Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension.

The reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/kg per min) while maintaining euglycemia. Hyperinsulinemia (50-60 microU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28 +/- 45 ng.liter-1.min-1 in hypertensives and 0.80 +/- 0.27 ng.liter-1 in normals; P less than 0.01). Forearm glucose uptake rose to 5.1 +/- .7 mg.liter-1.min-1 in response to insulin in hypertensives and to 7.9 +/- 1.3 mg.liter-1.min-1 in normotensives (P less than 0.05). To clarify whether insulin action was due to a direct effect on muscle NE metabolism, in another set of experiments insulin was infused locally into the brachial artery to expose only the forearm tissues to the same insulin levels as in the systemic studies. During local hyperinsulinemia, forearm NE release remained virtually unchanged both in hypertensive and in normal subjects. Furthermore, forearm glucose disposal was activated to a similar extent in both groups (5.0 +/- 0.6 and 5.2 +/- 1.1 mg.liter-1.min-1 in hypertensives and in normals, respectively). These data demonstrate that: (a) insulin evokes an abnormal muscle sympathetic overactivity in essential hypertension which is mediated by mechanisms involving the central nervous system; and (b) insulin resistance associated with hypertension is demonstrable in the skeletal muscle tissue only with systemic insulin administration which produces muscle sympathetic overactivity. The data fit the hypothesis that the sympathetic system mediates the pathophysiologic link between hyperinsulinemia and essential hypertension.

Insulin modulation of an endothelial nitric oxide component present in the alpha2- and beta-adrenergic responses in human forearm.

We explored in 51 normal subjects, distributed in various series of experiments, whether endothelium nitric oxide may play a role in insulin modulation of alpha2- and beta-adrenergic- evoked vascular responses. In particular, we examined the forearm blood flow response (FBF, ml.min-1.dl-1) to intrabrachial infusion of BHT-933 (0.5, 1, and 2 microg.min-1.dl-1) or isoproterenol (1, 3, and 6 ng. min-1.dl-1) in control conditions, during intrabrachial infusion of insulin alone (0.05 mU.kg-1.min-1) and associated with l-N-monomethylarginine (L-NMMA) (0.05 microg.min-1.dl-1), a nitric oxide synthase inhibitor. In control conditions both BHT-933 and isoproterenol induced a dose-dependent vascular response. Local hyperinsulinemia (deep venous plasma insulin 68.5+/-4 microU/ml) did not change basal FBF whereas attenuated BHT-933 vasoconstriction and enhanced isoproterenol vasodilation. L-NMMA reduced basal FBF and abolished the insulin effect on BHT-933 and isoproterenol response. To clarify whether a nitric oxide component is included in alpha2- and beta-adrenergic response and may be responsible for insulin vascular effect, we further examined BHT-933 and isoproterenol responses during nitric oxide inhibition. Interestingly, L-NMMA potentiated the BHT-933 vasoconstriction and attenuated the isoproterenol vasodilation and, in these conditions, insulin was no more able to exhibit its vascular effects. Finally, to rule out the possibility that the conteracting effect of L-NMMA may not be specifically related to insulin action, dose-response curves to phenylephrine (0.5, 1, and 2 microg.min-1.dl-1) or sodium nitroprusside (1, 2, and 4 microg.min-1.dl-1) were also performed. Both insulin and L-NMMA were unable to alter the phenylephrine-induced vasoconstriction and the sodium nitroprusside vasodilation. In conclusion, our data demonstrate an endothelial nitric oxide component in the alpha2- and beta-adrenergic vascular responses which is the target of the insulin vascular action.

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

To investigate whether the response of atrial natriuretic factor (ANF) to volume expansion is impaired in the early stages of dilated cardiomyopathy, the effects of saline load (SL; 0.25 ml/kg.min for 120 min) were assessed in 12 patients with dilated cardiomyopathy and asymptomatic to mildly symptomatic heart failure (HF) and in nine normal subjects (N). SL increased plasma ANF levels in N (from 14.3 +/- 2 to 19.5 +/- 3 and 26 +/- 4 pg/ml, at 60 and 120 min, respectively, P less than 0.001), but not in HF (from 42.9 +/- 9 to 45.9 +/- 9 and 43.9 +/- 8 pg/ml). Left ventricular end-diastolic volume (LVEDV) and stroke volume were increased (P less than 0.001) by SL in N but not in HF. Urinary sodium excretion (UNaV) increased in N more than in HF during SL, whereas forearm vascular resistance (FVR) did not change in N and increased in HF (P less than 0.001). In five HF patients SL was performed during ANF infusion (50 ng/kg, 5 ng/kg.min) that increased ANF levels from 37.1 +/- 10 to 146 +/- 22 pg/ml. In this group, SL raised both LVEDV (P less than 0.01) and ANF (P less than 0.05), whereas FVR did not rise. In addition, the UNaV increase and renin and aldosterone suppressions by SL were more marked than those observed in HF under control conditions. Thus, in patients with dilated cardiomyopathy and mild cardiac dysfunction, plasma ANF levels are not increased by volume expansion as observed in N. The lack of ANF response is related to the impaired cardiac adaptations. The absence of an adequate increase of ANF levels may contribute to the abnormal responses of HF patients to saline load.

Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency.

To circumvent the embryonic lethality of a complete deficiency in insulin-like growth factor 1 (IGF-1), we generated mice homozygous for a site-specific insertional event that created a mutant IGF-1 allele (igf1m). These mice have IGF-1 levels 30% of wild type yet survive to adulthood, thereby allowing physiological analysis of the phenotype. Miniaturized catheterization technology revealed elevated conscious blood pressure in IGF-1(m/m) mice, and measurements of left ventricular contractility were increased. Adenylyl cyclase activity was enhanced in IGF-1(m/m) hearts, without an increase in beta-adrenergic receptor density, suggesting that crosstalk between IGF-1 and beta-adrenergic signaling pathways may mediate the increased contractility. The hypertrophic response of the left ventricular myocardium in response to aortic constriction, however, was preserved in IGF-1(m/m) mice. We conclude that chronic alterations in IGF-1 levels can selectively modulate blood pressure and left ventricular function, while not affecting adaptive myocardial hypertrophy in vivo.

Noradrenergic vascular hyper-responsiveness in human hypertension is dependent on oxygen free radical impairment of nitric oxide activity.

BACKGROUND: Noradrenergic vascular hyper-responsiveness is a hallmark of essential hypertension. To evaluate whether nitric oxide plays a role in the enhanced vascular response to norepinephrine in hypertension, we examined 32 hypertensives and 28 normotensives who were distributed in 3 experimental series. METHODS AND RESULTS: In the first series, we measured the forearm blood flow (FBF) response to a norepinephrine infusion under control conditions and during the infusion of L-N-monomethylarginine (L-NMMA). Norepinephrine evoked dose-dependent vasoconstriction that was greater in hypertensives than in normotensives (maximum FBF, -61+/-1 versus -51+/-1%; P<0.01). During L-NMMA infusion, norepinephrine vasoconstriction was not modified in hypertensives; however, it was potentiated in normotensives (maximum FBF, -64+/-2%; P<0.01). In the second series, we tested whether norepinephrine vasoconstriction could be affected by an antioxidant such as ascorbic acid. Norepinephrine vasoconstriction was blunted by ascorbic acid administration only in hypertensives (maximum FBF, -49+/-3 versus -63+/-2%; P<0.01); the vasoconstriction became similar to that observed in normotensives. During ascorbic acid plus L-NMMA administration, the vascular response to norepinephrine increased to a similar extent in both study groups. To rule out the possibility that the effect of ascorbic acid on norepinephrine vasoconstriction could depend on adrenergic receptor-induced nitric oxide release, in the last series we inhibited endogenous nitric oxide and replaced it with an exogenous nitric oxide donor (sodium nitroprusside). Even in these conditions, ascorbic acid attenuated norepinephrine vasoconstriction only in hypertensives (maximum FBF, -50+/-2 versus -62+/-1%; P<0.01). CONCLUSIONS: Our data demonstrate that noradrenergic vascular hyper-responsiveness in hypertension is dependent on an impairment of nitric oxide activity that is realized through norepinephrine-induced oxygen free radical production.

Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat.

BACKGROUND: Left ventricular hypertrophy (LVH) represents both an adaptive response to increased cardiac work load and a precursor state of heart failure. Recent evidence linked cardiac myocyte death by apoptosis with LVH and heart failure. It remained unclear, however, whether apoptosis participated in the transition from LVH to left ventricular dysfunction (LVD). METHODS AND RESULTS: Cardiac myocyte apoptotic events and changes in apoptosis-specific genes were studied in a rat model of chronic pressure overload induced by transverse aortic constriction. The changes in left ventricular geometry and function were assessed by echocardiography. Transverse aortic constriction rats progressively developed "concentric" LVH and subsequently, LVD. A similar distribution of LVH and LVD was found 18 weeks after surgery. At this time point, we determined the occurrence of myocyte apoptosis by DNA laddering, in situ DNA TUNEL labeling, and light and electron microscopy. The monitoring of proapoptotic and antiapoptotic genes was determined by Western blot and immunohistochemistry. Our data demonstrated that cardiomyocyte apoptotic events increased from virtually undetectable (in sham-operated controls, SH) to 0.8/10(3) and 1.5/10(3) positive nuclei in LVH and LVD, respectively. Fibrosis also increased in the subendocardial and midwall regions of LVH and LVD rats compared with SH. Expression of the proapoptotic gene bax increased, whereas that of antiapoptotic gene bcl-2 decreased in LVH and LVD compared with SH. CONCLUSIONS: These data suggest that in response to chronic pressure overload, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD. LVH and LVD were accompanied by a dramatic cardiomyocyte upregulation of the proapoptotic gene bax and reduced bcl-2/bax ratio, predisposing cardiomyocytes to apoptosis.

Leptin induces direct vasodilation through distinct endothelial mechanisms.

In this study, we reveal that leptin evokes an acute hypotensive effect in 6-hydroxydopamine sympathectomized rats (response to maximal leptin dose, mean blood pressure: from 92 +/- 4 to 78 +/- 2 mmHg, P < 0.01). This hemodynamic effect is related to a direct action of the hormone on vascular tone, since in aortic and mesenteric rings increasing doses of leptin evoke a dose-dependent vasorelaxation (aorta: from 3 +/- 1 to 36 +/- 3, n = 15; mesenteric: from 6 +/- 1 to 30 +/- 5, n = 10), which is impaired by endothelial denudation. In particular, leptin-evoked vasorelaxation is impaired by nitric oxide synthase inhibition in aorta (delta% of maximal response: from 36 +/- 3 to 3 +/- 1, P < 0.01) and by endothelium-derived hyperpolarizing factor (EDHF) inhibition in mesenteric arteries (delta% of maximal response: from 30 +/- 5 to 7 +/- 2, P < 0.01), suggesting that vasorelaxation evoked by leptin is heterogeneous and related to the vascular bed. Finally, the inhibition of nitric oxide synthase by NG-nitro-L-arginine-methyl ester does not modify blood pressure response to leptin, suggesting a predominant role of the EDHF mechanism in the hypotensive effect of leptin.

Reflex control of coronary vascular tone by cardiopulmonary receptors in humans.

To examine whether cardiopulmonary receptors participate in the reflex control of coronary vascular resistance, systemic and coronary hemodynamics were assessed before and during -10 mm Hg lower body negative pressure in eight normal subjects and eight hypertensive patients with left ventricular hypertrophy. In both study groups, lower body negative pressure induced a significant decrease in right atrial pressure, left ventricular filling pressure and cardiac output, an increase in systemic vascular resistance and no change in mean arterial pressure and heart rate. In normal subjects, there was also a significant increase in plasma norepinephrine concentration (from 294 +/- 39 to 421 +/- 47 pg/ml, p less than 0.01). This increase was accompanied by a reduction in coronary blood flow, assessed by the continuous thermodilution method (from 101 +/- 5 to 79 +/- 4 ml/min, p less than 0.05). An increase in coronary vascular resistance (from 0.865 +/- 0.1 to 1.107 +/- 0.1 mm Hg/ml per min, p less than 0.05) and in myocardial oxygen consumption was detected in normal subjects during cardiopulmonary baroreceptor unloading. In contrast, in hypertensive patients, -10 mm Hg lower body negative pressure failed to induce any change in plasma norepinephrine, coronary blood flow or vascular resistance. Intravenous propranolol administration caused no significant change in the systemic hemodynamic response to -10 mm Hg lower body negative pressure in either study group, but it did abolish the decrease in coronary flow and the increase in plasma norepinephrine, coronary vascular resistance and myocardial oxygen consumption observed in normal subjects in control conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and hormonal effects of atrial natriuretic factor in patients with essential hypertension.

Hemodynamic and hormonal effects of two graded infusions of alpha-human-(1-28)-atrial natriuretic factor (0.5 microgram/kg prime followed by 0.05 microgram/kg per min for 20 minutes and by 0.1 microgram/kg per min for 20 minutes) were evaluated in 13 patients with mild to moderate essential hypertension. The lower dose of atrial natriuretic factor did not change significantly any of the considered variables, although it tended to reduce aortic mean blood pressure (from 132.6 +/- 5.3 to 125.5 +/- 4.6 mm Hg), cardiac index (from 3.67 +/- 0.2 to 3.54 +/- 0.18 liters/min per m2) and forearm vascular resistance (from 178.6 +/- 15 to 148.3 +/- 10 mm Hg/ml per s). The higher dose of atrial natriuretic factor significantly reduced mean aortic pressure (118.6 +/- 5 mm Hg), cardiac index (3.29 +/- 0.16 liters/min per m2) and stroke volume index (from 45.9 +/- 2.6 to 38.9 +/- 3 ml/m2) and slightly decreased pulmonary wedge pressure, whereas both total peripheral resistance and forearm vascular resistance were not modified. With this latter dose a reduction in aortic pressure was observed in all patients at the steady state, and this was associated with a fall in stroke volume index in 10 of the 13 patients and with a reduction in total peripheral resistance in only 6 patients. Heart rate and right atrial and pulmonary pressures did not change during infusion of atrial natriuretic factor. Plasma renin activity was only slightly reduced by atrial natriuretic factor, whereas plasma norepinephrine rose significantly (from 233 +/- 34 to 330 +/- 58 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Human basophil releasability. II. Changes in basophil releasability in patients with atopic dermatitis.

"Releasability" is the theory whereby biochemical events in basophils influence the capacity to release chemical mediators in response to activating stimuli. We have compared the releasability of basophils from 21 young patients with atopic dermatitis (AD) with that from 17 normal donors of matched ages. Basophils were challenged with several different stimuli: rabbit antihuman Fc epsilon (anti-IgE), N-formyl-methionyl-leucyl-phenylalanine (f-met-peptide), Ca++ ionophore A23187, and D2O. Basophils from patients with AD released significantly more histamine both "spontaneously" and in response to D2O than did controls. The basophils of patients with AD were significantly more responsive to anti-IgE and to A23187. There was no difference between the percent f-met-peptide-induced histamine release in patients with AD vs controls. No significant correlation between percent histamine release with optimal or suboptimal concentrations of the stimuli and serum IgE level was found. There was a significant correlation between the sensitivity of the cells to release with f-met-peptide and the response to A23187 both in control and in AD patients. Since basophils are thought to play some role at the site of inflammation in AD, their increased releasability might contribute to the symptoms of these patients.

Modulatory role of angiotensin-II in the secretion of atrial natriuretic factor in rabbits.

This study was designed to investigate whether the increase in circulating atrial natriuretic factor (ANF) levels produced by angiotensin II (Ang II) is a consequence of the hemodynamic changes or whether it occurs also in the absence of pressor changes. For this purpose in anesthetized and awake rabbits we evaluated the effects of Ang II (0.1 micrograms/kg.min) alone or during the simultaneous infusion of sodium nitroprusside (NP) at a dose titrated to abolish the pressor effects. Systemic blood pressure increased from 76 +/- 4 to 113 +/- 5 mm Hg (P less than 0.001) during Ang II and from 76 +/- 2 to 75 +/- 3 mm Hg (P = NS) during Ang II plus NP. The alpha-adrenergic agonist phenylephrine, used as a control, raised blood pressure from 65 +/- 2 to 101 +/- 8 mm Hg (P less than 0.001), and its pressor effect was abolished by the concomitant infusion of NP (64 +/- 2 to 61 +/- 1 mm Hg; P = NS). The increase in plasma ANF levels produced by Ang II alone (from 36.5 +/- 5 to 237 +/- 57 pg/ml; P less than 0.001) was not different from that observed during Ang II plus NP (from 46 +/- 10 to 207 +/- 88 pg/ml; P less than 0.001). In contrast, the stimulatory effect on ANF release of phenylephrine (from 56.1 +/- 9 to 202 +/- 40 pg/ml; P less than 0.001) was completely abolished when its pressor effects were prevented by the combined infusion of NP (from 58.5 +/- 15 to 42.3 +/- 10 pg/ml; P = NS). These results show that the stimulatory effect of Ang II on ANF release can be clearly dissociated from its pressor effect, whereas the increase in plasma ANF levels caused by phenylephrine is strictly related to its hemodynamic effect. Therefore, Ang II is capable of modulating ANF secretion in a manner that is independent of its pressor actions. In addition, our results suggest that ANF release is not solely linked to myocyte stretch.

A common variant of endothelial nitric oxide synthase (Glu298Asp) is an independent risk factor for carotid atherosclerosis.

BACKGROUND AND PURPOSE: Endothelium-derived NO is formed from L-arginine by endothelial NO synthase (eNOS) encoded by the NOS 3 gene on chromosome 7. Because several studies have indicated that NO plays a key role in the development of the atherosclerotic process, we investigated whether common variants in the eNOS gene are associated with an increased risk of plaque on carotid arteries. METHODS: We studied 375 subjects attending the hypertension center of our institution to be screened for arterial hypertension. The examined subjects were classified according to the presence of carotid plaques (intima-media thickness >/=1.5 mm), and 2 intronic (CA and 27-bp repeats) polymorphisms and 1 exonic (Glu298Asp) polymorphism of the eNOS gene were explored. RESULTS: Only the Glu298Asp polymorphism of eNOS was associated with the presence of carotid plaques (P:<0.05). In particular, there was an excess of homozygotes for the Asp298 variant among subjects with carotid plaques, whereas the number of subjects who had the Glu298 allele in exon 7 of the eNOS gene was equally distributed in both study groups. Interestingly, the risk of having carotid plaques was increased approximately 3 times in subjects who were homozygotic for the Asp298 variant compared with subjects who were homozygotic for the Glu298 variant and was independent of the other common risk factors (age, blood pressure, and smoking). CONCLUSIONS: Homozygosity for Asp298, a common variant of the eNOS gene, is an independent risk factor for carotid atherosclerosis in this study population.

Insulin modulation of vascular reactivity is already impaired in prehypertensive spontaneously hypertensive rats.

Hyperinsulinemia reduces the vasoconstrictive response to norepinephrine in Wistar-Kyoto rats (WKY) but not in spontaneously hypertensive rats (SHR). It has been hypothesized that this difference in the vascular effect of insulin could be a hallmark of the hypertensive state. To test this hypothesis we studied SHR before (5 weeks old, n = 10) and after (15 weeks old, n = 10) the establishment of hypertension as well as two groups of age- and sex-matched WKY (5 weeks old, n = 14; 15 weeks old, n = 13). Blood pressure was significantly higher in SHR compared with WKY (181 +/- 5 versus 118 +/- 6 mm Hg, respectively, P < .001) in the 15-week-old rats but not in the 5-week-old rats (121 +/- 5 versus 117 +/- 3 mm Hg, P < NS). We tested vascular reactivity using increasing amounts of norepinephrine (from 10(-10) to 10(-5) mmol/L) on isolated aortic rings in control conditions and after 30 minutes of exposure to 715 pmol/L insulin. In WKY insulin reduced the vascular response to norepinephrine in both the 5-week-old (repeated-measures ANOVA with grouping factor: F = 2.443, P < .05) and 15-week-old (F = 9.667, P < .01) groups. In SHR at both ages insulin failed to modify the vascular response to norepinephrine (5 weeks: F = 0.107, P < NS; 15 weeks: F = 0.075, P < NS). Sodium nitroprusside was able to attenuate the vascular response to norepinephrine in WKY and SHR at 5 and 15 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin blunts sympathetic vasoconstriction through the alpha 2-adrenergic pathway in humans.

We investigated the mechanisms underlying the insulin-induced attenuation of sympathetic forearm vasoconstriction in healthy humans. In 5 subjects, we applied 20 mm Hg lower body negative pressure for 30 minutes in control conditions and during a 60-minute infusion of insulin (0.05 mU/kg per minute) in the brachial artery and measured forearm norepinephrine kinetics and hemodynamics. In 11 subjects, we applied graded lower body negative pressure at 5, 10, 15, and 20 mm Hg for 5 minutes each in control conditions and during the simultaneous intrabrachial administration of insulin (0.05 mU/kg per minute) (5 subjects) or insulin plus ouabain (3.5 micrograms/min per liter) (6 subjects) to investigate whether insulin acts through a potentiation of the vascular smooth muscle Na+,K(+)-ATPase. To assess a possible effect of insulin on a specific adrenergic receptor pathway, in a further study group we evaluated (1) the forearm vascular response to intrabrachial infusion of the alpha 1-adrenergic receptor agonist phenylephrine (0.5, 1, and 2 micrograms/kg per minute; n = 7) and of the alpha 2-adrenergic receptor agonist BHT-933 (0.5, 1, 2, and 4 micrograms/kg per minute; n = 9), and (2) the effects of intra-arterial infusion of prazosin (0.5 microgram/100 mL per minute) alone or combined with insulin on the forearm vascular response to graded lower body negative pressure (7 subjects). Insulin blunted the peak increase in forearm vascular resistance (from 13 +/- 2 to 6 +/- 2 U, P < .05) but not the rise in forearm norepinephrine spillover induced by 20 mm Hg lower body negative pressure (from 8.3 +/- 1.8 to 11.1 +/- 3.5 pmol/min per liter, P = NS). Ouabain administration did not prevent the insulin-induced attenuation of the forearm vasoconstrictive response to graded lower body negative pressure. Insulin infusion in the brachial artery did not modify the forearm vasoconstriction induced by intra-arterial infusion of phenylephrine but significantly reduced the increase in forearm vascular resistance induced by BHT-933 (F = 6.111, P < .001). Finally, intra-arterial infusion of prazosin significantly attenuated the forearm vasoconstriction induced by graded lower body negative pressure. The residual vasoconstrictive response was abolished by insulin infusion. Taken together, these findings suggest that insulin interacts with the sympathetic nervous system at the vascular level predominantly through the alpha 2-adrenergic vasoconstrictive pathway.

Salt-induced plasticity in cardiopulmonary baroreceptor reflexes in salt-resistant hypertensive patients.

To investigate the effects of salt loading on cardiopulmonary and arterial baroreceptor reflexes, 34 hypertensive patients underwent two 4-day periods with different dietary sodium intakes (70 and 370 meq/day). The patients were classified as salt-sensitive or salt-resistant depending on whether the mean arterial pressure value obtained on day 4 of high salt intake did or did not increase by 8% or more. In 22 patients cardiopulmonary and carotid baroreceptor reflexes were assessed during each dietary period by measuring the reflex responses to the application of -10 mm Hg lower body negative pressure and of +60 mm Hg increase in neck tissue pressure. Salt-resistant patients (n = 16) retained less sodium than salt-sensitive patients (n = 6) and showed a reduction in plasma norepinephrine and forearm vascular resistance during high sodium intake, whereas the salt-sensitive patients did not. During low sodium diet, no significant differences could be detected in the reflex responses to cardiopulmonary and carotid baroreceptor unloading between the two groups. High salt diet, however, potentiated the gain of cardiopulmonary baroreceptor reflex, which was expressed as the increase in plasma norepinephrine or forearm vascular resistance per millimeter of mercury decrease in pulmonary capillary wedge pressure, only in the salt-resistant hypertensive patients. In addition, the atrial natriuretic factor response to changes in pulmonary capillary wedge pressure was significantly enhanced by high salt intake only in the salt-resistant hypertensive patients. The reflex responses to carotid baroreceptor unloading were unaffected by salt loading in either group. In the remaining 12 patients, the hemodynamic effects of graded lower body negative pressure (-5, -10, -15 mm Hg) and neck tissue positive pressure (+30, +45, +60 mm Hg) were tested for both diets. Again, high salt intake significantly potentiated the cardiopulmonary baroreceptor reflex gain, expressed as the slope of the linear correlation between the changes in forearm vascular resistance (mm Hg/ml/min/100 g) and pulmonary capillary wedge pressure (mm Hg), in salt-resistant (from 3.8 +/- 0.9 to 7.2 +/- 1.0, p less than 0.05) but not in salt-sensitive patients (from 4.2 +/- 0.9 to 3.2 +/- 0.6, NS). In conclusion, the present study demonstrates that high salt diet potentiates cardiopulmonary baroreceptor reflexes and enhances atrial natriuretic factor response in salt-resistant but not in salt-sensitive hypertensive patients. The salt-induced plasticity of cardiopulmonary baroreceptor reflexes may exert a protective effect against the development of salt-induced hypertension by augmenting the reflex vasodilatory response to volume expansion.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin reduces reflex forearm sympathetic vasoconstriction in healthy humans.

Previous in vitro studies indicate that insulin modifies vascular reactivity to different agents. We have previously demonstrated that in normotensive humans physiological hyperinsulinemia is associated with an increase of forearm norepinephrine release but does not modify vascular resistance. To explore whether insulin modulates peripheral vasoconstriction induced by reflex sympathetic activation, we studied its effects on forearm hemodynamics (strain-gauge plethysmography) during graded levels of lower body negative pressure (-5, -10, -15, and -20 mm Hg, each for 5 minutes) in normotensive subjects. For this purpose, eight subjects received an intrabrachial artery infusion of regular insulin at a systemically ineffective rate (0.05 milliunits/kg per minute) so that deep-venous insulin levels increased in the experimental forearm from 16.5 +/- 2.9 to 379.6 +/- 30 pmol/L (p < 0.01), whereas arterial insulin levels remained unchanged (from 40.9 +/- 8.6 to 43.1 +/- 7.9 pmol/L, NS). In the control arm, forearm vascular resistance (units) increased from 52.3 +/- 3 to a peak of 78.4 +/- 5 (p < 0.001) during lower body negative pressure. In the insulin-exposed forearm, vascular resistance (46.4 +/- 2 at baseline) remained unchanged during insulin infusion (45.8 +/- 3, NS) and rose to a peak of 54.8 +/- 6 (p < 0.05) during lower body negative pressure. The response of forearm vascular resistance to lower body negative pressure was different in the two forearms (F = 4.506, p < 0.01, repeated-measures analysis of variance with grouping factor). Our results demonstrate that in normotensive subjects local physiological hyperinsulinemia reduces the forearm vasoconstrictive response to reflex sympathetic activation.

Impaired control of vasopressin release in hypertensive subjects with cardiac hypertrophy.

The effects of graded lower body negative pressure (-10 and -40 mm Hg) on vascular resistance and plasma vasopressin, norepinephrine, and renin activity were assessed in seven hypertensive subjects with left ventricular hypertrophy and seven sex-matched and age-matched normotensive subjects. In both groups increasing levels of lower body negative pressure induced a progressive decrease in right atrial pressure and an increase in vascular resistance. In normal subjects plasma vasopressin, norepinephrine, and renin activity were progressively raised, whereas only the higher level of stimulation increased plasma renin activity, norepinephrine, and vasopressin in hypertensive subjects. Propranolol induced a significant increase in plasma vasopressin in normal subjects (from 1.3 +/- 0.1 to 2.0 +/- 0.1 pg/ml; p less than 0.05) but not in hypertensive subjects. In this latter condition -10 mm Hg lower body negative pressure failed to increase plasma vasopressin, norepinephrine, and renin activity in normal subjects. Propranolol abolished the change in plasma renin activity in both groups, reduced the increase in vascular resistance induced by -40 mm Hg lower body negative pressure in normotensive subjects, but did not modify the rise in vasopressin elicited by this stimulus in normal subjects or the humoral and hemodynamic reflex responses evoked in hypertensive subjects. These results suggest that cardiopulmonary receptors are involved in the control of vasopressin release in normal subjects, whereas in hypertensive subjects with left ventricular hypertrophy, this control is altered because of an impaired function of cardiopulmonary receptors.

Muscle sympathetic nerve activity in patients with acromegaly.

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 +/- 4 yr; body mass index, 28 +/- 2 kg/m2) and eight healthy subjects (age, 32 +/- 3 yr; body mass index, 25 +/- 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method [infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (approximately 90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 +/- 28 and 200 +/- 27 pg/mL (-1) and slightly increased during insulin infusion. Forearm NE release was 2.33 +/- 0.55 ng x liter(-1) x min(-1) in healthy subjects and 2.67 +/- 0.61 ng x liter(-1) x min(-1) in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 +/- 0.71 and 3.32 +/- 0.75 ng x L(-1) x min(-1), P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 +/- 0.4 mg x L(-1) x min(-1)) than in control subjects (7.9 +/- 1.3 mg x L(-1) x min(-1), P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms.

Insulin enhances endothelial alpha2-adrenergic vasorelaxation by a pertussis toxin mechanism.

To investigate whether insulin effect on endothelium is related to a specific signal transduction pathway or reflects a more generalized action of the hormone, we studied in aortic rings of Wistar-Kyoto (WKY) rats the effects of the hormone on endothelium-dependent relaxations generated by acetylcholine, adenosine diphosphate, the selective alpha2-adrenergic agonist UK 14,304, and the calcium ionophore ionomycin. The responses were evaluated both in control conditions and after 30 minutes of exposure to three different levels of insulin (30, 100, and 500 microU/mL). Insulin failed to modify the phenylephrine aortic contractions and the relaxations induced by acetylcholine, adenosine diphosphate, and ionomycin. In contrast, both 100 and 500 microU/mL insulin were able to potentiate the UK 14,304-induced vasorelaxation (+96+/-19% and +91+/-12%, respectively). Pertussis toxin, which causes alpha2-adrenergic receptor Gi uncoupling, reduced the alpha2-adrenergic vasorelaxation and prevented the insulin potentiation of the response to UK 14,304. Furthermore, in primary cultured aortic endothelial cells from WKY, we evaluated the conversion of [3H]arginine to [3H]citrulline in response to acetylcholine, ionomycin, and UK 14,304, both in control conditions and during insulin exposure. Again, insulin did not affect basal citrulline production or the increase induced by acetylcholine and ionomycin, whereas it potentiated the response to UK 14,304. Finally, in aortic rings of spontaneously hypertensive rats, insulin treatment (100 and 500 microU/mL) was unable to enhance the alpha2-adrenergic vasodilator response; in vascular endothelial cells from spontaneously hypertensive rats, insulin did not potentiate the increase in citrulline production evoked by UK 14,304. In conclusion, insulin selectively enhances alpha2-adrenergic endothelial vasorelaxation through a pertussis toxin-sensitive mechanism, by potentiating endothelial nitric oxide production. This vasorelaxant mechanism is altered in spontaneously hypertensive rats.

Dietary sodium restriction impairs endothelial effect of insulin.

Hyperinsulinemia and high salt intake represent two independent cardiovascular risk factors. However, it is still unknown whether the change in dietary salt intake may affect the ability of insulin to stimulate whole-body glucose uptake and to modulate endothelial function. Regarding this latter issue, we have recently demonstrated that insulin enhances endothelial-mediated alpha2-adrenergic vasorelaxation. In overnight-fasted, freely moving Wistar-Kyoto rats (10 to 12 weeks old), we assessed whole-body glucose uptake (in milligrams per kilogram per minute) during a euglycemic-hyperinsulinemic clamp (insulin infusion rate, 3 mU x kg(-1) x min(-1)) after 3 weeks of normal (NSD, 2% NaCl), high (HSD, 6% NaCl), and low (LSD, 0.6% NaCl) sodium diet. Three days after the clamp study, rats were killed to assess alpha2-adrenergic vasorelaxation evoked by UK 14,304 (10(-9) to 10(-6) mol/L) in aortic rings in control conditions and after insulin exposure (100 microU/mL). Different sodium intakes did not modify the mean blood pressure or the insulin-stimulated whole-body glucose uptake (NSD: 14+/-1.2, n=16; HSD: 15.4+/-1.7, n=14; LSD: 14.8+/-0.8, n=14; NS). In contrast, we confirmed the ability of insulin to enhance alpha2-adrenergic vasorelaxation during NSD and HSD (delta% of maximal relaxation, NSD: from 32+/-3% to 58+/-3.4%, n=9, P<0.01; HSD: from 33+/-3.8% to 59+/-3.5%, n=8, P<0.01), but this effect was impaired during LSD (delta% maximal relaxation, from 36+/-1.5% to 36+/-3.4%, n=8, NS). In conclusion, our data demonstrate that in Wistar-Kyoto rats, changes in dietary salt intake do not modify the insulin-stimulated whole-body glucose uptake. In contrast, LSD impairs the insulin potentiation of alpha2-adrenergic vasorelaxation, thus suggesting that dietary salt restriction provokes an impairment of insulin effect on endothelial function.