Intralipid enhances alpha1-adrenergic receptor mediated pressor sensitivity.

The dyslipidemia in obese hypertensive persons may contribute to their increased vascular alpha-adrenergic receptor reactivity and tone. To further examine this notion, we conducted 2 studies of pressor sensitivity to phenylephrine, an alpha1-adrenergic receptor agonist, in lean normotensive subjects. In the first study (n=6), pressor responses to phenylephrine were obtained before and during a saline and heparin infusion. On another day, pressor reactivity to phenylephrine was measured before and during infusion of 20% Intralipid at 0.5 mL . m-2 . min-1 with heparin at 1000 U/h to increase lipoprotein lipase activity and raise nonesterified fatty acids (NEFAs). In the second study (n=8), baseline reactivity to phenylephrine was obtained on 2 separate days and repeated after raising NEFAs and triglycerides either with 0.8 mL . m-2 . min-1 of 20% Intralipid alone or together with heparin. The infusion of saline and heparin did not significantly change plasma NEFAs from baseline (516+/-90 versus 512+/-108 micromol/L, respectively; P=NS) or the dose of phenylephrine required to raise mean blood pressure by 20 mm Hg ([PD20PE]; 1.00+/-0.14 versus 0. 95+/-0.10 microg . kg-1 . min-1, respectively, P=NS). Intralipid at 0.5 mL . m-2 . min-1 with heparin raised plasma NEFAs to 793+/-30 micromol/L per liter (P<0.05 versus baseline) and reduced PD20PE from 1.01+/-0.10 to 0.80+/-0.09 microg . kg-1 . min-1 (P<0.05). Compared with baseline, Intralipid alone increased plasma NEFAs to 946+/-80 micromol/L (P<0.05), and NEFAs increased further with the addition of heparin to 2990+/-254 micromol/L (P<0.01). Despite an apparently greater increase of plasma NEFAs with Intralipid and heparin, Intralipid alone and together with heparin similarly reduced PD20PE. Across all study conditions, changes in levels of triglycerides and NEFAs correlated with changes in mean arterial pressure responses to phenylephrine, especially at the 0.4- microg . kg-1 . min-1 infusion rate of phenylephrine (r=0.64, P<0.01 and r=0. 54, P<0.01, respectively). These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances alpha1-adrenoceptor mediated pressor sensitivity. The findings suggest that lipid abnormalities in obese hypertensives, which include elevated NEFAs and triglycerides, contribute to greater vascular alpha1-adrenergic reactivity.

Fatty acids augment endothelium-dependent dilation in hand veins by a cyclooxygenase-dependent mechanism.

Evidence supports the hypothesis that elevated nonesterified fatty acids (NEFAs) in patients with insulin resistance, eg, obese hypertensive subjects, contribute to increased vascular alpha-adrenergic reactivity and tone by impairing endothelium-dependent vasodilation. To generate further support for this notion, we studied responses to endothelium-dependent and independent dilators under control (0.9% NaCl/heparin) conditions in one hand and with elevated NEFAs in the contralateral hand (10% intralipid/heparin). To observe venodilator responses, the dorsal hand vein diameter was first reduced by approximately 60% with phenylephrine. Studies were repeated with indomethacin to block the generation of cyclooxygenase products. In contrast to previous in vitro data, elevating NEFAs locally in vivo augmented rather than suppressed venodilator responses to the two endothelium-dependent dilators acetylcholine and methacholine (P<.05). Responses to the endothelium-independent dilator nitroglycerin were unaffected. Indomethacin attenuated the capacity of intralipid/heparin to enhance endothelium-dependent dilator responses to acetylcholine and methacholine. Indomethacin did not affect venodilator responses to nitroglycerin. The effect of intralipid/heparin to significantly reduce the phenylephrine infusion rate required to reduce hand vein diameter by approximately 60% was reversed by indomethacin. These data indicate that raising fatty acids locally augments endothelium-dependent dilation by a cyclooxygenase-dependent mechanism. The findings also suggest that NEFAs augment alpha-adrenoceptor-mediated constriction in hand veins by a cyclooxygenase-dependent mechanism. These hand vein studies do not support the notion that the elevated NEFAs in obese hypertensive patients augment alpha1-adrenoceptor-mediated reactivity by reducing nitric oxide synthesis.

Fatty acids, not insulin, modulate alpha1-adrenergic reactivity in dorsal hand veins.

Resistance to the vasodilator action of insulin and its capacity to antagonize vascular alpha-adrenergic reactivity may contribute to the increased neurovascular tone and blood pressure in obese hypertensive subjects. We showed that nonesterified fatty acids (NEFAs) were elevated in obese hypertensive subjects and that raising NEFAs locally in dorsal hand veins of healthy normotensive subjects enhances alpha1adrenoceptor reactivity. Research by others suggests that insulin antagonizes alpha1-adrenoceptor tone in dorsal hand veins. Taken together with evidence that NEFAs antagonize several of the metabolic actions of insulin, these observations raise the possibility that NEFAs participate in resistance to the vascular effects of insulin and suggest that dorsal hand veins represent a good model for studying these interactions. Thus, we produced local hyperinsulinemia in the dorsal hand veins of six lean normal volunteers and quantified changes of venous distensibility in response to phenylephrine in the presence and absence of a local elevation of NEFAs. We confirmed that raising NEFAs locally decreased by twofold to threefold the phenylephrine ED50 (P<.01), but this alpha1-sensitizing action of NEFAs was not antagonized by insulin concentrations up to approximately 1000 microU/mL. Moreover, local hyperinsulinemia alone did not affect vascular alpha1-adrenergic sensitivity as measured by the phenylephrine ED50. To address the possibility that the absence of an insulin effect reflected a lack of nitric oxide-mediated, endothelium-dependent dilation in hand veins, responses to acetylcholine were obtained. Acetylcholine relaxed preconstricted hand veins by 60% to 80% (P<.01) in the presence and absence of indomethacin, which suggests substantial endothelium-dependent, cyclooxygenase-independent vasodilation. The results confirm that raising NEFAs locally enhances vascular alpha1-adrenoceptor sensitivity. Despite the presence of significant endothelium-dependent dilation in dorsal hand veins, insulin does not antagonize vascular alpha1-adrenoceptor sensitivity in the presence of either ambient or locally elevated fatty acids.

Adverse effects of short-term, very-low-salt diets in subjects with risk-factor clustering.

Obesity is associated with risk-factor clustering, including risk factors for hypertension, hyperinsulinemia, resistance to insulin's lowering of glucose and fatty acid concentrations, and a complex dyslipidemia. Obese hypertensive subjects are presumed to be salt sensitive because of the antinatriuretic actions of insulin. However, in our studies obese hypertensive subjects aged < 45 y were not more salt sensitive than were lean individuals. Subjects with the greatest evidence for risk-factor clustering had higher renin and aldosterone concentrations, which increased with salt restriction. The greater rise of fatty acids and activation of the renin-angiotensin system may explain the larger elevations of blood pressure, insulin, and triacylglycerol with salt restriction in high-risk subjects than in low-risk subjects. Regardless of mechanism, the adverse effects of short-term, very-low-salt diets in high-risk subjects suggest that continued moderation in advice for universal salt restriction is appropriate.

Fatty acids enhance neurovascular reflex responses by effects on alpha 1-adrenoceptors.

Abnormalities in plasma nonesterified fatty acids (NEFAs) may contribute to increased vascular alpha-adrenergic tone in obese hypertensive patients, because raising NEFAs locally enhances vascular reactivity to exogenously infused phenylephrine. However, responses to exogenous phenylephrine, a relatively selective alpha 1-adrenoceptor agonist, may not reflect the physiologically more important response to endogenous norepinephrine, a nonselective alpha-adrenoceptor agonist. To study the effects of NEFAs on vascular responses to endogenously released norepinephrine, dorsal hand venoconstrictor responses to thigh cuff inflation were quantified in nine healthy volunteers during coinfusion of Intralipid with heparin to raise fatty acids locally. Intralipid-heparin, which approximately doubled local linoleic and oleic acid concentrations (P < 0.05), increased the magnitude and duration of the venoconstrictor response to thigh cuff inflation (P < 0.005) and also enhanced venoconstrictor responses to locally infused phenylephrine but not clonidine, a relatively selective partial alpha 2-adrenoceptor agonist. The results of this study indicate that NEFAs enhance reflex vasoconstrictor responses largely through local effects on the vascular alpha 1-adrenoceptor and raise the possibility that fatty acids contribute to increased neurovascular tone in obese hypertensive patients.

Obesity hypertension is related more to insulin's fatty acid than glucose action.

Although resistance to insulin-mediated glucose disposal has emerged as a link between abdominal obesity and hypertension, abnormalities of nonesterified fatty acid metabolism may play a greater role. Analyses were performed on existing data from 17 abdominally obese subjects (11 hypertensive, 6 normotensive) to determine whether fatty acid concentration and turnover were related to blood pressure independently of hyperinsulinemia and resistance to insulin-mediated glucose disposal. Glucose utilization, fatty acid concentration, and fatty acid turnover were obtained fasting and during euglycemic hyperinsulinemia at 10 and 40 mU/m/min. Analyses were also performed on another group of 30 subjects with a wide range of risk factors who had blood pressure data as well as glucose and fatty acid measurements during an insulin tolerance test. Fatty acid concentration and turnover were markedly more resistant to suppression by insulin in obese hypertensive than in lean or obese normotensive individuals. In the 17 obese subjects, blood pressure measured at screening, in the laboratory, and over a period of 24 hours correlated significantly with fatty acid concentration and turnover but not with glucose disposal measured during the hyperinsulinemic clamp. These correlations remained significant after fasting insulin, the insulin area under the curve during an oral glucose tolerance test, and glucose disposal during the clamp were controlled for. In the second group of subjects, plasma fatty acids 15 minutes after intravenous insulin also correlated with blood pressure. These correlations remained significant after insulin and an index of sensitivity to insulin-mediated glucose disposal were statistically controlled for. The data indicate that blood pressure is related to the effects of insulin on fatty acid metabolism. The findings raise the possibility that resistance of hormone-sensitive lipase to insulin participates in elevating the blood pressure of abdominally obese hypertensive subjects by increasing fatty acid concentration and turnover.

Oleic acid inhibits endothelial nitric oxide synthase by a protein kinase C-independent mechanism.

Many obese hypertensive individuals have a cluster of cardiovascular risk factors. This cluster includes plasma nonesterified fatty acid concentrations and turnover rates that are higher and more resistant to suppression by insulin than in lean and obese normotensive individuals. The higher fatty acids may contribute to cardiovascular risk in these patients by inhibiting endothelial cell nitric oxide synthase activity. To test this hypothesis, we quantified the effects of oleic (18:1[cis]) and other 18-carbon fatty acids on nitric oxide synthase activity in cultured bovine pulmonary artery endothelial cells by measuring the conversion of [3H]L-arginine to [3H]L-citrulline. Oleic acid (from 10 to 100 mumol/L) caused a concentration-dependent decrease in nitric oxide synthase activity at baseline and during ATP and ionomycin (Ca2+ ionophore) stimulation. At 100 mumol/L, linoleic (18:2[cis]) and oleic acids caused similar reductions of nitric oxide synthase activity, whereas elaidic (18:1[trans]) and stearic (18:0) acids had no effect. Oleic acid also inhibited the endothelium-dependent vasodilator response to acetylcholine in rabbit femoral artery rings preconstricted with phenylephrine (P < .05) but had no effect on the response to nitroprusside. The pattern of 18-carbon fatty acid effects on nitric oxide synthase activity in endothelial cells is consistent with activation of protein kinase C. Although oleic acid increased protein kinase C activity in endothelial cells, neither depletion of protein kinase C by 24-hour pretreatment with phorbol 12-myristate 13-acetate nor its inhibition with staurosporine eliminated the inhibitory effect of oleic acid on nitric oxide synthase.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose metabolism in abdominally obese hypertensive and normotensive subjects.

To determine whether the combination of obesity and hypertension results in additive defects in oxidative and nonoxidative glucose metabolism and the association of these changes with altered hemodynamic actions of insulin, we studied 11 abdominally obese hypertensive, 6 abdominally obese normotensive, and 7 lean normotensive nondiabetic subjects. Endogenous glucose production and glucose metabolized were calculated from a euglycemic clamp at 72 and 287 pmol insulin/m2 per minute. Glucose metabolized divided by insulin was lower at 72 pmol/m2 per minute in both obese groups than in lean normotensive subjects, at 148 +/- 14, 144 +/- 33, and 373 +/- 69 (mumol/m2 per minute)/(pmol/L), respectively (P < .01). Similar results were obtained during the higher insulin dose. Nonoxidative and oxidative glucose disposals by indirect calorimetry were lower in both abdominally obese groups (P < .05). Hepatic glucose production was completely suppressed in lean subjects at the lower insulin dose and in all three groups at the higher insulin dose. Hemodynamic responses during the clamp were not significantly different among the three groups. Abdominal obesity is associated with defects in insulin-regulated oxidative and nonoxidative glucose disposal as well as in insulin suppression of hepatic glucose production. Mild hypertension does not exacerbate these defects. Whereas the global impairment in glucose metabolism suggests the presence of an early defect or defects, including reduced tissue perfusion, systemic and regional hemodynamic responses to insulin were not altered. These findings do not support a direct role for insulin resistance in the pathogenesis of the hypertension associated with abdominal obesity.

Fatty acids enhance vascular alpha-adrenergic sensitivity.

Hypertensive patients are heavier and have a more centralized body fat distribution, which is associated with risk factor clustering and resistance to insulin's actions, including suppression of plasma nonesterified fatty acids. We postulated that abnormalities of nonesterified fatty acids contribute to the increased vascular alpha-adrenergic reactivity and tone observed in our previous studies of obese hypertensive subjects. To test this hypothesis, in two separate protocols 10% Intralipid was infused into a dorsal hand vein with heparin to activate lipoprotein lipase and raise fatty acid levels locally. In protocol 1, the effects of Intralipid/heparin compared with those of 5% dextrose/heparin on dorsal hand vein sensitivity to phenylephrine were assessed by use of the linear variable differential transformer technique in 8 normotensive subjects. In protocol 2, the effects of Intralipid/heparin were compared with those of saline/heparin on hand vein responses to both phenylephrine and angiotensin II in 11 normotensive African American women. Intralipid/heparin reduced the dose of phenylephrine required to produce 50% of the maximal venoconstrictor response from 582 to 137 ng/min (compared with dextrose/heparin, P < .01) in protocol 1 and from 293 to 137 ng/min (compared with saline/heparin, P < .01) in protocol 2. Intralipid/heparin did not significantly alter hand vein responses to angiotensin compared with saline/heparin. These data suggest that abnormalities of nonesterified fatty acids in obese hypertensive patients with risk factor clustering may contribute to their increased neurovascular tone.

Additive effects of obesity and hypertension to limit venous volume.

The presence of reduced venous distensibility in obesity might have important hemodynamic effects and could indirectly implicate a role for metabolic factors in vascular control, because loading conditions are different in arterial and in venous vessels. Forearm blood flow and venous volume were measured plethysmographically in 58 subjects, including lean and obese hypertensives and normotensives. Venous volume at 30 mmHg (VV30) was decreased by both obesity and hypertension. This coincided with evidence for better preservation of central blood and stroke volumes with upright posture in obese than in lean subjects. Furthermore, obese hypertensives had lower VV30 than either lean hypertensives or obese normotensives. Postischemic forearm vascular resistance, a surrogate marker for structural luminal cross-sectional area, percent body fat, and fasting insulin each correlated independently with VV30 (P < 0.05) in multivariate analysis. Because nonesterified fatty acid levels are elevated in obese hypertensives and may have potent vascular effects, dorsal hand vein responses to coinfusion of Intralipid 10% and heparin to raise fatty acids locally were obtained in normal volunteers. The local infusion of Intralipid with heparin reduced hand vein distensibility, whereas dextrose and heparin did not (11 +/- 3% vs. 0 +/- 2%, respectively, P < 0.01). This study indicates that obesity and mild hypertension each reduce venous distensibility and that the coexistence of both conditions produces an even greater impairment in venous capacitance. The reduced venous distensibility in obesity appears to reflect structural as well as functional factors and to have systemic hemodynamic effects.

Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans.

To investigate the pathogenesis of hypertension in patients with obesity and insulin resistance and to explore the role of plasma lipids, we studied 30 subjects at the end of 7 days of low (20 mEq/d) then high (200 mEq/d) sodium diets. Glucose and insulin tolerance tests were performed at the end of each week and blood and urine collected for measurements of plasma aldosterone, renin activity, electrolytes, insulin, and lipoproteins. There was a strong negative correlation between plasma aldosterone and high-density lipoprotein cholesterol during both diets. There were weaker positive correlations between plasma aldosterone and insulin or triglycerides. When the aldosterone-renin ratio was the dependent variable and the correlation controlled for serum potassium, the inverse relationship with high-density lipoprotein cholesterol and the positive correlation with insulin remained, but only during the high salt diet. Subjects were divided into three groups based on high-density lipoprotein cholesterol. Subjects with the lowest high-density lipoprotein cholesterol levels showed the highest aldosterone, plasma triglycerides, body mass index, and waist-to-hip ratio. Those subjects also demonstrated the greatest resistance to insulin action on glucose and plasma unesterified fatty acids. There was a weak direct correlation between plasma aldosterone and systolic blood pressure during the high salt diet. These data suggest that high aldosterone levels may be a link between dyslipidemia, insulin resistance, and hypertension, a relationship made more evident by high salt intake.

Prolonged stimulation of intrarenal V1 vasopressin receptors results in sustained hypertension.

In an earlier study, we reported that chronic intravenous administration of the V1 agonist [Phe2,Ile3,Orn8]vasopressin (V1AG) results in sustained hypertension. The present study was designed to determine whether V1-induced hypertension may be related specifically to intrarenal actions of this peptide. Chronic infusion of the V1 agonist into the medullary interstitial space of a single remaining kidney of normal, conscious Sprague-Dawley rats at the rate of 2 ng.kg-1.min-1 for 14 days resulted in a sustained rise of 18 mmHg of mean arterial pressure (MAP). After withdrawal of V1AG, MAP returned to the baseline level. During the first day of V1AG infusion, there was a net loss of body sodium and no evidence of fluid retention throughout the period of hypertension. Plasma osmolality, sodium and potassium concentration, and water intake and body weight were not significantly affected by medullary interstitial infusion of V1AG. Renal medullary interstitial infusion of an equimolar amount of arginine vasopressin (AVP) did not affect MAP. Chronic medullary interstitial infusion of the selective V1 antagonist d(CH2)5[Tyr(Me)2,Ala-NH(2)9]AVP in equimolar amounts (2.5 ng.kg-1.min-1) prevented the MAP increase elicited by intravenous V1AG. However, intravenous administration of the V1 antagonist at the same rate together with V1AG (n = 7) failed to prevent hypertension. The results indicate that hypertension can be elicited by chronic stimulation of renal medullary V1 vasopressin receptors. They also suggest that some V2 agonistic properties of AVP may restrict the hypertensive action of this hormone. The mechanism for the rise of arterial pressure remains to be determined.

Renin and aldosterone are higher and the hyperinsulinemic effect of salt restriction greater in subjects with risk factors clustering.

Separate lines of evidence suggest that abdominal obesity, insulin, and renin are independent risk factors for coronary heart disease. Since insulin levels are higher in abdominally obese subjects and may enhance renin and aldosterone production, these risk factors may not be entirely independent. Moreover, the renin-angiotensin system may contribute to insulin resistance. These observations suggest that some inconsistencies in the literature regarding the effects of salt restriction on insulin may be explained by baseline anthropometric and metabolic differences in the subjects studied. To examine these issues, 29 volunteers with a range of risk factors were studied after 1 week each on isocaloric 20 and 200 mmol/day NaCl diets. Measurements included ambulatory blood pressures, plasma renin and aldosterone, and responses to oral glucose and intravenous insulin. Subjects were divided into three groups based on a composite score reflecting the risk factor cluster associated with abdominal obesity and hyperinsulinemia. The nine subjects with the highest scores had significantly greater values for renin and aldosterone on both the high and low salt diets than the nine subjects with the lowest scores. Fasting insulin and triglycerides, the insulin response to oral glucose, and plasma aldosterone all rose significantly more with salt restriction in the high than in the low risk subjects. Plasma renin activity also tended to increase more on the low salt diet in the high risk group. Ambulatory blood pressures were greater on the low than the high salt diet only in the high risk group.(ABSTRACT TRUNCATED AT 250 WORDS)

Compensatory hyperinsulinemia and the forearm vasodilator response during an oral glucose-tolerance test in obese hypertensives.

OBJECTIVE: To determine whether obese hypertensive patients manifest a diminished regional vasodilator response to an oral glucose challenge. METHODS: Nineteen obese hypertensives (body mass index 34.1 +/- 1.3 kg/m2, blood pressure 144 +/- 3/96 +/- 2 mmHg) and 13 lean controls (23.6 +/- 0.3 kg/m2, 127 +/- 4/83 +/- 3 mmHg) were studied. After 1 week on a standard diet, forearm blood flow (plethysmography), systemic hemodynamics (impedance cardiography), glucose and insulin levels were measured at baseline and again at 15, 30, 60, 90 and 120 min during an oral glucose-tolerance test (OGTT). RESULTS: Forearm blood flow increased after the oral glucose ingestion in obese hypertensives and lean controls. The rise in forearm blood flow was greater in obese hypertensives than in lean controls during the 2-h OGTT. Insulin levels also increased more in obese patients after the glucose load. During the second hour of the OGTT the ratio of changes in forearm blood flow and insulin level, an index of vascular insulin resistance, was similar in both groups. In contrast to the regional hemodynamic findings, total systemic vascular resistance decreased in lean controls but did not change in obese hypertensives during the second hour of the OGTT. CONCLUSION: The forearm vasodilator response to oral glucose in overweight, non-diabetic hypertensives is not impaired. If dynamic increases in flow are indeed important to insulin-mediated glucose disposal, then these observations raise the possibility that the greater increase of regional blood flow during an OGTT in obese hypertensives represents a component of the compensatory response for their defect in glucose metabolism.

Chronic intravenous administration of V1 arginine vasopressin agonist results in sustained hypertension.

Despite the well-recognized vasoconstrictor and fluid-retaining actions of vasopressin, prolonged administration of arginine vasopressin (AVP) to normal animals or humans fails to produce sustained hypertension. The present study was performed to elucidate the role of the V1 receptor in determining the ability of AVP to produce sustained hypertension. Conscious Sprague-Dawley rats with implanted catheters were infused with the selective V1 agonist, [Phe2,Ile3,Orn8]vasopressin (2 ng.kg-1.min-1), for 14 days in amounts that were acutely nonpressor. Blood pressure (MAP), heart rate (HR), body weight, and water intake (WI) were determined daily. Plasma AVP, plasma catecholamines norepinephrine and epinephrine, plasma osmolality, and electrolyte concentration were determined before and on days 1 and 7 of infusion. MAP increased significantly by 10.4 +/- 4.5 mmHg on day 1 and rose to 22 +/- 5 mmHg above control by day 14 (transient decrease on days 6-9) and then fell to control levels after the infusion was stopped. HR did not change significantly. Plasma AVP immunoreactivity increased from 2.5 +/- 0.3 to 10.9 +/- 2.1 pg/ml, whereas norepinephrine tended to fall only on day 1, with epinephrine only slightly elevated on day 7. No evidence of fluid retention was found, and rats lost sodium only on the first day of V1 agonist infusion. Body weight increased throughout the study but was unrelated to the changes of MAP. We conclude that chronic stimulation of V1 receptors results in sustained hypertension in rats.

Elevated blood pressures in obese young men with mild hypertension are sustained during the day and night.

The major goal of this study was to determine if the elevated blood pressures in obese men < 45 years old with mild hypertension persist outside the clinic. A secondary aim was to determine if hyperinsulinemia is associated with accentuated diurnal changes of blood pressure. To address these objectives, the clinic and ambulatory blood pressures as well as a 75-g, 2-h oral glucose tolerance test measurements were obtained from 9 lean normotensive, 9 lean hypertensive, and 22 obese hypertensive men < 45 years old. The week before study, volunteers ate an isocaloric diet with 220 mEq of NaCl/day. Obese hypertensives, subdivided by high (n = 11) and low (n = 11) insulin areas-under-the-curve (AUCs) in response to oral glucose, and lean hypertensives maintained higher ambulatory blood pressure than lean normotensives (130 +/- 3/74 +/- 1, 136 +/- 4/78 +/- 2, 132 +/- 5/77 +/- 3 v 118 +/- 4/65 +/- 2 mm Hg, respectively, P < .05). As expected, the insulin AUC during the glucose tolerance test was higher in obese hypertensives with higher insulin AUCs than in obese hypertensives with lower insulin AUCs, lean hypertensives, or lean normotensives (13.9 +/- 1.2 v 7.9 +/- 0.3, 7.2 +/- 0.7, 5.7 +/- 0.7 mU-min/dL, P < .05). Insulin AUCs were not significantly different in obese hypertensives with lower insulin levels, lean hypertensives, or lean normotensives. The diurnal increases of systolic and diastolic blood pressure as well as heart rate and pressure-rate product were similar in all four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Central cardiovascular effects of AVP and ANP in normotensive and spontaneously hypertensive rats.

The purpose of the present study was to compare influence of central arginine vasopressin (AVP) and of atrial natriuretic peptide (ANP) on control of arterial blood pressure (MAP) and heart rate (HR) in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Three series of experiments were performed on 30 WKY and 30 SHR, chronically instrumented with guide tubes in the lateral ventricle (LV) and arterial and venous catheters. MAP and HR were monitored before and after i.v. injections of either vehicle or 1, 10 and 50 ng of AVP and 25, 125 and 500 ng of ANP. Sensitivity of cardiac component of baroreflex (CCB), expressed as a slope of the regression line was determined from relationships between systolic arterial pressure (SAP) and HR period (HRp) during phenylephrine (Phe)-induced hypertension and sodium nitroprusside (SN)-induced hypotension. CCB was measured before and after administration of either vehicle, AVP, ANP, or both peptides together. Increases of MAP occurred after LV administration of 1, 10 and 50 ng of AVP in WKY and of 10 and 50 ng in SHR. ANP did not cause significant changes in MAP in both strains as compared to vehicle, but it abolished AVP-induced MAP increase in WKY and SHR. CCB was reduced in WKY and SHR after LV administration of AVP during SN-induced hypotension. In SHR but not in WKY administration of ANP, AVP and ANP + AVP decreased CCB during Phe-induced MAP elevation. The results indicate that centrally applied AVP and ANP exert differential effects on blood pressure and baroreflex control of heart rate in WKY and SHR and suggest interaction of these two peptides in blood pressure regulation at the level of central nervous system.

Insulin levels are similar in obese salt-sensitive and salt-resistant hypertensive subjects.

Evidence supports the hypothesis that hyperinsulinemia, especially in obesity, contributes to salt-sensitive hypertension by enhancing sodium retention and blunting the normal reduction of sympathetic drive and vascular resistance that occurs during a high versus low NaCl diet. To address these issues, we studied 18 obese (body mass index, > 27 kg/m2) subjects younger than 45 years old with mild hypertension to determine if the salt-sensitive versus salt-resistant subset had higher insulin levels, retained more volume, and failed to suppress sympathetic drive and vascular tone normally on a high (approximately 200 mEq/d) versus low (20 mEq/d) NaCl diet for 7 days each. Six obese subjects were salt sensitive, with an 8.4 +/- 2.1 (SEM) mm Hg increase of ambulatory mean blood pressure on the high versus low NaCl diet. Ten obese subjects were salt resistant, with a 7.1 +/- 0.9 mm Hg reduction of ambulatory mean blood pressure on high versus low NaCl. The salt-sensitive and salt-resistant groups had similar values, respectively, for the insulin area under the curve during an oral glucose tolerance test on low (14.6 +/- 1.8 versus 14.0 +/- 1.4 mU x min/dL, P = NS) and high (10.6 +/- 1.5 versus 10.6 +/- 1.0, P = NS) salt diets. Although insulin levels were similar, insulin raised calf blood flow in salt-resistant subjects (P < .05) but not in salt-sensitive subjects on the high NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketanserin's sympatholytic and serotonin2-receptor blocking actions precede the hypotensive effects.

The hypotensive action of ketanserin in humans remains incompletely defined but may be mediated by factors unrelated to vascular alpha 1 or serotonin2-receptor blockade. We examined the effects of ketanserin on indices of sympathetic drive, alpha 1- and serotonin2-receptor responses, and sympathetic tone in 13 elderly men with mild hypertension. Studies were performed after ten days and six weeks of double-blind assignment to placebo and ketanserin 40 mg twice daily. An eight week long single-blind, placebo washout period separated the double-blind phases. In the entire group, ketanserin lowered BP and heart rate significantly after six weeks but not at ten days. In contrast, plasma noradrenaline, an index of sympathetic drive, and platelet aggregation in response to 1 microM serotonin, an index of serotonin2-receptor antagonism, declined significantly after both ten days and six weeks (P < 0.05) on ketanserin versus placebo. Mean BP after six weeks on ketanserin fell to > 10% in seven patients (responders) and to < 10% in six subjects (nonresponders). Responders had higher baseline SBPs and heart rates compared with nonresponders. Even in responders, BP was reduced at six weeks but not after ten days on ketanserin versus placebo. Plasma and platelet noradrenaline, plasma renin activity, and platelet responses to serotonin at baseline and during ketanserin did not distinguish between responders and nonresponders. Ketanserin reduces sympathetic drive and antagonizes serotonin2-receptors in the short term. The relationship of these actions to the hypotensive effect of ketanserin, which is delayed and dependent on the initial BP, is unclear.

Insulin does not reduce forearm alpha-vasoreactivity in obese hypertensive or lean normotensive men.

Evidence supports the hypothesis that an impaired capacity of insulin to antagonize norepinephrine-induced vasoconstriction increases alpha-adrenergic tone in overweight young men with insulin resistance and mild hypertension. Therefore, the effects of regionally infused insulin at 100 microU/mL on forearm blood flow (milliliters per deciliter per minute) and responses to norepinephrine were measured in seven obese hypertensive and eight lean normotensive men younger than 45 years old. The obese hypertensive men were hyperinsulinemic and insulin resistant compared with the normotensive men, as evidenced by abnormal values for fasting insulin (15.5 +/- 1.6 versus 7.2 +/- 0.8 microU/mL, P < .001), the insulin area under the curve in response to a 2-hour oral glucose tolerance test (12.0 +/- 1.5 versus 6.7 +/- 1.1 mU x min/dL, P < .01), and the disappearance rate of glucose during a 15-minute insulin tolerance test (2.7 +/- 0.3 versus 4.1 +/- 0.3 mg%/min, P < .05). The logarithm of the norepinephrine EC50 was not significantly different in obese hypertensive men (mean, 95% confidence interval: -8.15, -8.42 to -7.87) versus lean normotensive men (-7.91, -8.23 to -7.59). The 2-hour regional insulin infusion at 100 microU/mL did not significantly alter the EC50 for norepinephrine in either group. Insulin at this concentration induced significant and similar increases of forearm blood flow in the hypertensive and normotensive groups (1.7 +/- 0.4 versus 1.7 +/- 0.6 mL/100 mL per minute, P = NS). At approximately 100 microU/mL, insulin does not antagonize norepinephrine-induced vasoconstriction in the forearm circulation of either obese hypertensive or lean normotensive men.(ABSTRACT TRUNCATED AT 250 WORDS)