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PubMed1998

Arthur C. Corcoran Memorial Lecture. The role of eicosanoids in angiotensin-dependent hypertension.

Many eicosanoids produced in vascular and renal structures are endowed with the ability to influence vascular and renal mechanisms of blood pressure regulation. Eicosanoids subserve both prohypertensive and antihypertensive mechanisms. The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of thromboxane A2 (TXA2) and of lipoxygenase-derived products with the ability to inhibit prostacyclin synthase. As a result of these abnormalities, the activity of pressor mechanisms mediated by TXA2 and/or prostaglandin (PG) H2 is increased. The cancellation of TXA2- and/or of PGH2-mediated pressor mechanisms, after treatment with thromboxane synthase inhibitors or TXA2/PGH2 receptor blockers, lowers blood pressure in rats with angiotensin-dependent hypertension. Inhibitors of lipoxygenase also lower blood pressure in such animals, in part by decreasing the synthesis of lipoxygenase-derived inhibitors of prostacyclin synthase. Thus, the vasodepressor effect of these agents is accompanied by increased vascular formation of PGI2 and can be prevented by cyclooxygenase inhibitors. Cyclooxygenase-derived eicosanoids, PGE2 and PGI2, also subserve antihypertensive mechanisms in angiotensin-dependent models of hypertension. The level of blood pressure in such models of hypertension reflects, in part, the interplay among prohypertensive and antihypertensive functions subserved by cyclooxygenase- and lipoxygenase-derived eicosanoids.

Angiotensin II↗

PubMed1999

Arthur C. Corcoran Memorial Lecture. Hormones and vasoprotection.

There is a strong link between menopause and increased cardiovascular disease incidence in women, and observational studies suggest that postmenopausal hormone replacement therapy reduces cardiovascular disease risk by about half. Observational studies suffer from important limitations, however, and the only published prospective controlled trial of the effects of hormone replacement therapy on cardiovascular outcomes, the Heart Estrogen-Progestin Replacement Study (HERS), showed no net benefit of continuous estrogen plus synthetic progestin treatment in women with established coronary disease. Fundamental mechanistic studies of the cellular and molecular events by which hormones protect (or fail to protect) blood vessels from damage are needed to define the role of postmenopausal hormone replacement therapy in cardiovascular disease prevention. Most studies suggest that estrogen inhibits the neointimal response to acute injury in normal blood vessels, but this vasoprotective effect was not seen in vessels with preexisting atherosclerosis. Studies from our laboratory in the rat carotid injury model have shown that estrogen inhibits neointima formation via effects on all 3 layers of the vascular wall, including inhibition of medial smooth muscle cell migration and proliferation, stimulation of regrowth of endothelium, and inhibition of adventitial cell migration into neointima. Our laboratory is currently using transduced (lacZ) syngeneic fibroblasts as 'reporter' cells to delineate the factors that stimulate migration of adventitial cells into neointima after vascular injury and their modulation by estrogen and the other sex hormones. These fundamental studies will establish more rational strategies for therapeutic intervention in vascular diseases, including the basis for future gene therapy.

Animals↗

PubMed1999

State-of-the-art-lecture: Obesity-induced hypertension: new concepts from the emerging biology of obesity.

offsity is associated with an increased risk of hypertension. In the past 5 years there have been dramatic advances into the genetic and neurobiological mechanisms of obesity with the discovery of leptin and novel neuropeptide pathways regulating appetite and metabolism. In this brief review, we argue that these mounting advances into the neurobiology of obesity have and will continue to provide new insights into the regulation of arterial pressure in obesity. We focus our comments on the sympathetic, vascular, and renal mechanisms of leptin and melanocortin receptor agonists and on the regulation of arterial pressure in rodent models of genetic obesity. We suggest 3 concepts. First, the effect of obesity on blood pressure may depend critically on the genetic-neurobiological mechanisms underlying the obesity. Second, obesity is not consistently associated with increased blood pressure, at least in rodent models. Third, the blood pressure response to obesity may be critically influenced by modifying alleles in the genetic background.

Animals↗

PubMed1999

State-of-the-Art lecture: influence of exercise training on neurogenic control of blood pressure in spontaneously hypertensive rats.

Exercise training plays an important role in the reduction of high blood pressure. In this review, we discuss the effect of distinct intensities of exercise training on the reduction of high blood pressure in spontaneously hypertensive rats (SHR). In addition, we present some hemodynamic mechanisms and associated neural controls by which exercise training attenuates hypertension in SHR. Low-intensity exercise training is more effective in reducing high blood pressure than is high-intensity exercise training in SHR. The decrease in blood pressure is due to resting bradycardia, and in consequence, lower cardiac output. Sympathetic attenuation to the heart is the major explanation for the resting bradycardia. Recovery of the sensitivity of baroreflex control of heart rate, which is usually impaired in SHR, is an important neurogenic component involved in the benefits elicited by exercise training.

Animals↗

PubMed1999

State of the Art lecture. Risk mechanisms in hypertensive heart disease.

In this report, some of the underlying pathophysiological alterations associated with the independent risk from hypertensive heart disease and left ventricular hypertrophy are discussed. Emphasized are the classically described coronary hemodynamic alterations of decreased coronary blood flow and flow reserve with increased coronary vascular resistance and minimal coronary resistance; more recent concepts of endothelial dysfunction are emphasized. Additionally, increased collagen deposition within the ventricular walls and perivascularly participates importantly. These changes are exacerbated by the aging process and perhaps by increased dietary salt intake. Consequences of these functional and structural changes include further endothelial dysfunction, impairment of coronary hemodynamics, and ventricular contractile function (diastolic as well as systolic). The clinical consequences of these alterations are angina pectoris (with or without atherosclerosis), myocardial infarction, cardiac failure, lethal dysrhythmias, and sudden cardiac death. Thus, not all that is clinically recognized as "left ventricular hypertrophy" is true myocytic hypertrophy with structural remodeling; other important comorbid changes occur that directly affect risk, including ventricular fibrosis, impaired coronary hemodynamics, and endothelial dysfunction.

Aging↗

PubMed1999

State-of-the-Art lecture. Role of endothelin-1 in hypertension.

Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension: deoxycorticosterone acetate salt-treated rats, deoxycorticosterone acetate salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME-treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET(A/B) and ET(A)-selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET(A/B) antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensin-converting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. Thus, ET-1 may be involved in experimental and human hypertension. Endothelin antagonists may prove effective as disease-modifying agents if they are shown clinically, as they are experimentally, to offer target organ protection and reduce long-term complications of hypertension. This remains to be demonstrated in humans.

Animals↗

PubMed1999

State-of-the-Art lecture. Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle.

Hemodynamic factors, circulating hormones, paracrine factors, and intracrine factors influence vascular smooth muscle growth and plasticity. The well-characterized role of angiotensin II in the modulation of vascular tone and cell function may be critically involved in the mechanisms by which vascular smooth muscle responds to signals associated with vascular endothelial dysfunction and increases in oxidative stress. Studies from this laboratory suggest that the trophic actions of angiotensin II may be intrinsically regulated by angiotensin-(1-7), a separate product of the angiotensin system derived from the common substrate, angiotensin I. Exposure of cultured vascular smooth muscle cells to angiotensin-(1-7) inhibited the trophic actions of angiotensin II and reduced the expression of the mitogenic effects of both normal serum and platelet-derived growth factor. The growth-inhibitory actions of angiotensin-(1-7) were blocked by the selective D-alanine(7)-angiotensin-(1-7) antagonist and the nonselective angiotensin receptor blocker sarcosine(1)-threonine(8)-angiotensin II. In contrast, subtype-selective antagonists for the AT(1) and AT(2) receptors had no effect on the inhibitory actions of angiotensin-(1-7), a finding that is consistent with the pharmacological characterization of a high-affinity (125)I-labeled angiotensin-(1-7) binding site in the vasculature by use of selective and nonselective angiotensin II receptor antagonists. The relevance of these findings to the proliferative response of vascular smooth muscle cells after endothelial injury was confirmed by assessment of the effect of a 12-day infusion of angiotensin-(1-7) on neointimal formation. In these experiments, the proliferative response produced by injuring the carotid artery was inhibited by angiotensin-(1-7) through a mechanism that could not be explained by changes in arterial pressure. Because plasma angiotensin-(1-7) increased to levels comparable to those found in animals and human subjects given therapeutic doses of angiotensin-converting enzyme inhibitors, angiotensin-(1-7) may be one factor participating in the reversal of vascular proliferation during inhibition of angiotensin II formation or activity.

Angiotensin I↗

PubMed1999

State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action.

In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer. This review analyzes the current knowledge on the pleiotropic properties of these classes of drugs. Direct comparison indicates that study of the associations among these drugs may eventually disclose additive or synergistic effects that, perhaps even at lower dosages, may provide improved vascular protection and a strong alliance against several atherogenic mechanisms.

Animals↗

PubMed2001

Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis.

There is increasing evidence that direct pathobiological events in the vessel wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactive oxygen species. Increased reactive oxygen species can inactivate NO and produce peroxynitrite. Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Taken together, angiotensin II can promote vasoconstriction, inflammation, thrombosis, and vascular remodeling. In this article, we propose a model that unifies the interrelationship among cardiovascular risk factors, angiotensin II, and the pathobiological mechanisms contributing to cardiovascular disease. This model may also explain the beneficial effects of ACE inhibitors on cardiovascular events beyond blood pressure reduction.

Angiotensin II↗

PubMed2003

Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture.

BACKGROUND: The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy. SUMMARY OF REVIEW: The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours. CONCLUSION: The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.

Albumins↗

PubMed2003

William Feinberg lecture 2002: emotions, mood, and behavior after stroke.

While emotional outcome is a critical factor influencing early evolution and late prognosis after stroke, few relevant studies have been performed on this subject. However, mood changes, modified judgment, and emotional reactions may also dramatically alter recruitment into clinical trials; for instance, up to one third of patients with acute stroke may have altered time perception, inappropriate self-evaluation of their condition, and attentional or memory dysfunction, with a subsequent increase in referral-to-hospital delays. In addition, the value of the "informed" consenting process may be questionable in the setting of urgent randomization into an acute stroke clinical trial. Data from ongoing studies suggest that behavior and emotional reactions in acute stroke patients may be classified into a few broad categories, with considerable overlap. Correlations between mood changes and the type, location, and severity of stroke may provide useful information for improving patient management, including the prediction of functional evolution and late prognosis. While depressive reactions have been widely studied in the recovery-rehabilitation phase after stroke, significant depression is uncommon shortly after stroke. On the other hand, related, though different, emotional behavioral changes may be more frequent; these have often been confused with depression and include catastrophic reaction, emotionalism, and athymhormia. Late depression is the most common mood alteration during the first year after stroke and has specific characteristics that differentiate it from classic endogenous and reactive depression, thus emphasizing the critical role of brain damage in the pathogenesis of poststroke depression. Early recognition and management of mood disorders after stroke are critical for the functional improvement of individual patients. However, little is known about specific indications for different antidepressant drugs in poststroke depression and related disorders. Ongoing research has identified a "new" emotional-behavioral disorder, poststroke fatigue, which is clearly distinct from depression in most instances. It is especially disabling and frustrating in that it typically involves patients with total or near-total neurological recovery, who should have been able to go back to their previous activities but who become severely disabled because of early and persisting exhaustion. Preliminary neuropsychological and MR and PET imaging studies suggest that disruption of subtle mechanisms underlying attention, in the absence of significant cognitive and mood alterations, may be responsible. Research projects are now being launched to better delineate poststroke fatigue and its management.

Acute Disease↗

PubMed2003

William M. Feinberg Lecture: stroke therapy in the year 2025: burden, breakthroughs, and barriers to progress.

BACKGROUND: More than 700 000 strokes occurred in the United States during 2002, of which approximately 500 000 are first-ever strokes and 200 000 recurrent strokes. If we would decrease the enormous burden of stroke throughout the world, we first need to know the barriers that we have to overcome. These are quite similar to the barriers that we have tried to surmount during the last 25 years. STOKE PREVENTION: We have developed many successful primary and secondary therapies to prevent stroke over the past 25 years and have begun to understand some of the genetic risk factors underlying stroke. Yet, the incidence rate of stroke in Rochester, Minn, remained unchanged from 1975 to the mid-1990s, and mortality rates for Ohio have changed little for men, women, blacks, and whites over the past decade. The primary reason that we have made little progress in decreasing the burden of stroke is that we have made little progress in modifying the primary risk factors for stroke in the population. Other barriers of improved stroke prevention in the future include costs of therapy and aging of blood vessels and brain, which is the most important risk factor for stroke. ACUTE STROKE: Breakthroughs in acute stroke treatment are likely to follow the steps of cardiology with the primary focus for ischemic stroke on the restoration of oxygenated blood flow to ischemic brain as quickly as possible. To improve acute stroke therapy in the year 2025, we need to have more focused messages sent to the lay public about stroke warning signs, better and safer methods to open arteries quickly, truly effective neuroprotection in the setting of reperfusion, regional organization for acute stroke therapy, and large randomized trials to find clinically important but smaller benefits. A scientifically proven treatment for treatment of acute intracerebral hemorrhage is another major goal. RECOVERY AFTER STROKE: Brain recovery after stroke is the area of scientific discovery with the largest potential for advances far into the next century. Obstacles that block effective therapies in the recovery from stroke include the extent of initial injury from stroke, the brain plasticity of a given patient, and, most importantly, understanding the "neural code"-how the brain is organized and how cells communicate with one another.

Acute Disease↗

PubMed2004