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.

Sympathetic deactivation by growth hormone treatment in patients with dilated cardiomyopathy.

AIMS: We examined the effects of growth hormone administration on the sympathetic nervous system in patients with idiopathic dilated cardiomyopathy. BACKGROUND: Growth factor therapy is emerging as a new potential option in the treatment of heart failure. Although growth hormone provides functional benefit in the short term, it is unknown whether it affects the sympathetic nervous system, which plays a role in the progression of heart failure. METHODS: Seven patients with idiopathic cardiomyopathy received 3 months treatment with recombinant human growth hormone (0.15-0.20 IU.kg-1.week-1). Standard medical therapy was unchanged. Myocardial norepinephrine release, both at rest and during submaximal physical exercise, plasma aldosterone, and plasma volume were measured before and after growth hormone treatment. Myocardial norepinephrine release was assessed from arterial and coronary venous plasma concentrations of unlabelled and tritiated norepinephrine and coronary plasma flow (thermodilution). RESULTS: Growth hormone induced a significant fall in myocardial norepinephrine release in response to physical exercise (from 180 +/- 64 to 99 +/- 34 ng.min-1; P < 0.05). Basally, plasma aldosterone was 189 +/- 28 and 311 +/- 48 pg.ml-1 in the supine and upright position, respectively, and fell to 106 +/- 16 (P < 0.01) and 182 +/- 29 pg.ml-1 (P < 0.05) after growth hormone therapy. Growth hormone increased plasma volume from 3115 +/- 493 ml to 3876 +/- 336 ml (P < 0.05), whereas serum sodium and potassium concentrations were unaffected. CONCLUSIONS: The data demonstrate that growth hormone administration to patients with idiopathic cardiomyopathy reduces myocardial sympathetic drive and circulating aldosterone levels. This neurohormonal deactivation may be relevant to the potential, long-term use of growth hormone in the treatment of patients with heart failure.

Insulin modulation of beta-adrenergic vasodilator pathway in human forearm.

BACKGROUND: Insulin modulates sympathetic vasoconstriction, but the mechanisms underlying this effect are not completely elucidated. We have recently investigated the insulin effect on the alpha 1- and alpha 2-adrenergic vasoconstriction pathway, where it is still conflicting with the possible insulin influence on the beta-adrenergic vasodilator pathway. The aim of the present study was to investigate this issue. METHODS AND RESULTS: The study was performed on the forearm of healthy humans, and all test substances were infused into the brachial artery at systemically ineffective rates. In five subjects, we evaluated isoproterenol-induced vasodilation (1, 3, 6, and 9 ng. kg-1. min-1) both under control conditions and during insulin infusion (0.05 mU. kg-1. min-1). In another group of five subjects, we tested whether the vasorelaxant effect of sodium nitroprusside (1, 2, 4, and 8 ng . kg-1 . min-1) was modified by insulin. Moreover, to explore whether the interaction between insulin and forearm beta-adrenergic pathway participates in insulin modulation of sympathetic-evoked vasoconstriction, we measured in six normal subjects the forearm vascular response to lower-body negative pressure under control conditions and during intrabrachial infusion of insulin alone and in combination with a selective beta-adrenergic blocking agent (propranolol 10 micrograms/100 mL per minute). Finally, to verify whether insulin interaction with the beta-adrenergic pathway may also account for insulin modulation of alpha 2-adrenergic vasoconstriction, we assessed the vascular response to a selective alpha 2-adrenergic agonist before and after propranolol administration. Insulin exposure potentiated the vascular responsiveness to isoproterenol but did not affect the vasodilator response to sodium nitroprusside. Furthermore, the insulin-induced attenuation of sympathetic vasoconstriction was partially corrected by propranolol. In contrast, the insulin modulation of alpha 2-adrenergic vasoconstriction was not influenced by beta-adrenergic blockade. CONCLUSIONS: Taken together, our results suggest that insulin modulation of sympathetic-induced vasoconstriction is carried out through an interaction of the hormone with the pathways of both alpha 2-and beta -adrenergic receptors.

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)

Forearm muscle insulin resistance during hypoglycemia: role of adrenergic mechanisms and hypoglycemia per se.

The forearm perfusion technique was used 1) to quantify the muscle metabolism of glucose and gluconeogenic precursors in response to insulin-induced hypoglycemia and 2) to assess the role of catecholamines and glucose concentration, pe se. Insulin (0.5 mU.kg-1.min-1) was infused for 4 h in three groups of healthy volunteers. In group I (n = 6), blood glucose (BG) was maintained at its basal level (4.5 +/- 0.1 mmol/l). In group II (n = 7), BG was allowed to fall to approximately 3 mmol/l. Group III (n = 6) was similar to group II except that propranolol was infused also. In addition, at 240 min, hypoglycemia was locally corrected by intrabrachial glucose infusion while maintaining the systemic milieu unperturbed. In group I, forearm glucose uptake (FGU) increased from 4.7 +/- 1.3 to a mean value of 37.8 +/- 5.0 mumol.l-1.min-1, whereas in group II it remained unchanged (8.3 +/- 2.0 mumol.l-1.min-1). In group III, propranolol partially prevented the suppression of FGU that increased to 21.6 +/- 5.2 mumol.l-1.min-1 (P < 0.05 vs. group II). Local correction of hypoglycemia normalized the FGU response (36.5 +/- 8.0 mumol.l-1.min-1). Muscle release of lactate, but not of alanine, was slightly higher during hypoglycemia (P = not significant). Forearm blood flow remained unchanged in groups I and III, whereas it increased by approximately 40% in group II (P < 0.05). It is concluded that, during mild hypoglycemia 1) extreme insulin resistance develops in the skeletal muscle, mediated by beta-adrenergic stimulation and reduced glucose mass effect and 2) mobilization of gluconeogenic precursors is only weakly activated.

[Non-hemodynamic mechanisms of cardiovascular risk in the hypertensive patient: insulin resistance]. / Rischio cardiovascolare nel paziente iperteso, i meccanismi non emodinamici: l'insulino-resistenza.

Insulin resistance is a condition which is present in many different diseases all characterized by an increased risk of cardiovascular morbidity and mortality. Generally, the contribution of insulin resistance to the development of cardiovascular pathology is considered to be due to its metabolic consequences. However, recent findings suggest alternative mechanisms by which insulin resistance could exert its role of cardiovascular risk factor. In fact, it has been demonstrated that insulin resistant hypertensive patients have a sympathetic response to euglycemic hyperinsulinemia which is three-fold greater than in normal subjects. This phenomenon could represent an important link between sympathetic nervous system and arterial hypertension. Furthermore, in normal subjects it has been demonstrated that hyperinsulinemia modulates the sympathetic induced vascular response and that this effect is lost in insulin resistant hypertensives. This latter phenomenon could further worsen the consequences of sympathetic overactivity.

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.

Forearm vascular responsiveness to alpha 1- and alpha 2-adrenoceptor stimulation in patients with congestive heart failure.

BACKGROUND: The alpha-adrenergic component of the sympathetic nervous system plays a major role in the pathophysiology, clinical manifestations, and natural history of human congestive heart failure (CHF). However, the functional integrity of vascular alpha 1- and alpha 2-adrenoceptors in CHF remains to be elucidated. The present study was designed to assess the vascular responsiveness of alpha 1- and alpha 2-adrenoceptors in patients with CHF. METHODS AND RESULTS: To evaluate alpha 1- and alpha 2-adrenoceptor responsiveness, we studied the effects of the regional infusion into the brachial artery of increasing doses of phenylephrine (a selective alpha 1-adrenoceptor agonist) and BHT 933 (a selective alpha 2-adrenoceptor agonist) on vascular responses in 12 healthy subjects and in 24 patients with CHF secondary to primary dilated cardiomyopathy or ischemic heart disease. Left ventricular ejection fraction was measured by radionuclide angiography, and forearm blood flow was determined by venous occlusion plethysmography. Phenylephrine reduced forearm blood flow in normal subjects from 5.2 +/- 0.9 to 2.5 +/- 0.6 mL per 100 mL of tissue/min (P < .05) at the highest dose (-50.8 +/- 4.8% versus baseline). A similar vasoconstriction was obtained in patients with CHF (from 3.5 +/- 0.5 to 1.5 +/- 0.2 mL per 100 mL of tissue/min (P < .05) (-58.7 +/- 5.0% versus baseline). The dose-response curves produced by phenylephrine in the two groups were comparable. The highest dose of BHT 933 reduced forearm blood flow in normal subjects from 5.3 +/- 0.9 to 2.3 +/- 0.6 mL per 100 mL of tissue/min (P < .05) (-59.0 +/- 4.9% versus baseline). In patients with CHF, a similar vasoconstriction was obtained (from 4.2 +/- 0.8 to 1.5 +/- 0.3 mL per 100 mL of tissue/min, P < .05, -62.1 +/- 6.5% versus baseline). The dose-response curves produced by BHT 933 also were comparable in the two groups. In patients with CHF, plasma concentrations of norepinephrine were significantly higher than in normal subjects. CONCLUSIONS: The results of the present study demonstrate that alpha 1- and alpha 2-adrenoceptor stimulations produced an equivalent vasoconstriction in patients with CHF and in normal subjects. This indicates that the vascular responsiveness to alpha-adrenoceptor agonists may be preserved in the limb vessels of patients with CHF.

Acute noradrenergic activation induces insulin resistance in human skeletal muscle.

We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (approximately 60 microU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 +/- 1 to 7.94 +/- 1.33 ng.l-1.min-1; P < 0.05). Forearm glucose uptake rose from 0.97 +/- 0.13 to 5.2 +/- 0.2 mg.l-1.min-1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 +/- 0.52 to 12.7 +/- 1.46 ng.l-1.min-1; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 +/- 0.10 to 3.2 +/- 0.7 mg.l-1.min-1; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE.

Trandolapril in patients with essential hypertension: effects on vascular and cardiac structural changes.

Elevated arterial pressure levels increase the hemodynamic load on heart and vessels, thus leading to functional and structural abnormalities. Because cardiac and vascular changes increase the risk of cardiovascular disease, their reversal is an important target of antihypertensive therapy, even though the prognostic value of this regression has not been fully established. In patients with untreated mild-to-moderate essential hypertension and left ventricular hypertrophy, trandolapril, a new angiotensin-converting enzyme inhibitor, reduces blood pressure by decreasing total peripheral resistance and improves both systolic and diastolic ventricular function. The latter effect is not only functional in nature because, after long-term antihypertensive treatment, the improvement in diastolic ventricular function is detectable also after 1-month withdrawal of trandolapril. The concurrent reversal of left ventricular hypertrophy may contribute to the improved left ventricular diastolic function. However, plethysmographic studies suggest that long-term antihypertensive treatment with trandolapril is also able to reverse structural vascular changes in the forearm vascular bed, because after 1-month washout forearm peripheral resistance also is lower than in control conditions. Finally, in hypertensive patients, trandolapril induces significant increases in brachial artery compliance and diameter that persist after 1 month of withdrawal from treatment. The latter observation suggests that trandolapril also is able to reverse the structural changes of the large artery wall.(ABSTRACT TRUNCATED AT 250 WORDS)

Digitalis restores the forearm sympathetic response to cardiopulmonary receptor unloading in hypertensive patients with left ventricular hypertrophy.

OBJECTIVE: To investigate whether the impaired reflex response to cardiopulmonary baroreceptor unloading in hypertensive patients with left ventricular hypertrophy can be promptly improved by a pharmacological challenge. For this purpose we studied the effects of acute digitalis administration on cardiopulmonary baroreflex, evaluated by forearm noradrenaline spillover. METHODS: Eleven hypertensives with left ventricular hypertrophy and 10 age- and sex-matched normotensives underwent the application of -5 and -10 mmHg lower-body negative pressure (LBNP) before and after the administration of digitalis. Forearm noradrenaline spillover, measured using a tracer technique, was used to estimate the reflex sympathetic response. RESULTS: Under control conditions LBNP evoked a similar fall in right atrial pressure in the two study groups. In the normotensives there was a significant increase in forearm noradrenaline spillover. In the hypertensives no significant changes in forearm noradrenaline spillover were found. Intravenous administration of 0.02 mg/kg lanatoside C was associated with an increase in systolic blood pressure and a reduction in forearm noradrenaline spillover in both groups. In the normotensives the percentage change in forearm noradrenaline spillover induced by LBNP increased significantly in response to digitalis administration. However, digitalis restored the response of forearm noradrenaline spillover to LBNP in the hypertensives, so that no significant difference in this response was detected between the two study groups. Digitalis did not modify the effects of LBNP on cardiac pressures in either group. CONCLUSIONS: The present results demonstrate that administration of lanatoside C restores the response of forearm noradrenaline spillover to cardiopulmonary baroreceptor unloading in hypertensive patients with left ventricular hypertrophy. This indicates that the impairment of cardiopulmonary baroreflexes in these patients can be reversed by acute pharmacological treatment. Therefore, impairment of this reflex response seems to be related to functional rather than to structural abnormalities of the hypertrophied ventricle.

Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure.

BACKGROUND: Sodium retention and hormonal activation are fundamental hallmarks in congestive heart failure. The present study was designed to assess the ability of patients with asymptomatic to mildly symptomatic heart failure and no signs or symptoms of congestion to excrete ingested sodium and to identify possible early abnormalities of hormonal and hemodynamic mechanisms related to sodium handling. METHODS AND RESULTS: The effects of a high salt diet (250 mEq/day for 6 days) on hemodynamics, salt-regulating hormones, and renal excretory response were investigated in a balanced study in 12 untreated patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (NYHA class I-II, ejection fraction < 50%) (HF) and in 12 normal subjects, who had been previously maintained a 100 mEq/day NaCl diet. In normal subjects, high salt diet was associated with significant increases of echocardiographically measured left ventricular end-diastolic volume, ejection fraction, and stroke volume (all P < .001) and with a reduction of total peripheral resistance (P < .001). In addition, plasma atrial natriuretic factor (ANF) levels increased (P < .05), and plasma renin activity and aldosterone concentrations fell (both P < .001) in normals in response to salt excess. In HF patients, both left ventricular end-diastolic and end-systolic volumes increased in response to high salt diet, whereas ejection fraction and stroke volume failed to increase, and total peripheral resistance did not change during high salt diet. In addition, plasma ANF levels did not rise in HF in response to salt loading, whereas plasma renin activity and aldosterone concentrations were as much suppressed as in normals. Although urinary sodium excretions were not significantly different in the two groups, there was a small but systematic reduction of daily sodium excretion in HF, which resulted in a significantly higher cumulative sodium balance in HF than in normals during the high salt diet period (P < .001). CONCLUSIONS: These results show a reduced ability to excrete a sodium load and early abnormalities of cardiac and hemodynamic adaptations to salt excess in patients with mild heart failure and no signs or symptoms of congestion.

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.

Angiotensin converting enzyme inhibition restores cardiac and hormonal responses to volume overload in patients with dilated cardiomyopathy and mild heart failure.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibition exerts a favorable effect on the response to exercise in heart failure. This study was planned to define the influence of ACE inhibition on the adaptation to volume overload. METHODS AND RESULTS: We studied the hemodynamic, hormonal, and renal responses to acute volume expansion (sodium chloride, 0.9%, 0.25 ml.kg-1.min-1 for 2 hours) in patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (New York Heart Association class I or II, ejection fraction < or = 50%). The patients were studied without any pretreatment (n = 14) or after 1 week of treatment with the oral ACE inhibitor quinapril at a dosage of 10 mg/day (n = 11). Seven patients were studied during constant intravenous infusion with nitroglycerin (0.1 micrograms.kg-1.min-1). The study groups had similar hemodynamic and clinical characteristics and hormonal profile at baseline evaluation. In the untreated patients, volume expansion did not increase left ventricular end-diastolic volume measured by echocardiography and was associated with a reduction in ejection fraction (p < 0.05) and with a paradoxical increase in forearm vascular resistance (p < 0.05) estimated by plethysmography. In addition, plasma atrial natriuretic factor did not change, and plasma norepinephrine was increased by saline loading. In contrast, in the patients treated with quinapril, volume expansion induced an increase of both left ventricular volumes (p < 0.001) without changing ejection fraction and reduced forearm vascular resistance (p < 0.05). In addition, in this group, plasma atrial natriuretic factor levels increased (p < 0.05) and plasma norepinephrine did not change during volume overload. During nitroglycerin infusion, volume expansion was associated with peripheral vasodilatation, increases of left ventricular volumes, and no change in ejection fraction. In this group, however, plasma atrial natriuretic factor levels did not change in response to volume overload. CONCLUSIONS: We conclude that pretreatment with the ACE inhibitor quinapril significantly improves compromised responses to acute isotonic volume overload in patients with dilated cardiomyopathy and mild heart failure. The favorable influence of ACE inhibition on cardiovascular and hormonal responses to volume expansion seems to be related to the cardiac unloading produced by this treatment.

Role of alpha 2-adrenoceptors in normal and atherosclerotic human coronary circulation.

BACKGROUND: Experimental studies on the effects of alpha 2-adrenoceptors on regional coronary blood flow in normal and ischemic myocardium are highly controversial. A beneficial effect on regional ischemic myocardium has been demonstrated in different animal preparations with either alpha 2-adrenoceptor blockade or stimulation. Animal studies also demonstrated that postsynaptic alpha 2-adrenoceptors mediate vasoconstriction in coronary and femoral vascular beds. The aims of the study were 1) to investigate the effects of regional alpha 2-adrenoceptor stimulation on regional coronary blood flow in subjects with angiographically normal coronary arteries, 2) to assess the effect of alpha 2-adrenoceptor blockade on coronary circulation in control subjects, and 3) to examine the influence of atherosclerosis on coronary blood flow response to alpha 2-adrenoceptor blockade. METHODS AND RESULTS: The effect of regional administration of BHT 933 (a selective alpha 2-adrenoceptor agonist) was studied in eight subjects with angiographically normal coronary arteries. The coronary blood flow velocity was measured using a subselective intracoronary 3F Doppler catheter and coronary diameter by quantitative coronary angiography. BHT 933 induced a reduction in coronary artery diameter from 2.5 +/- 0.6 mm to 1.8 +/- 0.4 mm (p less than 0.05) as well as in coronary blood flow velocity (from 6.4 +/- 0.9 cm/sec to 4.6 +/- 1.9 cm/sec, p less than 0.01). In some subjects, ST segment abnormalities occurred. In patients with angiographically normal coronary arteries (n = 6), the regional infusion of a selective alpha 2-adrenoceptor blocking agent after beta-blockade did not change coronary diameter or coronary blood flow velocity. In contrast, in patients with significant coronary stenoses (n = 6), regional infusion of an alpha 2-adrenoceptor blocking agent reduced regional coronary artery diameter (from 2.3 +/- 0.5 mm to 2.1 +/- 0.6 mm, p less than 0.01) as well as coronary blood flow velocity (from 5.8 +/- 0.8 cm/sec to 3.7 +/- 0.6 cm/sec, p less than 0.05); in addition, alpha 2-adrenoceptor blockade significantly increased coronary sinus plasma norepinephrine levels (from 300 +/- 144 pg/ml to 429 +/- 207 pg/ml, p less than 0.01). CONCLUSIONS: The selective in vivo stimulation of alpha 2-adrenoceptors produces a reduction in coronary blood flow and diameter in humans with angiographically normal coronary arteries. alpha 2-Adrenergic blockade does not change coronary blood flow in subjects with angiographically normal coronary arteries (suggesting no resting alpha 2-adrenergic vasoconstrictor tone), whereas in patients with coronary artery stenosis, regional coronary blood flow decreases after alpha 2-receptor blockade. Finally, our data also suggest that alpha 2-adrenoceptors participate in the modulation of sympathetic neuronal norepinephrine release in the human heart.

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.

Skeletal muscle is a primary site of insulin resistance in essential hypertension.

To determine the contribution of skeletal muscle to the insulin resistance of essential hypertension, insulin-stimulated forearm glucose uptake was quantitated in 12 control (age, 32 +/- 3 years) and 12 hypertensive subjects (age, 36 +/- 2 years) using the forearm perfusion technique. Peripheral insulin levels were raised acutely (approximately 60 microU/mL), while blood glucose concentration was clamped at its basal value (90 mg/dL) by a variable glucose infusion. During insulin stimulation, whole body glucose uptake was lower in hypertensive (4.5 +/- .3 mg.kg-1.min-1) than in normal subjects (5.8 +/- .4 mg.kg-1.min-1, P less than .05). Similarly, the amount of glucose taken up by the forearm was markedly reduced in the hypertensive (5.3 +/- .91 mg.L-1.min-1) compared with the control group (8.7 +/- 1.1 mg.L-1.min-1). No appreciable difference was observed as to forearm blood flow (39 +/- 4 mL.L-1.min-1 and 37 +/- 5 mL.L-1.min-1) in hypertensive patients. These results indicate that skeletal muscle is a major site of insulin resistance in essential hypertension and that this defect is independent of muscle perfusion.

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)

Abnormal hormonal and renal responses to saline load in hypertensive patients with parental history of cardiovascular accidents.

BACKGROUND: Acute cardiac and cerebrovascular accidents are more frequent in hypertensive subjects with a family history of acute vascular accidents. The mechanisms underlying the susceptibility to vascular disease in these subjects are unknown. We investigated whether a parental history of premature heart attack or stroke in hypertensive subjects is associated with abnormalities of sodium handling. METHODS AND RESULTS: Patients with mild, uncomplicated essential hypertension were divided into two subgroups according to family history: a subgroup with a parental history of premature heart attack or stroke (FV+, n = 18) and a subgroup with a family history completely negative for vascular accidents (FV-, n = 14). The two subgroups were comparable with respect to age, weight, sex distribution, blood pressure, duration of hypertension, cardiovascular risk factors, renal function, and organ damage. Baseline plasma renin activity (PRA), concentrations of aldosterone (PA), atrial natriuretic factor (ANF), and norepinephrine, and urinary electrolyte excretion were also comparable in the two subgroups. Despite these similarities, the responses to an acute saline load, measured under controlled metabolic and experimental conditions, were different in the two subgroups. In the FV+ subgroup at 60 minutes of saline load, PRA fell by 1.0 +/- 0.2 ng/ml/hr and PA concentration by 89.4 +/- 26 pg/ml and ANF concentration increased by 38 +/- 9 pg/ml, whereas in the FV- subgroup the corresponding responses were -2.3 +/- 0.3 ng/ml/hr (p less than 0.005), -190 +/- 43 pg/ml (p less than 0.05), and 80 +/- 13 pg/ml (p less than 0.005), respectively. Urinary sodium excretion was delayed in the FV+ subgroup (270 +/- 67 mu eq/min at 60 minutes) compared with the FV- subgroup (555 +/- 157 mu eq/min at 60 minutes, p less than 0.05). At 120 minutes of saline load, significant (p less than 0.005) differences in PRA and ANF concentration were still observed. In a control group of eight normal subjects the responses to a saline load were comparable to those in the FV- subgroup but greater than those in the FV+ subgroup at 60 minutes. CONCLUSIONS: These results provide evidence that the hormonal and renal adjustments to an acute salt load are impaired in hypertensive patients with a parental history of vascular accidents. We speculate that abnormalities of sodium handling may represent markers of a more rapid development of vascular injury in human hypertension.