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It has been proposed that hyperinsulinemia may not constitute a cardiovascular risk in women, and that the metabolic risk profile is less apparent in women than in men. In two different studies, we have assessed the interrelationship between classical coronary risk factors in women with untreated essential hypertension and looked for possible hypertensive-normotensive differences. Hypertensive women (HT1, 156 +/- 2/98 +/- 1 mm Hg, n = 18) in study I turned out to be overweight and had nearly three times higher fasting serum insulin levels than the normotensive control subjects (NT1, 118 +/- 3/77 +/- 2 mm Hg, n = 9). HT1 women with a body mass index (BMI) above 25 kg/m2 had significant higher insulin levels than HT1 women with a BMI less than 25 kg/m2, and when adjusting for BMI the hypertensive-normotensive difference in insulin levels was lost. In HT1 women, the serum insulin level correlated positively to the BMI and triglycerides. In study II, insulin was positively associated with the systolic blood pressure in HTII women (150 +/- 3/99 +/- 1 mm Hg, n = 29), and a negative correlation appeared between the glucose/insulin ratio and the systolic as well as diastolic blood pressure. No difference was observed in BMI and insulin between HTII and NTII women (121 +/- 3/79 +/- 1 mm Hg, n = 18). In HTII women, plasminogen activator inhibitor (PAI-1) levels were higher and the euglobulin clot lysis time prolonged compared to NTII women. PAI-1 was positively correlated to insulin and triglycerides and negatively to high-density lipoprotein (HDL) cholesterol in HTII women. Strong associations between potential cardiovascular risk factors seem to be present even in untreated women with mild hypertension, with insulin being correlated to hypertension, BMI, fibrinolytic activity, triglycerides, and HDL cholesterol.
J Cardiovasc Pharmacol 1992
PMID:Hypertension and the metabolic cardiovascular syndrome: special reference to premenopausal women. 128 64

Hypercholesterolemia is seen as an important risk factor for coronary artery disease (CAD), as the incidence of CAD is strongly correlated with the level of serum cholesterol in epidemiological studies. However, hypercoagulability and reduced fibrinolytic capacity, often seen in survivors of myocardial infarction, are associated with hypertriglyceridemia (possibly concomitant with low levels of high-density lipoprotein cholesterol) and not with increased levels of total or low-density lipoprotein cholesterol. The important role of thrombogenesis in CAD is supported by the fact that initial high levels of plasma fibrinogen, coagulation factor VII (VIIc), and plasminogen activator inhibitor (PAI-1) are all independent risk factors for CAD or recurrent myocardial infarction as found in multivariate analyses of epidemiological studies. Furthermore, high plasma levels of VIIc and PAI-1 are associated with hypertriglyceridemia, reduced glucose tolerance, overweight, and hyperinsulinemia. The contribution of thrombogenic risk factors to the metabolic cardiovascular syndrome (MCVS) is thus established. Diet intervention is preferable for the normalization of hypercoagulability and hypofibrinolysis associated with MCVS. In familial combined hyperlipidemia, however, and especially with concomitant thromboembolic disease, diet alone is often not sufficient, and drug treatment with anticoagulants and/or lipid-lowering drugs may be necessary.
J Cardiovasc Pharmacol 1992
PMID:Hypercoagulability and reduced fibrinolysis in hyperlipidemia: relationship to the metabolic cardiovascular syndrome. 128 67

Diabetes mellitus is commonly associated with systolic and diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive controls, a heightened plasma insulin response to a glucose challenge is found consistently. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. Using the insulin/glucose clamp technique in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: sodium retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth-muscle cells. Physiological maneuvers, such as caloric restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; good evidence indicates that these maneuvers also can lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia also are associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate density and low-density lipoproteins, both of which are atherogenic. Last, insulin per se, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth-muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth-muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of a variety of growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including type II diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
J Cardiovasc Pharmacol 1992
PMID:Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic web. 128 37

As hypertension advances, secondary pathophysiologic changes are induced in multiple organs. Consequently, we investigated the pathophysiology of the earliest forms of hypertension--e.g., borderline hypertension. Borderline hypertension is associated with abnormal autonomic control of the circulation; sympathetic drive to the heart, blood vessels, and kidney is increased, cardiac parasympathetic inhibition is decreased, and plasma norepinephrine is increased. The hemodynamic picture is one of increased cardiac output not met by adequate vasodilation. The condition of "hyperkinetic" borderline hypertension is a precursor of more severe hypertension. In due course, a transition from high cardiac output to high vascular resistance occurs, while the enhanced sympathetic tone recedes toward normal values. The mechanism of hemodynamic transition is easily understood: cardiac output decreases due to structural changes and receptor downregulation, whereas ensuing vascular hypertrophy increases vascular resistance. The apparent regression of plasma norepinephrine values is explained in the framework of our hypothesis of the "blood pressure-seeking properties of the central nervous system." Large body mass and overweight are a consistent feature of borderline hypertension. A recent study in Tecumseh, Michigan shows that weight, plasma norepinephrine, a hyperkinetic state, and plasma insulin values are correlated in the general population. The explanation of this interrelationship will greatly advance our understanding of hypertension. From the pathophysiological viewpoint, the paradoxical outcome of clinical trials involving older antihypertensive medication is not surprising. The complexity of pathophysiologic interrelationships and the fact that risk factors for atherosclerosis are increased in hypertension suggest that reduction of blood pressure cannot be expected to ameliorate all consequences of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1990
PMID:Hemodynamic and neurohumoral evidence of multifaceted pathophysiology in human hypertension. 169 32

The effect of antihypertensive therapy with guanabenz or hydrochlorothiazide (HCTZ) on the secretion of growth hormone, prolactin, insulin, and glucagon was evaluated in double-blind fashion in 45 patients. Fifteen patients were treated with HCTZ, 50 mg twice daily, and 30 patients were treated with twice-daily dosages of guanabenz ranging from 4 to 32 mg. Blood samples for hormone analysis were collected during maintenance therapy when blood pressure was controlled as well as 1 week after the withdrawal of the antihypertensive medications. Serum levels of growth hormone and prolactin were within the normal ranges and were unchanged during treatment with HCTZ or guanabenz at any dose level. Interpatient variability in insulin levels was high, although within-subject insulin levels generally were consistent. No treatment effects were seen for insulin levels among guanabenz- or HCTZ-treated patients. Glucagon levels generally were above the expected range for fasting patients and were lower in patients receiving 4 or 8 mg of guanabenz twice daily than in those receiving 16 mg twice daily (p less than 0.05) and in those treated with HCTZ (p less than 0.01). However, analysis of paired data revealed no changes in glucagon levels upon withdrawal of guanabenz, whereas glucagon levels were higher during HCTZ treatment than after drug withdrawal (p = 0.012). Since guanabenz treatment did not affect the secretion of pancreatic or pituitary hormones, it may be preferable to other centrally acting agents and thiazide diuretics for hypertensive patients who are elderly, overweight, or diabetic.
J Cardiovasc Pharmacol 1984
PMID:Endocrinologic effects of antihypertensive therapy with guanabenz or hydrochlorothiazide. 608 24

The effects of propranolol and prazosin on plasma lipoproteins in patients with essential hypertension were evaluated according to a crossover protocol of two 8-week periods with a washout of 4 to 6 weeks. Eleven patients with moderate hypertension (greater than 90 but less than or equal to 144 mm Hg, diastolic) and slightly overweight (+10% to +/- +30%, according to Metropolitan Life Insurance tables) were selected. No dietary changes were prescribed. Plasma cholesterol, triglycerides (TG), and lipoprotein changes were monitored at the beginning of each sequence and at 2-, 4- and 8-week intervals. Prazosin, when given first, did not essentially modify any of the metabolic parameters, except for a slight elevation in plasma apoprotein AI levels, i.e., the main protein component of high density lipoprotein (HDL); propranolol caused a significant rise in total TG and very low density lipoprotein TG (VLDL-TG) levels (+37.3% and +23.9%, respectively). Somewhat lower total TG (+19.6%) and vLDL (17.8%) TG elevations were noted when propranolol was given first; plasma glucose was also significantly raised (+12.8%). Triglyceride and glucose levels returned to normal upon changing to prazosin. Total plasma- and lipoprotein-associated cholesterol levels were essentially unchanged with either drug; similarly, no significant changes were detected in total plasma apoprotein B (the main protein component of LDL and also VLDL), a component of apoprotein AI levels. Uric acid levels were slightly raised on propranolol. There was an 8.8% reduction in uric acid levels when the medication changed from propranolol to prazosin.
J Cardiovasc Pharmacol 1982
PMID:Plasma lipid and lipoprotein changes in hypertensive patients treated with propranolol and prazosin. 617 63

The pathophysiology of various stages of hypertension is different. In early hyperkinetic borderline hypertension, the sympathetic drive to the heart and blood vessels is increased while the parasympathetic cardiac inhibition is decreased. The elevated cardiac output, vascular resistance, and blood pressure at that stage can be fully normalized by autonomic blockade. As hypertension advances, a hyperkinetic circulation is less evident, since beta-adrenergic responsiveness and cardiac compliance tend to decrease. Simultaneously hypertrophy of the resistance vessels increases the baseline vascular resistance and the vessels' responsiveness to constrictive stimuli. Eventually a picture of a normal cardiac output/high vascular resistance typical for established essential hypertension emerges. As the blood vessels become hyperreactive, the same degree of vasoconstriction/blood pressure elevation can be achieved with less sympathetic tone. In that phase the sympathetic overactivity is less evident, as the brain resets itself to maintain the same blood pressure elevation with a small amount of sympathetic discharge. While sympathetic overactivity may be less evident in established hypertension, it remains an important pathophysiologic factor, not only for the maintenance of blood pressure, but also for a number of other abnormalities in hypertension. Hypertension is intimately associated with higher levels of pressure-unrelated risk for development of atherosclerosis: dyslipidemia, overweight, and hyperinsulinemia. Furthermore, a number of factors in hypertension favor a poorer outcome from coronary heart disease. These pressure-independent factors increase the risk of coronary thrombosis, arrhythmic deaths, and coronary spasms. Sympathetic overreactivity appears to be crucially implicated in the evolution of this added coronary risk in hypertension. Understanding the pathophysiology of coronary risk and its relationship to sympathetic overreactivity in hypertension is helpful in seeking further improvements in clinical practice. At present antihypertensive treatment is less efficacious in reducing coronary events in hypertension than would be expected. Judicious use of appropriate drugs promises to further improve the efficacy of antihypertensive treatment in those patients who, in addition to high blood pressure, also have other associated risk factors.
Cardiovasc Drugs Ther 1994 Mar
PMID:Abnormalities of autonomic nervous control in human hypertension. 806 76

To assess the effects of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril on insulin sensitivity, plasma insulin, and lipoprotein metabolism in overweight hypertensive patients, we measured the insulin sensitivity index (SI, determined according to the minimal model method of Bergman), fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure (BP) in 30 overweight [mean body mass index (BMI) 30.9 kg/m2], nondiabetic patients with essential hypertension after a 4-week run-in period and after 6 weeks of perindopril (n = 20) or placebo (n = 10) administered in a double-blind fashion. Furthermore, we estimated their state of physical fitness using the Conconi bicycle ergometer test before and after perindopril or placebo administration. SI was low in our study population (3.2 vs. 13.3 10(-4) ml.microU-1.min-1 in normal lean control subjects). It did not differ between the perindopril and placebo group after the placebo run-in period (3.1 vs. 3.3 x 10(-4) ml.microU-1.min-1) and was not influenced by perindopril (3.3 x 10(-4) ml.microU-1.min-1) or placebo (3.6 x 10(-4) ml.microU-1.min-1) treatment. Moreover, no significant changes were apparent in fasting plasma insulin and glucose, the areas under the glucose and insulin curves, the glucose disappearance rates, serum total triglycerides (TG), or cholesterol or lipoprotein cholesterol fractions between run-in and active treatment phases in the perindopril or the placebo group, respectively. Heart rate (HR), body weight, and anaerobic threshold remained stable in both groups. Compliance, assessed by pill counting was > 90% in both groups at all visits. Therefore, the ACE inhibitor perindopril is neutral with regard to insulin sensitivity, plasma insulin and glucose, and lipoprotein metabolism in overweight, nondiabetic patients with essential hypertension.
J Cardiovasc Pharmacol 1996 Jun
PMID:Metabolic neutrality of perindopril: focus on insulin sensitivity in overweight patients with essential hypertension. 876 42

Obesity, a major health problem in industrialized societies, is associated with a high incidence of cardiovascular complications such as hypertension, ischemic heart disease and stroke. However, the underlying mechanism relating obesity and these cardiovascular events is not clear. In lean subjects even slight elevations in plasma insulin concentration exert marked effects on the cardiovascular system, and these effects are directly related to insulin (rather than to insulin-induced stimulation of intermediary metabolism). Moreover, insulin's vascular effects are mediated both by the sympathetic nervous system and the L-arginine nitric oxide pathway. Obesity is characterized by sustained sympathetic activation (possibly related to chronic hyperinsulinemia) and an impaired vasodilator responsiveness to insulin. Although, undoubtedly many factors contribute to the increased incidence of cardiovascular complications in overweight subjects, sympathetic activation could be one important mechanism and either trigger acute events or--possibly in conjunction with an impairment in insulin-induced vasodilation--contribute to sustained elevation of arterial pressure.
Cardiovasc Drugs Ther 1996 Jun
PMID:Body fat and sympathetic nerve activity. 882 43

To examine the antihypertensive action of the centrally acting antiadrenergic drugs moxonidine and clonidine, systolic and diastolic blood pressure as well as heart rate were monitored by radio telemetry in spontaneously hypertensive rats (SHR) with established high blood pressure. Increasing doses were administered with regular rat chow for 6-8 day periods. Moxonidine reduced (p < 0.05) diastolic blood pressure at a dose of 8 mg/kg/day and systolic blood pressure at 13 mg/kg/day. Heart rate was reduced during high activity of rats corresponding to an antitachycardiac action. After withdrawal of 18 mg/kg administered for only 1 day, blood pressure returned to pretreatment values within 8 days. Clonidine reduced systolic and diastolic blood pressure at 0.3 mg/kg/day. At 0.8 and 1.3 mg/kg/day, systolic blood pressure reduction was less pronounced, although heart rate was reduced further, reaching values that were below those of untreated sleeping rats. When 1.3 mg/kg/day clonidine was discontinued, systolic as well as diastolic blood pressure increased above pretreatment values within 1 day. A rebound was also observed in heart rate, which increased by 150 beats/ min. A comparable rebound in blood pressure was observed after withdrawal of 0.3 mg/kg/day. Since a blood pressure rebound occurred also after withdrawal of 0.3 mg/kg/day clonidine in normotensive rats, the rebound phenomenon was independent of the presence of high blood pressure. No blood pressure rebound was observed when moxonidine (8 mg/kg/ day) was administered (chow or gavage) in normotensive rats. These findings in unanesthetized undisturbed rats demonstrate distinct differences in the mode of action of moxonidine and clonidine, which can be accounted for by specific interactions of moxonidine with imidazoline I1-receptors, whereas clonidine would interact not only with I1-receptors but also with alpha2-adrenoceptors, and most probably also with the vagal activity. In view of our previous studies demonstrating a rise in blood pressure and heart rate after a hypercaloric dietary intake, the selective I1-receptor agonist moxonidine appears particularly appropriate for treating overweight hypertension associated with an enhanced sympathetic outflow of the brain. Of importance in this respect is that a moxonidine-induced reduction in sympathetic outflow was not associated with a gain in body weight but resulted in reduced caloric intake.
Cardiovasc Drugs Ther 1996 Jun
PMID:Drug withdrawal and rebound hypertension: differential action of the central antihypertensive drugs moxonidine and clonidine. 882 48


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