Glycemic Modulation of Insulin/IGF-1 Mediated Skeletal Muscle Blood Following Sympathetic Denervation in Normal Rats

Both insulin and IGF-1 decrease vascular resistance and increase blood flow in skeletal muscle, and it has been suggested that the mechanistic action for insulin may be by increasing autonomic vasodilatory activity. In this study we evaluated the effects of insulin and IGF-1 on blood flow to denervated and non-denervated skeletal muscle as part of a continuing investigation into the mechanism of regulation of cardiovascular responses by these hormones. Normal rats were prepared for measurements of mean arterial pressure (MAP), heart rate (HR) and vascular flow in the left and right ijiac artery. Resection of the left lumbar sympathetic chain increased flow (expressed as conductance, flow/MAP) in the denervated left iliac but not in the intact right artery. Subsequent insulin infusion where hypoglycemia was allowed to occur increased conductance in both arteries, but more so in the denervated artery. Similarly, IGF-1 infusion increased conductances in both intact and denervated iliac arteries, and the effect was slightly greater in the denervated artery. Insulin infusion when euglycemia was maintained increased conductance to a similar extent in denervated and intact iliac arteries. Contrastingly, IGF-1 infusion under euglycemic conditions resulted in a much greater increased conductance in the intact iliac.     

The effect of the removal of the area postrema on insulin and IGF-1-induced cardiovascular and sympathetic nervous responses

Previous studies have demonstrated that insulin and IGF-1 both increase lumbar sympathetic nerve activity (LSNA) and decrease mean arterial pressure (MAP). We hypothesized that the peripheral responses to insulin and IGF-1 are mediated, at least in part, via the central nervous system. In this study we determined the effects of the peripheral administration of both insulin and IGF-1 on cardiovascular dynamics and LSNA following removal of the area postrema (APX), a major site of blood-brain communication. Insulin infusion in normal rats decreased MAP but increased HR and LSNA. When insulin was infused in APX rats it also decreased the MAP but the MAP recovered rapidly and plateaued at a level equivalent to normals after 40 min. Insulin significantly increased the HR and LSNA in the APX rats compared to normals. However, when hypoglycemia was prevented by glucose infusion, the HR and LSNA responses to insulin in the APX rats were similar to normals. IGF-1 also decreased MAP and to a greater extent in the APX rats compared to normals but the increased LSNA in APX rats was equivalent to normals. The APX rats when compared to normals had a greater sensitivity to insulin-induced hypoglycemia while IGF-1 decreased the plasma glucose to a lesser degree in APX rats. We conclude that insulin and IGF-1 entry into the CNS at least via the area postrema does not contribute significantly to the hypotensive response and that the greater depressor response to IGF-1 is likely due to enhanced vascular sensitivity in APX rats. The increased HR and LSNA following insulin were likely mediated by an increased reflexive response to hypoglycemia.     

Cardiovascular action of insulin-like growth factor-1 is not mediated by calcitonin gene-related peptide neurons

Calcitonin gene-related peptide (CGRP) is a potent vasodilator located in the peripheral nerves including the perivascular nerves. Previous studies in our laboratory determined that the vasodilatory action of insulin is mediated in part by CGRP-containing neurons. Since insulin-like growth factor-1 (IGF-1) and insulin share molecular and receptor structural similarity as well as functional similarity, we investigated the role of the CGRP-containing neurons in IGF-1-mediated vasodilation. Wistar rats were made CGRP deficient by treatment with capsaicin (50 mg/kg) 1-3 d after birth. Vehicle-treated controls and CGRP-deficient rats were maintained for 12 to 13 wk. At this time rats were fasted overnight, anesthetized with urethane and chloralose, and prepared for cardiovascular recordings. The basal mean arterial pressure (MAP) was higher in CGRP-deficient rats when compared with controls. The infusion of IGF-1 resulted in an equivalent decrease in MAP in both the CGRP-deficient and control rats. IGF-1 infusion did not change the heart rate in control rats but decreased it in CGRP-deficient rats. IGF-1 also increased flow as determined by conductance in the iliac, renal, and superior mesenteric vascular beds in both vehicle controls and CGRP-deficient rats. We concluded that unlike insulin the IGF-1-mediated vasodilatory response is not mediated by the CGRP-dependent perivascular neurons.     

Effects of general and selective β-adrenergic antagonists on insulin-induced cardiac and selected vascular responses in rats

Insulin administration results in vasodilation, decreased mean arterial blood pressure (MAP) and increased conductances (flow/MAP) in various vascular beds. β-adrenergic blockers antagonize this response, but the mechanism of the interplay between insulin-induced vasodilation and β-adrenergic antagonism is unknown. In this study, we evaluated the effects of β-blockade using the selective β₂ antagonist ICI 118551 or the general β-antagonist propranolol on insulin-induced cardiac and regional flow responses in normal rats. Insulin-induced responses were also examined following adrenalectomy. Rats were anaesthetized and the femoral vein and artery were cannulated for infusions, sampling or monitoring of MAP and heart rate (HR). The iliac, renal, and superior mesentery arteries were equipped with pulsed-Doppler flow probes. Blood samples were collected at selected intervals. Insulin decreased blood glucose, MAP and increased conductances. Pretreatment with propranolol not only antagonized the insulin-induced decrease in MAP and increased conductance but insulin also then increased MAP and decreased conductances. ICI 11851, like propranolol, antagonized the insulin-induced decrease in MAP and increased iliac and renal artery conductances. Adrenalectomy did not alter the maximum insulin-induced effects on MAP and conductances but prevented the rebound recovery phase. β-blockade following adrenalectomy had the same effects as β-blockade alone on the insulin-induced responses. We conclude that the insulin-induced decrease in MAP and the increased flow in the selective vascular beds are modulated by a sympathetic β₂-receptor-mediated pathway and this response is not due primarily to the release of adrenal catecholamine. Received: 13 July 1998 / Accepted in revised form: 2 March 1999     

Regulation and counterregulation of lipolysis in vivo: different roles of sympathetic activation and insulin

To obtain further information on the regulation of lipolysis in vivo, the effect of increasing sympathetic nerve activity via lower body negative pressure (LBNP, -20 mm Hg) was studied in 11 healthy human subjects. Subcutaneous and muscle microdialysis as well as blood flow measurements were performed in the postabsorptive state and during an euglycemic hyperinsulinemic clamp. LBNP for 30 min in the postabsorptive phase resulted in an approximately 50% increase (P < 0.005) in the interstitial-arterial concentration difference for glycerol in adipose tissue, whereas no such effect was registered in muscle. Blood flow in adipose tissue and the forearm remained unaltered. During euglycemic hyperinsulinemic conditions (p-insulin 645 +/- 62 pmol/liter), both interstitial adipose tissue and arterial concentrations of glycerol were reduced. LBNP resulted in an increase in interstitial-arterial concentration difference in glycerol similar to that seen in the postabsorptive state (approximately 50%, P < 0.05). Muscle glycerol was not changed by either insulin or LBNP. Glucose infusion rate during the clamp was significantly decreased during LBNP (7.82 +/- 0.88 vs. 8.67 +/- 1.1 ml/kg.min, P < 0.05). We conclude that the sympathetic nervous activation by LBNP results in an increased lipolysis rate in adipose tissue both in the postabsorptive phase and during insulin infusion. On the other hand, muscle glycerol output was not affected by either LBNP or insulin. The data suggest that 1) lipolysis is regulated differently in muscle and adipose tissue, 2) postabsorptive lipolysis is mainly regulated by insulin, and 3) sympathetic nervous activation effectively inhibits the antilipolytic action of insulin by inducing insulin resistance.     

Failure of acute hyperinsulinemia to alter blood pressure is not due to baroreceptor feedback

It is well documented that acute insulin administration stimulates the sympathetic nervous system in both humans and animals. Despite marked sympathetic activation during acute hyperinsulinemia, blood pressure is generally not increased because it is overridden by the vasodilator action of insulin. The maintenance of blood pressure in the face of sympathetic activation is unknown. A possible mechanism includes feedback regulation by the baroreceptor reflex arc. In normotensive states, hyperinsulinemic-induced sympathetic activation may tend to elevate blood pressure, but this change is rapidly sensed by the baroreceptors in the carotid arteries (and aortic arch), and a counterbalancing increase in vasodilation could return blood pressure to normal. Thus, it can be speculated that, in the event of diminished baroreceptor sensitivity and suppressed vasodilator actions of insulin, common abnormalities in hypertension, acute insulin infusion would be expected to increase blood pressure.We undertook the present study to determine whether the baroreceptor reflex arc modulated the blood pressure response to acute hyperinsulinemia. To this end, six normotensive dogs underwent saline or insulin infusions before and after deactivation of the carotid and aortic baroreceptors. Baroreceptor dysfunction was documented after denervation in all cases by an abnormal response to phenylephrine injections. Before denervation, insulin infusions caused a slight but nonsignificant rise in mean arterial pressure (MAP; 110 ± 5 to 120 ± 5 mm Hg; P = 0.13). Baroreceptor denervation caused a marked variability in blood pressure. However, basal mean arterial pressure was not significantly altered. Neither saline nor insulin infusions (105 ± 10 v 105 ± 8 mm Hg, basal v steady state) caused a significant change in MAP in denervated dogs. Likewise, insulin and saline did not change heart rates significantly in intact or denervated animals. Furthermore, glucose metabolism was similar in both groups of animals. This study demonstrates that the baroreceptor reflex arc does not mediate the blood pressure response to acute hyperinsulinemia.     

Neurogenic histaminergic vasodilation in canine skeletal muscle: mediation by alpha 2-adrenoceptor stimulation

This study examines the neurogenic effect of alpha 2-adrenoceptor stimulation on skeletal muscle vascular resistance and its relation to the level of background sympathetic activity. The isolated, separately perfused, neurally intact canine gracilis muscle preparation was used since it permits deliberate and quantifiable alterations in background sympathetic activity, as measured by skeletal muscle vascular resistance. Systemic intravenous UK-14304, a highly selective alpha 2-adrenoceptor agonist, produced a precipitous, neurogenic vasodilation that lowered vascular resistance below the subsequently denervated resistance, thus indicating that an active vasodilation was involved. The overall magnitude of the vasodilation was much greater in animals that had been hemorrhaged to elevate background sympathetic activity than in animals that had been transfused to lower background activity. The neurogenic vasodilation was unaffected by baroreceptor and cardiopulmonary receptor denervation and by prior cholinergic-receptor blockade of the gracilis muscle. Prior H1- and H2-histaminergic-receptor blockade, on the other hand, eliminated the active vasodilation but not a vasodilation down to the subsequently denervated resistance. Prior alpha 1-adrenoceptor blockade lowered resistance down to the subsequently denervated resistance and greatly attenuated the active vasodilation. The present study demonstrates that withdrawal of sympathetic activity by alpha 2-adrenoceptor stimulation produces an active vasodilation resulting from histamine release in skeletal muscle as well as a passive vasodilation resulting from lysis of peripheral vasoconstrictor tone.     

Basal NO locally modulates human iliac artery function in vivo

We demonstrated previously that endogenous NO influences large-artery distensibility in the ovine hindlimb. However, the role of basal NO in larger human conduit arteries is controversial. The aim of this study was to investigate whether basal production of NO, acting locally, influences iliac artery distensibility in humans. Distensibility was assessed by intra-arterial measurement of the pulse wave velocity. Eighteen subjects, free of significant coronary or iliac artery disease, were studied after diagnostic cardiac catheterization. Simultaneous pressure waveforms were recorded with a high-fidelity dual-pressure sensing catheter, placed in the common iliac artery during intra-arterial infusion of saline (baseline), glyceryl trinitrate (4 nmol/min), or NG-monomethyl-L-arginine (8 and 16 micromol/min). Drugs were infused proximally, via the catheter to perfuse the segment of artery under study, or distally, via the sheath, to control for any reflex changes in flow or sympathetic activation. Velocity was calculated using the foot-to-foot methodology. Six subjects received glyceryl trinitrate and 12 NG-monomethyl-L-arginine. There was no change in velocity after infusion of glyceryl trinitrate or NG-monomethyl-L-arginine via the sheath. However, infusion of glyceryl trinitrate via the catheter significantly reduced velocity by 31.43+/-5.80% (mean+/-SEM; P<0.01; P=0.02 for comparison). Likewise, infusion of the highest dose of NG-monomethyl-L-arginine via the catheter significantly increased velocity by 27.25+/-8.20% (P=0.001; P=0.02 for comparison). Importantly, there was no change in mean arterial blood pressure throughout the studies. These data indicate that under resting conditions, local NO production modulates human iliac artery distensibility and that exogenous NO increases arterial distensibility.     

Rosiglitazone improves muscle insulin sensitivity,irrespective of increased triglyceride content,in ob/ob mice

The present study was performed to examine the effects of rosiglitazone treatment on tissue-specific insulin sensitivity. Therefore, we used obese, insulin-resistant ob/ob mice and measured the effects of rosiglitazone treatment on insulin sensitivity and simultaneously tissue-specific uptake of glucose and free fatty acids (FFA) under hyperinsulinemic euglycemic clamp conditions. Rosiglitazone treatment resulted in significantly higher body weight and decreased plasma levels of glucose, insulin, and triglyceride (TG). Glucose tolerance, as well as insulin sensitivity, was improved upon rosiglitazone treatment, as assessed by glucose tolerance and insulin sensitivity tests. Hyperinsulinemic euglycemic clamps showed increased glucose infusion rates with increased whole body insulin sensitivity. Rosiglitazone treatment resulted in increased glucose uptake by cardiac and skeletal muscle under hyperinsulinemic euglycemic clamp conditions, while no differences were observed in FA uptake. Measurement of TG content showed that rosiglitazone treatment resulted in decreased TG content of cardiac muscle, but increased TG content of skeletal muscle. We conclude that rosiglitazone treatment leads to strong improvement of insulin sensitivity, irrespective of increased muscle TG content, in ob/ob mice.     

Exogenous angiotensin II does not facilitate norepinephrine release in the heart

Studies on the effect of angiotensin II on norepinephrine release from sympathetic nerve terminals through stimulation of presynaptic angiotensin II type 1 receptors are equivocal. Furthermore, evidence that angiotensin II activates the cardiac sympathetic nervous system in vivo is scarce or indirect. In the intact porcine heart, we investigated whether angiotensin II increases norepinephrine concentrations in the myocardial interstitial fluid (NE(MIF)) under basal conditions and during sympathetic activation and whether it enhances exocytotic and nonexocytotic ischemia-induced norepinephrine release. In 27 anesthetized pigs, NE(MIF) was measured in the left ventricular myocardium using the microdialysis technique. Local infusion of angiotensin II into the left anterior descending coronary artery (LAD) at consecutive rates of 0.05, 0.5, and 5 ng/kg per minute did not affect NE(MIF), LAD flow, left ventricular dP/dt(max), and arterial pressure despite large increments in coronary arterial and venous angiotensin II concentrations. In the presence of neuronal reuptake inhibition and alpha-adrenergic receptor blockade, left stellate ganglion stimulation increased NE(MIF) from 2.7+/-0.3 to 7.3+/-1.2 before, and from 2.3+/-0.4 to 6.9+/-1.3 nmol/L during, infusion of 0.5 ng/kg per minute angiotensin II. Sixty minutes of 70% LAD flow reduction caused a progressive increase in NE(MIF) from 0.9+/-0.1 to 16+/-6 nmol/L, which was not enhanced by concomitant infusion of 0.5 ng/kg per minute angiotensin II. In conclusion, we did not observe any facilitation of cardiac norepinephrine release by angiotensin II under basal conditions and during either physiological (ganglion stimulation) or pathophysiological (acute ischemia) sympathetic activation. Hence, angiotensin II is not a local mediator of cardiac sympathetic activity in the in vivo porcine heart.     

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 activation of pyruvate dehydrogenase complex is enhanced by exercise training.

We studied the effects of exercise training on the activity of the pyruvate dehydrogenase (PDH) complex in rat gastrocnemius muscle (experiment 1) and the response of the complex to glucose and insulin infusion (euglycemic clamp) in trained and sedentary rats (experiment 2). In experiment 1, half of the rats were randomly allocated as sedentary animals and the other half were trained by voluntary running exercise for 8 weeks. The total activity of the PDH complex was not affected by exercise training, and the activity state (proportion of the active form) of the PDH complex was decreased from 15.0%+/-2.4% to 7.5%+/-1.1% by exercise training. The activity of 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase ([3-HADH] an enzyme in beta-oxidation) was significantly higher in trained versus sedentary rats. In experiment 2, sedentary and trained rats were starved for 24 hours before performing the euglycemic clamp. Glucose and insulin infusion was performed by a euglycemic clamp (insulin infusion rate, 6 mU/kg/min) for 90 minutes. The PDH complex was inactivated to less than 1% in both sedentary and trained rats after 24 hours of starvation. The glucose infusion rate (GIR) during the euglycemic clamp was higher in trained versus sedentary rats. The euglycemic clamp resulted in activation of the PDH complex in both sedentary and trained rats, but the response of the PDH complex to the euglycemic clamp was significantly higher in trained rats (5.8%+/-0.5%) than in sedentary rats (2.9%+/-0.5%). These results suggest that exercise training promotes fatty acid oxidation in association with suppression of glucose oxidation in skeletal muscle under resting conditions, but increases the rate of carbohydrate oxidation when glucose flux into muscle cells is stimulated by insulin.     

Impaired modulation of sympathetic vasoconstriction in contracting skeletal muscle of rats with chronic myocardial infarctions: role of oxidative stress

Skeletal muscle perfusion during exercise is impaired in heart failure, but the underlying mechanisms are poorly understood. One possibility is that sympathetic vasoconstriction is enhanced in exercising muscle in heart failure as a result of impaired counterregulatory mechanisms that normally act to attenuate vasoconstrictor responses. In healthy animals, sympathetic vasoconstriction in contracting skeletal muscle is attenuated by endogenously produced nitric oxide (NO). Because the NO pathway may be dysfunctional in heart failure, we hypothesized that reduced NO in contracting muscle would result in enhanced sympathetic vasoconstriction. In sham rats and rats with chronic myocardial infarctions (MIs) produced by coronary artery ligation, we measured arterial pressure and femoral artery blood flow responses to sympathetic nerve stimulation (1, 2.5, and 5 Hz) in resting and contracting hindlimb. In resting hindlimb, sympathetic stimulation decreased femoral vascular conductance similarly in sham and MI rats. In contracting hindlimb, these vasoconstrictor responses were attenuated to a greater extent in sham than in MI rats. NO synthase inhibition enhanced sympathetic vasoconstriction in contracting hindlimb of sham, but not MI, rats. Conversely, infusion of L-arginine or a superoxide scavenger, tempol or tiron, attenuated sympathetic vasoconstriction in contracting hindlimb of MI rats. NO synthase expression was similar, but malondialdehyde (a marker of free radical damage) was greater in skeletal muscle from MI than from sham rats. These data suggest that impaired metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle of MI rats is a consequence of superoxide-mediated disruption of the NO pathway.     

Effects of sympathetic nerves on collateral vessels in the limb of atherosclerotic primates

This study was performed to examine effects of sympathetic nerves on collateral vessels in the limb. We studied normal (N) and atherosclerotic (AS) cynomolgus monkeys that were fed atherogenic diet for 21 months. A common iliac artery was ligated 13 months before hemodynamic measurements. Using histofluorescence microscopy, a plexus of noradrenergic nerves was identified in the adventitia of collateral vessels. We measured blood flow to the limb with microspheres, and the pressure gradient from aorta to the iliac artery beyond the occlusion. The lumbar sympathetic chain was stimulated electrically at 3 Hz (SNS-3) and 15 Hz (SNS-15). In normal monkeys, conductance of collateral vessels (in ml/min per 100 g per 100 mm Hg) was 19 ± 3.6 (mean ± SE) during control, 14 ± 1.6 during SNS-3, and 9.8 ± 0.9 during SNS-15 (P < 0.05 vs control). In AS monkeys, collateral conductance was 12 ± 2.9 during control, 7.5 ± 1.7 during SNS-3 and 3.9 ± 1.8 during SNS-15 (P < 0.05). In summary, collateral vessels in the limb are innervated and sympathetic stimulation produces pronounced constriction of collateral vessels in both normal and atherosclerotic monkeys. Thus, the effectiveness of collateral vessels in maintaining blood flow to the limb may be compromised by increased activity of sympathetic nerves.     

Effect of insulin on plasma norepinephrine and 3,4-dihydroxyphenylalanine in obese men

Increasing evidence relates serum insulin level and blood pressure in obese individuals. Although the connection between these two factors is not established, a common presumption is that the sympathetic nervous system is somehow involved, in part, because laboratory studies demonstrate insulin stimulation of sympathetic and cardiovascular activity. Because the obese may exhibit altered responsiveness to insulin action, the current investigation compared cardiovascular and neurohumoral responses to euglycemic insulin infusion (200 mU/m2/min) in obese and lean men. At baseline, obese men displayed higher glucose and insulin levels, faster pulse rates, and elevated mean arterial pressures (MAP) than lean controls; plasma norepinephrine (NE) and 3,4-dihydroxyphenylalanine (DOPA) concentrations, however, did not differ. During insulin infusion, pulse rate increased equally in obese and lean subjects (from 69 to 78 min-1 in obese and from 56 to 66 min-1 in lean subjects), while MAP remained unchanged in both groups. Elevations in plasma NE (+85 pg/mL in obese and +109 in lean pg/mL) and reductions in plasma DOPA (-233 pg/mL in obese and -376 pg/mL in lean) did not differ between groups. Sodium excretory rate decreased during insulin infusion in lean subjects by 2.2 mEq/h but increased in obese by 5.3 mEq/h (difference in response between groups, P = .024). Thus, in these obese men, cardiovascular and sympathetic responses to insulin persist despite evidence of moderate insulin resistance; increased sympathetic activity, as a cause for the resting tachycardia and borderline hypertension at baseline, seems unlikely.     

Association between insulin resistance and reduced coronary vasoreactivity in healthy subjects

BACKGROUND: Insulin resistance appears to be an important risk factor for coronary artery disease. OBJECTIVE: To examine the role of insulin resistance on coronary vasoreactivity in healthy subjects. PATIENTS AND METHODS: Myocardial blood flow was quantitated using positron emission tomography and oxygen-15-labelled water in 10 healthy, nonobese men. The perfusion measurements were performed basally and during adenosine infusion, which has been used as a measure of coronary vasoreactivity. After perfusion measurements were taken, whole-body glucose uptake was determined using the euglycemic hyperinsulinemic clamp technique. RESULTS: Basal myocardial blood flow was 0.89+/-0.21 mL.g(-1).min(-1); adenosine significantly increased the flow to 4.00+/-1.13 mL.g(-1).min(-1). Adenosine-stimulated myocardial blood flow was inversely associated with fasting serum insulin concentration (r=-0.69, P<0.05). Concordantly, hyperemic blood flow was associated with whole-body glucose uptake during euglycemic hyperinsulinemic conditions (r=0.64, P<0.05). Basal myocardial blood flow was not affected by insulin resistance. CONCLUSION: The results of the present study demonstrate the novel finding that insulin resistance is associated with reduced coronary vasoreactivity, even in healthy subjects.     

Heterogeneous Vasomotor Responses of Coronary Conduit and Resistance Vessels in Hypertension

Objectives. The purpose of our study was to investigate the relation between conductance and resistance coronary vasomotor responsiveness in hypertensive patients without atherosclerosis.Background. Although similar in morphology, conduit and resistance coronary vessels differ importantly in size, function and local environment and appear to be differentially affected in certain disease processes, such as atherosclerosis and hypertension. However, little is known about the effect of hypertension on contiguous coronary conduit and resistance vessels in humans.Methods. Changes in coronary blood flow (a measure of resistance vessel reactivity) and coronary artery diameter (a measure of conduit vessel reactivity) were investigated in response to graded infusion of the endothelium-dependent agonist acetylcholine (ACh) in 98 patients with normal coronary arteries.Results. In 31 normotensive, euglycemic patients, conduit and resistance coronary artery responses to intracoronary infusion of ACh were significantly correlated (r = 0.73, p = 1 × 10⁻⁶), although eight patients (26%) had constriction of conduit but dilation of resistance arteries at peak effect. In 28 hypertensive patients without left ventricular hypertrophy (LVH), conduit and resistance artery responses to ACh remained significantly correlated (r = 0.5, p = 0.006), although 12 patients (43%) had discordant findings. Finally, in 39 hypertensive patients with LVH, conduit and resistance artery responses to ACh displayed the lowest correlation (r = 0.38, p = 0.02), with 22 patients (56%) demonstrating conduit artery constriction and resistance artery dilation.Conclusions. Despite angiographically normal coronary arteries, heterogeneous vasomotor responses (dilation and constriction) were demonstrated in contiguous conduit and resistance arteries in normotensive and hypertensive patients referred for cardiac catheterization because of chest pain. In addition to more severe endothelial dysfunction among conduit and resistance arteries, a greater frequency of discordant conduit and resistance artery responses and resistance vessel constriction was found with increasing severity of hypertension. Our study suggests differing mechanisms of endothelium responsiveness to ACh among conduit and resistance coronary arteries.     

Differential regional haemodynamic changes during mineralocorticoid hypertension

BACKGROUND: Primary aldosteronism is a cause of hypertension in up to 10% of hypertensive patients, but the mechanisms by which excess aldosterone raises arterial pressure remain unclear. OBJECTIVE: To investigate the systemic and regional haemodynamic changes during the development and maintenance of aldosterone-induced hypertension and the effect of sympathetic and vasopressin blockade. METHODS: Responses to intravenous infusion of aldosterone (10 microg/h) for 4 weeks were determined in five conscious sheep. The effects of sympathetic blockade with propranolol and phentolamine or vasopressin V1-receptor blockade with SR59049 were investigated in six further sheep infused with aldosterone. RESULTS: Aldosterone progressively increased the mean arterial pressure by 20 mmHg over 4 weeks (P < 0.001). The changes in cardiac output were variable between animals, resulting in no overall significant change. Total peripheral conductance was significantly decreased due to selective reductions in mesenteric conductance (from 6.17 +/- 0.27 to 4.46 +/- 0.15 ml/min per mmHg, P < 0.001) and iliac conductance (from 1.54 +/- 0.21 to 1.27 +/- 0.15 ml/min per mmHg, P < 0.001). In contrast, renal and coronary conductance were unchanged and renal blood flow increased from 290 +/- 17 to 350 +/- 28 ml/min (P < 0.01) and coronary blood flow from 34.7 +/- 3.0 to 44.6 +/- 2.5 ml/min (P < 0.05). These aldosterone-induced changes were not inhibited by sympathetic or vasopressin V1-receptor blockade. CONCLUSION: Excess aldosterone caused a slow progressive increase in arterial pressure, which in the long term depended on reduced total peripheral conductance. This resulted from vasoconstriction in the gut and skeletal muscle, but not the kidney. These effects were not mediated by the sympathetic nervous system or vasopressin.     

Effect of insulin-induced hypokalemia on lumbar sympathetic nerve activity in anesthetized rats

OBJECTIVE: Acute euglycemic hyperinsulinemia produces sympathoexcitation and a profound fall in plasma potassium levels. Because hypokalemia may activate the renin-angiotensin system to produce the observed increases in sympathetic nerve activity (SNA), the present study was designed to determine whether acute euglycemic-hyperinsulinemia in rats causes decreases in plasma potassium accompanied by increases in plasma renin activity (PRA) as well as elevations in SNA, and whether these alterations would be prevented by maintaining normokalemia with an exogenous potassium infusion. METHODS: We infused vehicle (control; n = 10) or insulin (10 mU/min) in anesthetized untreated rats (insulin; n = 11), or in rats receiving simultaneous KCl infusion (Insulin + K+; n = 10), while measuring mean arterial pressure (MAP), heart rate (HR), SNA, plasma potassium, and PRA during euglycemic clamp. RESULTS: As expected, insulin rats had a large fall in plasma potassium (4.6 +/- 0.1 to 3.9 +/- 0.1 mEq/l), contrasting with no change in the control (4.8 +/- 0.2 to 4.8 +/- 0.2 mEq/l) and insulin + K+ (4.4 +/- 0.1 to 4.6 +/- 0.2 mEq/l) groups. However, PRA levels at study completion were not different in the three experimental groups. In addition, insulin rats had large increases in lumbar SNA (194 +/- 11% from 100% baseline) compared with modest elevations in control rats (122 +/- 10%), and prevention of hypokalemia failed to affect sympathetic increases (213 +/- 20%) in insulin + K+ rats. MAP and HR did not change in any of the experimental groups. CONCLUSIONS: These findings indicate that insulin per se, rather than insulin-induced hypokalemia or hormonal and compensatory adjustments secondary to hypokalemia, is the main mechanism that triggers increases in lumbar SNA.     

Vascular and cardiac contractile reserve in the dog heart with chronic multiple coronary occlusions.

Nineteen mongrel dogs survived chronic occlusion of the left circumflex and of the right coronary artery without infarction due to the timely development of a collateral circulation. Only 38 per cent of the conductance of the arteries before occlusion was restored by collateral vessels. In these animals and in 15 control dogs with normal coronary arteries myocardial contractility, contractility reserve, and myocardial blood flow were studied. The same was done in dogs with chronic coronary artery occlusion after aortocoronary bypass. Myocardial blood flow was determined woth the tracer microsphere technique. Contractility reserve was tested and defined as isovolumetric left ventricular pressure and dp/dt max with norepinephrine infusion and cross-clamping of the aorta. Contractile reserve was not significantly different between normal dogs and dogs with chronic coronary artery occlusion before and after aortocoronary bypass. Myocardial blood flow during control conditions was homogenously distributed in all three groups studied. The ratio of blood flow to the endocardium and the epicardium was not significantly different from inity. Coronary reserve was determined at peak reactive hyperemia following a 20 second period of coronary artery occlusion, with ongoing norepinephrine infusion. Under these conditions subendocardial fow in normal dogs rose by a factor of 7.9 while subepicardial flow increased 7.4 times. In dogs with chronic occlusion of two coronary arteries the increase of myocardial flow was nonnomogenous; subendocardial flow to areas supplied by a normal coronary artery rose by a factor of 7.0 while subepicardial flow increased 5.7 times control. Subendocardial collateral flow rose by a factor of 2.4 and subepicardial collateral flow increased 3.5 times control. In normal dogs norepinephrine alone did not result in maximal coronary flow but only 57 per cent thereof. Dogs with chronic coronary occlusion, however, required the entire coronary reserve in areas that were supplied by a normal coronary artery, whereas areas supplied by collaterals became ischemic. Opening of an aortocoronary bypass restored normal flow to previously ischemic areas, and reduced the flow to areas supplied by a normal artery. With the bypass open no differences existed between normal dogs and those with two occluded coronary arteries. We conclude that the norepinephrine-stimulated contractile reserve of hearts with chronic coronary occlusion was comparable to that of normal hearts; however, norepinephrine forced these hearts to spend the entire flow reserve of the remaining normal artery while producing ischemia in collateral-dependent areas. The same dose of norepinephrine did not require the entire flow reserve of normal dogs.