptible patients. Effects of beta 1-selective blockers: beta 1-Selective antagonists cause less vasoconstriction and less bronchoconstriction than non-selective beta-blockers, but the reduction in cardiac output may still activate a sympathetically mediated increase in peripheral resistance. beta 1-blockers with beta 2 agonist activity are vasodilatory because they activate postsynaptic beta 2 receptors on vascular smooth muscle cell membranes, via the formation of cyclic AMP. Non-selective beta-blockers with alpha 2-adrenoceptor blocking activity: Non-selective beta-adrenoceptor blockers with alpha 1-adrenoceptor blocking activity, such as carvedilol, labetalol, medroxalol and bucindolol, combine the advantages of beta- and alpha 1-blockade, including peripheral vasodilation. As an example of this class of agent, carvedilol has been shown to be effective in the treatment of hypertension by reducing peripheral resistance. There are some indications, still to be confirmed, that it improves left ventricular diastolic function and causes regression of left ventricular hypertrophy, and that it may be useful in the treatment of some patients with congestive heart failure or arrhythmia. In animal models of myocardial ischemia, carvedilol has proved to be cardioprotective.

Influence of ketanserin on regional myocardial blood flow after myocardial infarction in baboons.

Serotonin (5-hydroxytryptamine, 5-HT) mediates vasoconstriction and vasodilation in normal coronary circulation of various animal species. In the presence of coronary artery disease, serotonin may inhibit coronary collateral formation and stimulate predominantly vasoconstriction. We tested the effect of ketanserin, a selective 5-HT2 receptor antagonist and platelet aggregation inhibitor, on ischemic myocardium blood flow (BF) and collateral formation after coronary artery occlusion in primates. Fifteen baboons were subjected to left anterior descending coronary artery (LAD) ligation and thrombus formation. Hemodynamics and regional myocardial blood flow (RMBF) (microsphere technique) were measured before and 45 min and 1 week after coronary artery occlusion. There was no significant difference in the hemodynamic measurements, gross infarct size, or infarct-ischemic zone MBF in the experimental group (ketanserin 1 mg/kg daily, n = 9) as compared with the control group (injectable water, n = 6). Both groups had a significant increase in BF ratio of infarct-ischemic/normal myocardium at 1 week as compared with shortly after coronary occlusion. Thus, selective 5-HT2 receptor blockade has neither an adverse nor a protective effect on myocardial infarct resulting from acute thrombotic coronary occlusion in baboons.

An unsaturated fat diet prevents the increased angiotensin II vascular responses in renal artery stenosis.

OBJECTIVE: The aim was to characterise angiotensin II constrictor responses in two kidney, one clip (2K1C) renal hypertensive rats fed a diet with a high unsaturated fatty acid content. METHODS: Two diets with the same total fat (37% by energy; 17% by weight) but different unsaturated fat contents were fed to rats for a three month period. Thirty four Sprague Dawley rats were used per diet group. After one month on the diets, a group of 19 rats in each diet group was operated upon to induce 2K1C hypertension. A separate group of 15 rats within each diet group received sham operations. Systolic blood pressure was measured weekly from prior to surgery to the end of the three month feeding period. At three months, angiotensin II constrictor responses were evaluated in the isolated kidney vascular preparation and in intact anaesthetised rats fed the different diets. Phenylephrine constrictor responses were also evaluated in intact anaesthetised rats in order to exclude structural vascular changes accounting for differences in angiotensin II constrictor responses. RESULTS: The diet high in unsaturated fats prevented the development of hypertension in 2K1C rats [systolic pressure 134(7) mm Hg at eight weeks] compared to their own preoperative blood pressures [124(3) mm Hg], and to the 2K1C rats fed the control diet [163(7) mm Hg at eight weeks]. The diet high in unsaturated fats did not alter blood pressures in sham operated rats. In isolated perfused kidneys and in anaesthetised 2K1C rats fed the control diet, angiotensin II caused a greater vascular response compared to the sham operated groups. The unsaturated fat diet prevented this effect. No differences were found in blood pressure responses to phenylephrine. CONCLUSIONS: These data suggest that the antihypertensive effect of a high unsaturated fat diet may in part be due to a depressed responsiveness of vascular smooth muscle to endogenous angiotensin II. The effect is likely to be due to modulation of angiotensin II vascular responses by local vascular changes that cannot be accounted for by structural vascular differences.

Adenosine dephosphorylates myosin light chain in primary cultures of vascular smooth muscle cells from normotensive and spontaneously hypertensive rats.

OBJECTIVE: The aim was to determine whether vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) respond differently to adenosine than those from normotensive Wistar-Kyoto (WKY) rats. DESIGN: Confluent primary cultures of VSMC derived from SHR and WKY aorta and mesenteric arteries and cerebral arteries were used. The effect of adenosine upon cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) formation and the phosphorylation of myosin light chain (MLC) was studied. METHODS: MLC phosphorylation was estimated by subjecting VSMC extracts incubated with 32P to gel electrophoresis, followed by autoradiography and laser densitometry. cAMP and cGMP levels were measured by radioimmunoassay. RESULTS: Baseline MLC phosphorylation levels were not significantly different in SHR and WKY VSMC. Adenosine caused dephosphorylation of MLC in a time- and dose-dependent manner. A maximal response of approximately 40% below control values was observed 5 min after addition of 10(-5) mol/l adenosine in SHR and WKY VSMC with no significant difference between the two strains. The maximally effective concentration of 10(-5) mol/l adenosine evoked increases in both cAMP and cGMP in VSMC from SHR and WKY rats to the same degree. CONCLUSION: We conclude that the overall ability of VSMC to relax, as evidenced by a marked decrease in MLC phosphorylation in response to adenosine, is unaltered in SHR.

Alpha-adrenergic and angiotensin II pressor sensitivity in hypertensive patients treated with an angiotensin-converting enzyme inhibitor.

We investigated pressor sensitivity to infused phenylephrine (PE), 0.05 to 0.4 micrograms/kg/min, and angiotensin II (Ang II), 2.5 to 10 ng/kg/min, in 35 patients with mild-to-moderate hypertension, before and at the end of a 4-week treatment period with the angiotensin-converting enzyme (ACE) inhibitor, cilazapril, 2.5 or 5.0 mg/day. Cilazapril lowered the mean systolic and diastolic blood pressure by 10.6/3.5 mm Hg, but had no effect on the dose-response curves of dose of PE or Ang II vs. the increase in systolic, diastolic, or mean blood pressure, or heart rate. There were also no significant effects of cilazapril on PD20 values, i.e., the dose of PE or Ang II required to increase mean arterial blood pressure (MAP) by 20 mm Hg, or on delta R-R/delta MAP (ratio of the increase of the ECG R-R interval to the increase in mean arterial blood pressure) as a measure of baroreflex sensitivity. Plasma renin activity was significantly increased by cilazapril therapy, but there were no changes in plasma concentrations of Ang II or atrial natriuretic factor. We conclude that cilazapril, an ACE inhibitor, does not alter alpha 1-adrenoceptor and Ang II receptor sensitivity to selective agonists, nor does it affect baroreflex sensitivity.

Reversal of structural changes in hypertensive arteries--a major prospect for the future.

Arteriosclerosis is the hallmark of hypertension and of its complications, namely stroke, coronary artery disease and ischaemic renal failure. The earliest morphological change in the arteriosclerotic process is vascular smooth muscle hypertrophy and hyperplasia. Angiotensin II is an important growth factor in vascular smooth muscle cells. The chronic administration of ACE inhibitors will reverse many of the changes of vascular hypertrophy in experimental animal models, and will improve vascular compliance in hypertensive patients. Some differences have been reported between different ACE inhibitors with respect to blood pressure-lowering effect and regression of medial hypertrophy in spontaneously hypertensive rats.

Angiotensin II induced phosphorylation of myosin light chain in vascular smooth muscle cells from spontaneously hypertensive and normotensive rats.

STUDY OBJECTIVE: The aim was to determine the changes in the phosphorylation of myosin light chain induced by angiotensin II in cultured vascular smooth muscle cells derived from normotensive (WKY) and spontaneously hypertensive rats (SHR). DESIGN: Extracts of vascular smooth muscle cells incubated with [32P]orthophosphoric acid were subjected to 4M urea-SDS electrophoresis, followed by autoradiography and laser densitometry. EXPERIMENTAL MATERIAL: Confluent primary cultures of vascular smooth muscle cells from aorta, superior mesenteric arteries and cerebral arteries were used. MEASUREMENTS AND MAIN RESULTS: The basal myosin light chain phosphorylation of SHR did not differ significantly from that of WKY. Stimulation with 1 nM angiotensin II increased incorporation of 32P into the myosin light chain, which peaked at 4 min and then slowly declined until 15 min. Exposure to angiotensin II (0.001-10 nM) for 4 min evoked a dose dependent increase in the phosphorylation of myosin light chain with a maximal response 40-45% above basal values. No significant differences in the response to angiotensin II were detected between cells derived from the two strains. Saralasin, a specific angiotensin II antagonist, did not affect the basal phosphorylation of myosin light chain but completely abolished the effect of angiotensin II. CONCLUSIONS: Angiotensin II enhances the phosphorylation of the myosin light chain from vascular smooth muscle cells in aorta, mesenteric arteries, and cerebral arteries, but there are no differences in response between SHR and WKY.

The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart.

The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and euthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dtmax) was lower in the hyperthyroid (0.81 +/- 0.07 mM) than in the euthyroid hearts (1.12 +/- 0.09 mM, p less than 0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p less than 0.01) depression in dP/dtmax after 12 min in the hyperthyroid (50 +/- 7%) than in the euthyroid heart (15 +/- 2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.