Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.     

Effects of nifedipine on baroreflex modulation of vascular resistance in man

Studies in animals have demonstrated that, in addition to their vascular effects, calcium channel blockers have important effects on baroreceptor function. We performed a series of experiments to determine if nifedipine, in doses employed clinically, alters baroreflex control of vascular resistance in normal humans. Forearm vasoconstrictor responses of 14 normal subjects to unloading of baroreceptors with lower body negative pressure (LBNP), to a cold pressor test and during intra-arterial infusions of norepinephrine were studied in the control state and following administration of nifedipine. Nifedipine had no effect on baseline mean arterial pressure or central venous pressure. Heart rate and forearm blood flow (FBF) increased significantly following nifedipine: heart rate = 59.7 +/- 2.4 bpm before and 72.6 +/- 4.4 bpm after nifedipine (mean +/- SE, p less than 0.001, n = 14); FBF = 4.6 +/- 0.4 ml X min-1 X 100 ml-1 before and 6.7 +/- 1.0 ml X min1 X 100 ml-1 after nifedipine (p less than 0.02, n = 14). Forearm vascular resistance (FVR) tended to decrease following nifedipine but the difference was not significant: FVR = 21.1 +/- 1.4 units before and 17.8 +/- 2.3 units after nifedipine (p = 0.07, n = 14). Nifedipine attenuated forearm vasoconstrictor responses to cold pressor stimulus: delta FVR during cold pressor test = +10.3 +/- 2.4 units before and +4.7 +/- 1.4 units after nifedipine (p less than 0.02, n = 14). Likewise, nifedipine depressed vasoconstrictor responses to intra-arterial infusion of norepinephrine: delta FVR during norepinephrine = +15.5 +/- 3.4 units before and +10.2 +/- 2.9 units after nifedipine (p less than 0.05, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exogenous melatonin administration modifies cutaneous vasoconstrictor response to whole body skin cooling in humans

Humans and other diurnal species experience a fall in internal temperature (T(int)) at night, accompanied by increased melatonin and altered thermoregulatory control of skin blood flow (SkBF). Also, exogenous melatonin induces a fall in T(int), an increase in distal skin temperatures and altered control of the cutaneous active vasodilator system, suggesting an effect of melatonin on the control of SkBF. To test whether exogenous melatonin also affects the more tonically active vasoconstrictor system in glabrous and nonglabrous skin during cooling, healthy males (n = 9) underwent afternoon sessions of whole body skin temperature (T(sk)) cooling (water-perfused suits) after oral melatonin (Mel; 3 mg) or placebo (Cont). Cutaneous vascular conductance (CVC) was calculated from SkBF (laser Doppler flowmetry) and non-invasive blood pressure. Baseline T(int) was lower in Mel than in Cont (P < 0.01). During progressive reduction of T(sk) from 35 degrees C to 32 degrees C, forearm CVC was first significantly reduced at T(sk) of 34.33 +/- 0.01 degrees C (P < 0.05) in Cont. In contrast, CVC in Mel was not significantly reduced until T(sk) reached 33.33 +/- 0.01 degrees C (P < 0.01). The decrease in forearm CVC in Mel was significantly less than in Cont at T(sk) of 32.66 +/- 0.01 degrees C and lower (P < 0.05). In Mel, palmar CVC was significantly higher than in Cont above T(sk) of 33.33 +/- 0.01 degrees C, but not below. Thus exogenous melatonin blunts reflex vasoconstriction in nonglabrous skin and shifts vasoconstrictor system control to lower T(int). It provokes vasodilation in glabrous skin but does not suppress the sensitivity to falling T(sk). These findings suggest that by affecting the vasoconstrictor system, melatonin has a causal role in the nocturnal changes in body temperature and its control.     

Baroreflex control of muscle sympathetic nerve activity in borderline hypertension

Patients with borderline hypertension have exaggerated vascular responses to orthostatic stress produced by tilt or lower body negative pressure (LBNP). It has been suggested that 1) in the supine position, these patients have augmented activity of cardiopulmonary baroreceptors that exerts an increased restraint on sympathetic vasoconstrictor tone; 2) withdrawal of this augmented inhibitory baroreceptor activity during orthostatic stress elicits augmented reflex sympathetic vasoconstrictor outflow; and 3) augmented cardiopulmonary baroreceptor activity may be secondary to impaired arterial baroreflex mechanisms. To test these hypotheses, we recorded muscle sympathetic nerve activity from the peroneal nerve in seven borderline hypertensive subjects and seven age-, sex-, and weight-matched normotensive subjects during three levels of nonhypotensive LBNP and infusions of phenylephrine and nitroprusside. During LBNP, reductions of central venous pressure were similar in borderline hypertensive and normotensive subjects, and arterial pressure and heart rate values were unchanged. Increases of sympathetic nerve activity, however, were significantly greater in borderline hypertensive than in normotensive subjects at each level of LBNP, indicating an augmented gain of the cardiopulmonary baroreflex. To determine whether this augmentation is related to impairment of arterial baroreflexes, we measured changes of sympathetic nerve activity during increases and decreases of arterial pressure produced with infusions of intravenous phenylephrine and nitroprusside. Central venous pressure was held at control levels by LBNP during phenylephrine and saline infusion during nitroprusside. Changes of sympathetic nerve activity during alterations of arterial pressure were similar in borderline hypertensive and normotensive subjects. These data show that cardiopulmonary baroreflex control of SNA is augmented in borderline hypertensive subjects and that this augmentation does not result from an attenuation of the arterial baroreflex.     

Desipramine blocks augmented neurogenic vasoconstrictor responses to epinephrine

The forearm vasoconstrictor response to lower body negative pressure (LBNP), a reflex stimulus to norepinephrine release, can be augmented by a prior brachial artery infusion of epinephrine. We wished to determine whether this sustained aftereffect of epinephrine could be replicated by systemic infusion and, if so, whether it could be prevented by prior uptake-1 blockade with desipramine. Eight normal men (mean age 30 years) were studied on two separate study days at least 1 week apart, 2.5 hours after taking, at random, either desipramine (125 mg p.o.) or placebo. Forearm vascular resistance was measured at rest and at the end of 6 minutes of LBNP at -40 mm Hg. This was done both before and 30 minutes after a 60-minute infusion of epinephrine (1.5 micrograms/min i.v.). From similar baselines, the forearm vasoconstrictor response to LBNP was significantly augmented 30 minutes after epinephrine on the placebo day (+17 +/- 4 vs. +12 +/- 3 resistance units, mean +/- SEM, p less than 0.01) but not on the desipramine day (+14 +/- 2 vs. +16 +/- 3 resistance units). The heart rate response to LBNP was also greater after epinephrine on the placebo day (+20 +/- 3 vs. +16 +/- 2 beats/min, p less than 0.05). Mean arterial pressure was higher after epinephrine infusion on the placebo (p less than 0.01) but not on the desipramine day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of lower-body negative pressure on sympathetic nerve responses to static exercise in humans. Microneurographic evidence against cardiac baroreflex modulation of the exercise pressor reflex

Although previous studies in both animals and humans have suggested that cardiac baroreceptors modulate reflex sympathetic vasoconstriction during exercise, more recent studies in conscious animals have not supported this view. To further test this concept in humans, we measured sympathetic nerve discharge with intraneural microelectrodes while we used static handgrip to activate the exercise pressor reflex and nonhypotensive lower-body negative pressure (LBNP) to selectively unload the cardiac baroreflex. In nine healthy subjects, we measured blood pressure, heart rate, central venous pressure, and muscle sympathetic nerve activity (MSNA) from the peroneal nerve (resting leg) during 2 minutes of static handgrip at 20% and 30% of maximal voluntary contraction (MVC) alone and in combination with LBNP at -5 mm Hg. Handgrip alone (exercise reflex) at 20% and 30% MVC caused graded increases in MSNA. LBNP alone (cardiac reflex) did not alter blood pressure or heart rate but decreased central venous pressure by 2.5 +/- 0.1 mm Hg (mean +/- SEM, p less than 0.05) and increased MSNA by 92 +/- 22% over the control value. Most important, handgrip performed during LBNP (interaction of reflexes) caused increases in MSNA that were comparable with the increases during handgrip alone: +114 +/- 32% versus +175 +/- 89% at 20% MVC and +328 +/- 101% versus +431 +/- 110% at 30% MVC (handgrip plus LBNP vs. handgrip alone, p greater than 0.1). Pressor and heart rate responses to handgrip also were unaffected by LBNP. In five additional experiments, comparable findings were obtained when the LBNP was superimposed on handgrip rather than handgrip being superimposed on LBNP. In conclusion, this study provides direct evidence in humans that nonhypotensive LBNP does not augment muscle sympathetic outflow during static handgrip and challenges the concept of an important interaction between cardiac baroreceptor and exercise pressor reflexes during this form of exercise.     

Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans

BACKGROUND. Digitalis glycosides augment cardiopulmonary baroreceptor mechanisms in animals. This could result from inotropic actions or from direct sensitization of cardiac mechanoreceptors. METHODS AND RESULTS. To determine if digitalis has similar actions in humans and to evaluate the mechanisms involved, we measured muscle sympathetic nerve activity (MSNA; microneurography) during unloading of cardiopulmonary baroreceptors with incremental lower body negative pressure (LBNP; 0 to -15 mm Hg) and during the cold pressor test in 22 normal subjects (age 22 +/- 1 year, mean +/- SEM). Arterial and central venous pressures, heart rate, and MSNA were measured during LBNP before and after intravenous digitalis (Cedilanid 0.02 ng/kg, n = 8), dobutamine (2.8 +/- 0.5 micrograms/kg/min, n = 8), or placebo (n = 6). Digitalis and dobutamine produced similar increases in baseline mean arterial pressure and decreases in central venous pressure and MSNA. LBNP produced similar decreases in central venous pressure in all groups before and after drug administration. The MSNA responses to LBNP were markedly potentiated by digitalis but not by dobutamine or placebo. CONCLUSIONS. Digitalis did not alter responses to the cold pressor test. Thus, digitalis selectively potentiated cardiopulmonary baroreflex regulation of sympathetic neural responses in normal humans, whereas dobutamine (another positive inotropic agent) did not produce this effect. We conclude that digitalis augments cardiopulmonary baroreflex control of sympathetic activity, probably by direct baroreceptor sensitization.     

The effect of bretylium and clofilium on dispersion of refractoriness and vulnerability to ventricular fibrillation in the ischemic feline heart

Bretylium has been shown to have a pronounced antifibrillatory effect. The purpose of this study was to examine the effects of bretylium on changes in vulnerability to ventricular fibrillation (VF) and refractoriness which occur during acute myocardial infarction. Right ventricular VF thresholds and effective refractory periods (ERP) at six left ventricular sites were measured before and serially after left anterior descending coronary occlusion in chloralose-anesthetized cats. In eight untreated animals, there was a decrease in VF thresholds of 73% (p less than 0.01) immediately after occlusion and dispersion of refractoriness (DR) (maximum difference in ERP between normal and ischemic left ventricular sites) increased from 18 +/- 4 to 50 +/- 6 msec (p less than 0.01). Five of eight animals manifested spontaneous VF within the first minutes of occlusion but none had nonsustained VF. Pretreatment with bretylium (10 to 20 mg/kg intravenously) increased resting ERP from 181 +/- 9 to 201 +/- 9 msec (p less than 0.05) and VF threshold from 32 +/- 5 to 85 +/- 7 mA (p less than 0.001). Bretylium also prevented spontaneous VF in all eight animals and abolished occlusion-related changes in VF and DR. Fourteen animals were similarly studied using clofilium, a bretylium congener which is devoid of sympatholytic effect (no effect on blood pressure response to bilateral carotid artery occlusion). Clofilium increased resting ERP and VF thresholds at both low (0.5 mg/kg intravenously) and high doses (5 mg/kg intravenously). High-but not low-dose clofilium blunted the fall in VF threshold after coronary occlusion. In addition, DR correlated with VF threshold changes at both doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary thromboxane B2 and prostaglandin E2 in the hepatorenal syndrome: evidence for increased vasoconstrictor and decreased vasodilator factors

Vasodilatory prostaglandins function to maintain renal perfusion in patients with cirrhosis and ascites. To evaluate the potential contribution of the vasodilator prostaglandin E2 and the vasoconstrictor metabolite thromboxane B2 to the development of the hepatorenal syndrome, we measured urinary excretion of these products in 14 patients with hepatorenal syndrome and in control populations with acute or chronic liver or kidney failure. Radioimmunoassay measurements were confirmed by bioassay and by mass spectrometry. Prostaglandin E2 was decreased compared with healthy controls (2.2 +/- 0.3 vs. 6.3 +/- 0.8 ng/h, p less than 0.01) and compared with acute renal failure (9.6 +/- 2.1 ng/h) and with alcoholic hepatitis (9.2 +/- 3.3 ng/h). Thromboxane B2 concentration was normal in patients with alcoholic hepatitis (0.12 +/- 0.02 vs. 0.15 +/- 0.03 ng/ml) and minimally increased in acute renal failure (0.18 +/- 0.15 ng/ml), but markedly elevated in hepatorenal syndrome (0.69 +/- 0.15 ng/ml, p less than 0.001). Urinary thromboxane B2 concentration fell with improved renal function in 3 patients who survived. These data suggest an imbalance of vasodilator and vasoconstrictor metabolites of arachidonic acid in patients with the hepatorenal syndrome.     

Paradoxical vasodilation during lower body negative pressure in patients with vasodepressor carotid sinus syndrome

OBJECTIVES: To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syndrome (CSS) by maneuvers designed to induce generalized sympathetic activation after baroreceptor unloading (lower body negative pressure, LBNP) or direct peripheral adrenoreceptor stimulation via local administration of norepinephrine (NA). DESIGN: Subjects were identified with VD of CSS through diagnostic testing. SETTING: Research laboratory. PARTICIPANTS: Eleven young controls (YC) (mean age +/- standard error of mean = 22.8 +/- 0.7), eight elderly controls (EC) (72.6 +/- 0.6), and eight elderly patients with VD (78.7 +/- 1.7). MEASUREMENTS: Forearm arterial blood flow (FABF) was measured in the left and right arms by venous occlusion plethysmography. Measurements were performed during baseline conditions, LBNP (-20 mmHg), and intra-arterial NA infusion in the left brachial artery at three progressively increasing rates (60, 120, and 240 pmol/min). RESULTS: During LBNP, FABF significantly decreased in YC (baseline 3.61 +/- 0.30 vs -20 mmHg 2.96 +/- 0.24 mL/100 g/min, P =.030) and EC (4.05 +/- 0.74 vs 3.69 +/- 0.65 mL/100 g/min, P =.033) but increased in elderly patients with VD (3.65 +/- 0.60 vs 4.54 +/- 0.80 mL/100 g/min, P =.020). During NA infusion, a significant forearm vasoconstriction occurred in YC (FABF left:right ratio 1.00 +/- 0.05 at baseline; 0.81 +/- 0.08 at 60 pmol/min, P =.034; 0.81 +/- 0.05 at 120 pmol/min, P <.001; 0.72 +/- 0.04 at 240 pmol/min, P <.001), whereas no significant FABF changes were observed in EC (1.04 +/- 0.06; 0.96 +/- 0.07, P =.655; 0.89 +/- 0.10, P =.401; 0.94 +/- 0.10, P =.590) or elderly patients with VD (1.04 +/- 0.06; 1.16 +/-0.10, P =.117; 1.04 +/- 0.08, P =.602; 1.11 +/- 0.10, P =.305). CONCLUSION: VD of CSS is associated with a paradoxical vasodilatation during LBNP and an impairment of peripheral alpha-adrenergic responsiveness, which may be age-related.     

Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans.

Naloxone, an opioid antagonist, augments baroreflex mechanisms in animals; this occurrence suggests that endogenous opioids blunt baroreflex responses. Limited human studies suggest an inhibitory action of endogenous opioids on baroreflex-mediated vagal responses during arterial baroreceptor deactivation. To evaluate the potential effect of endogenous opioids on cardiopulmonary baroreflex mechanisms in humans, we measured arterial and central venous pressures, heart rate, and efferent muscle sympathetic nerve activity (MSNA, by peroneal microneurography) during unloading of cardiopulmonary baroreceptors with incremental lower body negative pressure (LBNP, from 0 to -15 mm Hg) and during the cold pressor test in 21 normal subjects (aged 24 +/- 1 [mean +/- SEM] years). In 14 subjects, we performed LBNP before and after naloxone (0.15 mg/kg i.v.) and placebo (n = 11) on separate days. In six of these 14 subjects and an additional seven subjects (n = 13), studies were also performed before and after administration of a lower dose of naloxone (0.075 mg/kg i.v.) on separate days. Neither dose of naloxone significantly altered control arterial or central venous pressures or heart rate. Control MSNA was reduced after the higher but not after the lower dose of naloxone. Comparable reductions in central venous pressure were produced by LBNP in all groups before and after naloxone or placebo, whereas LBNP did not alter arterial pressure. Cardiopulmonary baroreflex sympathetic sensitivity, which was derived as the slope of the linear regression relation between percent change in total MSNA (units) per absolute change in central venous pressure (mm Hg) during incremental LBNP, was significantly augmented after both the high dose (from 18.6 +/- 4.7%/mm Hg to 39.3 +/- 8.1%/mm Hg, p = 0.001) and low dose of naloxone, whereas placebo had no effect. MSNA responses to the cold pressor test were not altered by either dose of naloxone. Thus, naloxone selectively potentiates cardiopulmonary baroreflex regulation of sympathetic neural activity in normal humans. These findings suggest that endogenous opioids exert a tonic inhibitory effect on sympathetic responses to orthostatic stress in normal humans.     

Adverse influence of baroreceptor dysfunction on upright exercise in congestive heart failure

To test the hypothesis that baroreceptor autoregulation is an important determinant of exercise performance, the hemodynamic responses to the gravitational stress of head-up tilt and upright exercise were assessed in 41 patients with severe chronic congestive heart failure. Three patterns of autonomic dysfunction during head-up tilt were identified. Group A patients had near-normal circulatory reflexes whereas Group B patients experienced orthostatic hypotension and Group C patients lacked the afferent stimulus of venous pooling. Group A patients had a significantly longer exercise duration than both Groups B and C (607 +/- 104 versus 330 +/- 86 and 365 +/- 53 seconds, respectively, p less than 0.05) and a significantly higher double product at peak exercise (17,779 +/- 956 versus 12,235 +/- 869 and 13,760 +/- 998, respectively, p less than 0.05). Thus, baroreceptor abnormalities in the autoregulatory response to postural change are important determinants of the cardiovascular responses required during exercise and influence exercise performance. These abnormalities may help clarify the discrepancies between supine and upright exercise performance and may influence the long-term efficacy of vasodilator therapy in chronic congestive heart failure.     

Contributions of endothelial nitric oxide synthase,noradrenaline, and neuropeptide Y to local warming-induced cutaneous vasodilatation in men

We performed a two-part study to determine the roles of endothelial nitric oxide synthase (eNOS) and the vasoconstrictor nerves neurotransmitters noradrenaline (NA) and neuropeptide Y (NPY) in the cutaneous vasodilator response to local skin warming. Forearm skin sites were instrumented with intradermal microdialysis fibres, local heaters, and laser-Doppler flow (LDF) probes. Sites were locally heated from 34 to 42 °C. LDF was expressed as cutaneous vascular conductance (CVC; LDF/mean arterial pressure). In Part I, we tested whether sympathetic noradrenergic nerves acted via eNOS. In 8 male participants, treatments were as follows: 1) untreated; 2) bretylium tosylate (BT), preventing sympathetic neurotransmitter release; 3) l-NAA to inhibit eNOS; and 4) combined BT + l-NAA. At treated sites, the initial peak response was markedly reduced, and the plateau phase response to 35 min of local warming was also reduced (P < 0.05), which was not different among those sites (P > 0.05). In Part II, we tested whether NA and NPY were involved in the vasodilator response to local warming. In Part IIa, treatments were: 1) untreated; 2) propranolol and yohimbine to antagonize α- and β-receptors; 3) l-NAA; and 4) combined propranolol, yohimbine, and l-NAA. In Part IIb, conditions were: 1) untreated; 2) BIBP to antagonize Y₁-receptors; 3) l-NAA; and 4) combined BIBP and l-NAA. All treatments caused a reduction in the initial peak and plateau responses to local skin warming (P < 0.05). The results of Part II indicate that both NA and NPY play roles in the cutaneous vasodilator response and their actions are achieved via eNOS. These data indicate that NA and NPY are involved in the initial, rapid rise in skin blood flow at the onset of local skin warming. However, their vasodilator actions in response to local skin warming appears to be manifested through eNOS.     

Impaired skin blood flow response to environmental heating in chronic heart failure.

AIMS: We examined the thermoregulatory response to heat exposure in patients with chronic heart failure. METHODS AND RESULTS: Skin blood flow (SkBF) was measured in HF subjects and matched controls. Cutaneous vascular conductance (CVC) was calculated from laser-Doppler SkBF and blood pressure. To assess the nitric oxide contribution to thermoregulatory responses, subcutaneous microdialysis membranes were placed beneath the laser-Doppler probes to infuse N(G)-nitro-l-arginine methyl ester (l-NAME), or Ringer's solution. Core (T(C)) and skin temperatures (five sites, T(Sk)) were continuously recorded. Subjects were studied during normothermia then at 38 degrees C, 50%RH within a climate chamber. T(C) and T(Sk) did not differ between HF and controls during normothermia and heating induced similar increases in both groups. During heating, CVC rose in both groups, but significantly less so in HF (HF 43.9+/-7.8 vs. controls 58.0+/-7.5% CVC(max), P<0.05). l-NAME attenuated SkBF responses in the control (58.0+/-7.5 vs. 34.6+/-5.1% CVC(max), P<0.001) and HF subjects (43.9+/-7.8 vs. 27.0+/-2.2% CVC(max), P<0.005), with a larger effect evident in the controls (P<0.05). CONCLUSION: HF patients exhibit impaired thermoregulatory responses to heat exposure. Lower SkBF in HF, which defends blood pressure during heat exposure, also predisposes these subjects to heat intolerance.     

Inhibition of muscle sympathetic nerve activity in humans by arginine vasopressin

Arginine vasopressin, a potent vasoconstrictor, does not raise arterial pressure in normal humans even at pathophysiological plasma levels. To examine whether the pressor effect of vasopressin in humans is buffered by baroreceptor reflex inhibition of sympathetic nerve activity, we recorded postganglionic muscle sympathetic nerve activity directly from the peroneal nerve in 12 normal men before, during, and after a 20-minute intravenous infusion of vasopressin, 4 ng/kg/min, that increased mean plasma concentrations from 6.2 +/- 0.6 to 320 +/- 68 (SE) pg/ml. During the first 5 minutes (n = 8), mean arterial pressure increased from 91 +/- 3 to 97 +/- 4 mm Hg (p less than 0.05) and integrated sympathetic nerve activity decreased from 271 +/- 45 to 156 +/- 33 units (p less than 0.05). At 15 minutes (n = 12), arterial pressure did not differ from control values whereas forearm vascular resistance fell (p less than 0.05) and central venous pressure and heart rate increased (p less than 0.05). Sympathetic nerve activity remained below control levels throughout the infusion (202 +/- 31 vs 254 +/- 40 units before infusion; p less than 0.05). An effect of vasopressin on ganglionic transmission was excluded, since the sympathoexcitatory response to apnea was not attenuated during vasopressin. Thus, pathophysiologic levels of vasopressin in humans cause inhibition of muscle sympathetic nerve activity that is not due to a ganglionic blocking action. The sympathoinhibition may be caused in part by the modest increases in mean arterial and central venous pressures and attendant stimulation of arterial and cardiac baroreceptors. The reflex decrease in sympathetic nerve activity would be expected to buffer the direct vasoconstrictor effects of vasopressin.     

Limited coronary flow reserve after dipyridamole in patients with ergonovine-induced coronary vasoconstriction

Patients with anginal chest pain despite angiographically normal coronary arteries and left ventricles may have abnormalities of coronary flow reserve. Twenty-five patients were found to have limited flow reserve during rapid atrial pacing after administration of 0.15 to 0.30 mg iv ergonovine, associated with precipitation of chest pain and hemodynamic and metabolic evidence of myocardial ischemia. No significant narrowing occurred in epicardial coronary artery luminal diameter. An additional 15 patients had no chest pain during pacing; because they developed significantly higher great cardiac vein flow and lower coronary resistance they were considered to have normal vasodilator reserve. After administration of dipyridamole (0.5 to 0.75 mg/kg iv), the lowest absolute levels to which coronary resistance fell (0.79 +/- 0.23 vs 0.47 +/- 0.12 mm Hg X min/ml; p less than .001) and the maximal absolute levels to which great cardiac vein flow rose (134 +/- 34 vs 202 +/- 45 ml/min; p less than .001) were impaired in the 25 patients with ergonovine-induced flow limitation compared with the 15 patients without flow limitation after ergonovine. In addition, 18 of the 25 patients with limited flow reserve after dipyridamole experienced chest pain despite an increase in coronary flow. In these patients, dipyridamole-induced increased flow across small prearteriolar coronary arteries, which were narrowed because of abnormal tonus or sensitivity to vasoconstrictor stimuli, could have resulted in a transmural redistribution of blood flow away from the subendocardium, precipitating subendocardial ischemia. These studies suggest that patients with anginal chest pain despite normal epicardial coronary arteries may have exaggerated coronary responses to vasoconstrictor stimuli, which can result in myocardial ischemia during stress, as well as attenuated responses to coronary vasodilator stimuli.     

Dietary treatment of atherosclerosis abolishes hyperresponsiveness to serotonin: implications for vasospasm

Diet-induced atherosclerosis in primates impairs vasodilator responses and greatly potentiates vasoconstrictor responses to serotonin. Serotonin may play an important role in the pathogenesis of vasospasm. In diet-induced regression of atherosclerosis, intimal lesions are reduced, but maximal vasodilator responses do not improve, perhaps because of vascular fibrosis. Our goal was to determine whether dietary treatment of atherosclerosis reverses the augmented vasoconstrictor responses to serotonin and thus might reduce susceptibility to vasospasm. Normal cynomolgus monkeys, atherosclerotic monkeys, and atherosclerotic monkeys that were given a normal (regression) diet for 18 months were studied. Morphometric studies indicated that the regression diet reduced lesions in the iliac and femoral artery since intimal area was reduced by about 50%. In the hind limb perfused at constant flow, residual resistance during maximal vasodilatation produced by infusion of adenosine tended to be greater in atherosclerotic monkeys than in normals and failed to improve in regression monkeys. In contrast, vasoconstrictor responses to serotonin were greatly potentiated in atherosclerotic monkeys and were restored to normal in regression monkeys. Serotonin (20 micrograms i.a.) decreased hind limb resistance (in mm Hg/ml/min) 0.34 +/- 0.06 (mean +/- SE) in normal monkeys, increased resistance 0.58 +/- 0.17 in atherosclerotic monkeys (p less than 0.05 vs. normal), and decreased resistance 0.70 +/- 0.15 in regression monkeys (p less than 0.05 vs. atherosclerotic). Thus, dietary treatment of atherosclerosis abolishes augmented vasoconstrictor responses to serotonin. It is proposed that treatment of atherosclerosis may be beneficial, even when vasodilator responses fail to improve, by reducing susceptibility to serotonin-induced vasospasm.     

Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium

The coronary vasomotor response to the cold pressor test was studied with use of quantitative coronary angiography in 32 patients without evidence of coronary artery disease and 55 patients with such disease; in a subset of 22 patients (9 with normal coronary arteries and 13 with coronary artery disease), the effects of the cold pressor test were compared with the effects of the endothelium-dependent vasodilator acetylcholine with simultaneous intracoronary Doppler flow velocity measurements to assess the influence of endothelial dysfunction. The cold pressor test induced vasodilation of 8.9 +/- 5.7% in all 77 analyzed vessel segments of the group with normal arteries (p less than 0.01). In contrast, in patients with coronary artery disease, the 52 analyzed stenotic segments were constricted by -12.1 +/- 9.5% (p less than 0.01), the 57 analyzed vessel segments with luminal irregularities were constricted by -8.9 +/- 5.2% (p less 0.01) and 40 (85%) of 47 angiographically normal segments also were constricted by -7.0 +/- 4.9% (p less than 0.05). Preserved vasodilating capability was demonstrated by intracoronary nitroglycerin in all analyzed segments. In nine patients with normal coronary arteries, the analyzed vessel segments were dilated in response to both the cold pressor test and intracoronary acetylcholine by 10.9 +/- 5.4% and 13.4 +/- 4.7%, respectively. In contrast, in all 13 patients with coronary artery disease, vasoconstriction of identical vessel segments by -9.1 +/- 3.7% and -23 +/- 10.4%, respectively, was observed after both the cold pressor test and intracoronary acetylcholine. Intracoronary propranolol did not significantly affect either the vasodilative response in 11 normal coronary arteries (11.3 +/- 4.4% before and 8.6 +/- 4.3% after beta-blockade) or the vasoconstrictor response in 8 atherosclerotic coronary arteries (-11.4 +/- 4.6% before and -14.6 +/- 5.3% after beta-blockade). The dilation of normal and the constriction of atherosclerotic coronary arteries with cold pressor testing exactly mirror the response to the endothelium-dependent dilator acetylcholine. Endothelial dysfunction in coronary atherosclerosis resulted in a loss of normal dilator function and permitted vasoconstrictor responses to sympathetic stimulation. Thus, coronary vasomotion of large epicardial arteries in response to sympathetic stimulation by the cold pressor test in humans is intimately related to the integrity of endothelial function.     

Digitalis-induced augmentation of cardiopulmonary baroreflex control of forearm vascular resistance

We sought to determine whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mm Hg, which decreased central venous pressure but did not alter blood pressure or heart rate. Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after administration of lanatoside C (Cedilanid) than before, and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after lanatoside C. Vasoconstrictor responses to the cold pressor test did not differ before and after lanatoside C, which suggested that augmented responses to LBNP after the drug were not caused by a generalized change in reflex control. These results suggest that lanatoside C augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.     

Initial and long-term effects of prazosin on sympathetic vasopressor responses in essential hypertension

In 10 untreated hypertensive patients who received an initial dose of 3 to 5 mg prazosin, supine blood pressure (BP) decreased significantly, from an average of 171 +/- 24/96 +/- 10 to 157 +/- 22/90 +/- 10 mm Hg (p less than 0.025). The Valsalva overshoot, response to cold pressor test and digital vasoconstrictor response to a deep breath were not inhibited. However, during 55 degrees passive headup tilt there was a significant decrease in BP. Seven patients received prazosin for a period of 3 months. After long-term therapy BP returned to baseline levels and a dose of prazosin similar to that given initially produced an average decrease in BP from 174 +/- 20/101 +/- 8 to 167 +/- 23/99 +/- 7 mm Hg. Upright tilting no longer resulted in a decrease in BP. The Valsalva overshoot, cold pressor test and digital vasoconstrictor responses remained unchanged. Orthostatic hypotension after the first dose of prazosin without blockade of the other sympathetic reflex responses suggests that the drug has a greater blocking effect on capacitance vessels than on resistance vessels. Prazosin showed a loss of antihypertensive effectiveness during long-term treatment.