Evidence for a systemic defect of resistance-sized arterioles in hypertrophic cardiomyopathy.

BACKGROUND: To investigate whether the abnormalities of coronary arterioles observed in association with hypertrophic cardiomyopathy represent a generalized phenomenon, both forearm and coronary vasodilator reserve were measured in 12 patients with hypertrophic cardiomyopathy. METHODS: Forearm vasodilator reserve was evaluated by measuring minimal forearm vascular resistance (Rmin, the ratio of mean intra-arterial pressure to peak forearm blood flow measured by venous plethysmography) under conditions of maximal postocclusive reactive hyperemia. RESULTS: In a subgroup (n = 5) of patients, the intra-arterial infusion of sodium nitroprusside combined with arterial occlusion did not produce additional vasodilation, indicating that the ischemic stimulus was indeed maximal. Coronary reserve was quantitated by measuring left ventricular blood flow (13N-ammonia and positron emission tomography) and coronary resistance at baseline and after intravenous dipyridamole (0.56 mg/kg). Rmin was significantly greater in patients than in a group of age- and sex-matched controls. The percentage change in coronary resistance after dipyridamole was significantly related to Rmin, whereas no correlation was found between change in coronary resistance and individual septal thickness values. CONCLUSIONS: Independent of cardiac hypertrophy, systemic and coronary arterioles of patients with hypertrophic cardiomyopathy are affected by an abnormality that may contribute to the clinical evolution of this syndrome.

Does a digoxin-like substance participate in vascular and pressure control during dietary sodium changes in patients with primary aldosteronism?

To evaluate the importance of an endogenous sodium pump inhibitor in the pathogenesis of low renin human hypertension, the urinary excretion of a digoxin-like immunoreactive substance (DLIS) was measured in eight patients with primary aldosteronism (n = 5, with adenomas) during two sequential 1-week periods of low- (20 mmol/l NaCl) and high- (200 mmol/l NaCl) sodium intake. DLIS excretion increased consistently during high-sodium intake while urinary aldosterone, plasma renin activity, cortisol and adrenocorticotropic hormone did not change. Although blood pressure showed a time-course parallel to that of the urinary DLIS, the blood pressure increments were not accompanied by evidence of vasoconstriction since forearm blood flow (plethysmographic technique) increased and forearm vascular resistances were reduced. Moreover, the reactivity of forearm arterioles to local norepinephrine was unchanged during the period of low- and high-salt intake, despite the fact that an endogenous sodium pump inhibitor should, supposedly, sensitize the responses to an adrenergic agonist. Finally, forearm vasoconstrictor responses to ouabain, a pharmacological Na+,K(+)-ATPase antagonist, were potentiated during the high-salt diet, a result not expected if an increased number of sodium pumps were occupied by an endogenous inhibitor. These results provide unequivocal evidence for a modulation by salt intake of the urinary excretion of a DLIS in patients with primary aldosteronism. This substance might participate in the regulation of body fluid volume in this syndrome and possibly in other physiological conditions. However, no evidence could be found for a cause--effect relationship between blood pressure and DLIS increments during high-salt intake, at least during the short-term course of the study.

An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension.

Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (-10 mm Hg x 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 micrograms/kg/min x 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 micrograms/kg/min x 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell x 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium entry blockade and agonist-mediated forearm vasoconstriction in hypertensive patients. Difference between nicardipine and verapamil.

The interference by nicardipine and verapamil with the response to vasoactive stimuli, such as lower body negative pressure and angiotensin II, has been evaluated in the forearm of hypertensive patients. Forearm blood flow was monitored during the intraarterial infusion of either drug at rates equieffective on basal flow. Nicardipine blunted the peak forearm vasoconstrictor action of lower body negative pressure and a comparable result was obtained when angiotensin II was administered intraarterially. In spite of a comparable increase in forearm flow, nicardipine was more potent than verapamil in inhibiting vasoconstriction following both stimuli. Thus, nicardipine suppressed regional vascular reactivity, probably by blockade of the influx of extracellular calcium, in response to receptor activation, since both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. However, the results of the comparison with an unrelated calcium entry blocker, such as verapamil, may suggest that nicardipine, and possibly other dihydropiridine derivatives, preferentially antagonize agonist-mediated vasoconstriction in the human forearm.

Calcium entry blockade and adrenergic vascular reactivity in hypertensives: differences between nicardipine and diltiazem.

The interference of nicardipine and diltiazem infused into the brachial artery at systemically ineffective rates, with the forearm vascular response to graded exogenous norepinephrine, was evaluated in hypertensive patients. Nicardipine (1 and 3 micrograms/dl forearm tissue/min in both absence and presence of propranolol) increased forearm blood flow (venous plethysmography) and antagonized dose dependently the vasoconstrictor effect of norepinephrine, suggesting that functional alpha-antagonism may participate in the vasodilating and possibly the antihypertensive effect of the drug. On the contrary, no antagonism but rather potentiation of the responses to norepinephrine occurred after diltiazem (0.5 and 1 microgram/dl forearm tissue/min). Because intra-arterial propranolol abolished that potentiating action of the drug, whereas the local vasodilation to isoproterenol was clearly reduced, diltiazem probably interfered with beta-adrenergic receptor-mediated vasorelaxing mechanisms in human forearm arterioles. The data further stress the heterogeneity of calcium entry blockers in humans.

Atrial natriuretic factor as a vasodilator agent in hypertensive patients.

To investigate the role of Atrial Natriuretic Factor (ANF) in modulating arteriolar tone in hypertension, a synthetic 25 AA human ANF-analogue (anaritide) was infused intraarterially in the forearm vascular bed of five patients with mild hypertension. A dose-dependent increase in blood flow (plethysmographic technique) was seen at rates covering a thousand-fold range (0.008, 0.08, 0.8, 8.0 micrograms/dl tissue/min x 15 minutes each). At the lowest infusion rate, the forearm blood flow increment was associated with changes in local venous ANF concentrations comparable with those reported during biological stimuli in hypertensive man and consistent with an ANF physiologic role in forearm arterioles of hypertensive patients. However, at local venous concentrations greater than 1000 pg/ml, ANF did not relax forearm vessels by more than about one-fourth of the total forearm vasodilator capacity (as assessed through a maximally active ischemic stimulus). These data confirm the low potency of ANF as an endogenous vasodilator, although vasodilator potency is not a necessary requirement for physiologic systems involved in the regulation of muscular vascular tone. Systemic arterial pressure, heart rate, and contralateral flow did not change during the study in spite of the markedly increased peripheral ANF levels recirculating from the local forearm administration. This behavior indicates that arteriolar vasodilation is apparently not the main mechanism of action of ANF on systemic hemodynamics in hypertensive patients.

Calcium entry blockade and agonist-mediated vasoconstriction in hypertensive patients.

The effects of two chemically unrelated calcium channel blockers--nicardipine and verapamil--on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 microgram/100 ml forearm tissue/min dilated the forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 microgram/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 micrograms/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipine.

Regional and systemic hemodynamic and humoral effects of transdermal nitroglycerin in mild hypertension.

Venous distensibility, forearm blood flow (FBF, plethysmographic technique), systemic blood pressure (BP), and derived forearm vascular resistances were measured in 11 borderline-mild hypertensive, otherwise healthy male subjects for a 24-h period during either placebo or transdermally delivered nitroglycerin (NTG 10 mg/24 h). The drug caused arteriolar and venular forearm vasodilation and hypotension which, although persisting throughout the 24-h observation period, reached an apparent maximum during the first hours but later tended to wane. Since NTG plasma levels were constant at that time, the data may suggest development of vascular hyporesponsiveness during continuous exposure to NTG. Venous hematocrit (Hct) decreased during transdermal NTG, indicating the plasma volume expanding action of the drug, apparently dissociated from vasodilation per se. Because no significant changes in either plasma norepinephrine (NE) or plasma renin activity occurred in these subjects, counterregulatory sympathetic or angiotensin II (AII)-mediated vasoconstriction was probably not involved in the hemodynamic action of transdermally delivered NTG.

Low dose atrial natriuretic factor in primary aldosteronism: renal, hemodynamic, and vascular effects.

Whether atrial natriuretic factor (ANF) plays a physiological role in primary aldosteronism has yet to be determined. In the present study, the renal, hemodynamic, humoral, and vascular effects of a synthetic (WY-47663) human analogue were studied in five water-loaded (15 ml H2O/kg) patients with adenomatous primary aldosteronism, a salt-sensitive, low renin, volume-expanded syndrome. ANF was infused for 3 hours at a low rate (0.005 micrograms/kg/min), which approximately doubled circulating immunoreactive ANF. Glomerular filtration rate and renal blood flow (inulin and para-aminohippurate clearance) remained stable, but sodium excretion increased significantly suggesting a dissociation between renal hemodynamics and natriuresis as well as a direct inhibitory effect on tubular sodium reabsorption by ANF. Intra-arterial diastolic blood pressure, heart rate, forearm blood flow (plethysmographic method), and arterial plasma norepinephrine did not change, but systolic blood pressure declined and hematocrit rose suggesting plasma volume contraction by ANF. Plasma aldosterone levels were unchanged indicating a loss of ANF-mediated aldosterone inhibition, possibly related to qualitative or quantitative alterations of ANF receptors in tumoral adrenal tissue. Infusion of the analogue into the brachial artery was at a rate of 0.005 micrograms/dl forearm tissue/min x 30 minutes, which also doubled local immunoreactive venous ANF concentrations and vasodilated forearm arterioles. These data suggest a physiological role for ANF in modulating body fluid volume even in human primary aldosteronism.

Magnetic resonance imaging for the study of cervical myelopathy in rheumatoid arthritis.

Cervical myelopathy is found fairly often with rheumatoid arthritis. It is one of the worst complications of the disease and can lead to tetraplegia or even to sudden death. However, when we consider the high incidence of involvement of the cervical spine in rheumatoid arthritis, the number of cases of cervical myelopathy, even of slight degree, is not very high. We have used magnetic resonance to identify the condition of the cervical structures, especially the nerve structures, in 15 patients with rheumatoid arthritis, with involvement of the cervical articulations but without neurological symptoms. We found anterior compression of the spinal cord caused by the odontoid process of the epistropheus in 13 cases. One case had lateral deviation of the spinal cord and another had compression of a vertebral artery. In another the lumen of the nasopharynx was decreased and one had posterior compression of the spinal cord by the posterior arch of the atlas. Magnetic resonance also makes it possible to detect a rheumatoid pannus on the affected articulations. We conclude that magnetic resonance is at present a useful instrument for evaluation of the presence of cervical myelopathy in rheumatoid arthritis patients, to prevent more serious complications.

Dietary sodium change in primary aldosteronism. Atrial natriuretic factor, hormonal, and vascular responses.

Atrial natriuretic factor (ANF) may be physiopathologically involved in several clinical conditions including human hypertension. However, few data are available regarding this putative hormone and its relationship to aldosterone, blood pressure, and vascular responsiveness to alpha-adrenergic receptor stimulation in primary aldosteronism, a volume-expanded, low-renin model of human hypertension. For this reason, the behavior of supine and upright plasma ANF as related to aldosterone, blood pressure, and forearm alpha-adrenergic sensitivity (plethysmographic technique) to intra-arterial norepinephrine infusion was studied in eight patients with primary aldosteronism (five with adenomas, three with hyperplasia) before and at the end of two sequential 1-week low (20 mmol/day) and high sodium (200 mmol/day) diet periods. Basal, predict ANF concentrations decreased and increased after low and high sodium intakes, respectively. Furthermore, highly significant postural ANF decrements after 1 hour of standing occurred with each diet, although they were lower after the low than after the high sodium diet. Plasma aldosterone, either supine or upright, was insensitive to dietary sodium manipulations, suggesting the absence of ANF-mediated control of aldosterone secretion in our patients. In spite of about twofold higher ANF concentrations during the high than during the low sodium diet, forearm vascular sensitivity to intra-arterial norepinephrine infusion did not change during the study. Furthermore, systemic arterial blood pressure rose to a highly significant extent after dietary sodium content was increased, thus casting doubt on a role for ANF as an endogenous long-term modulator of systemic blood pressure and peripheral alpha-adrenergic sensitivity in patients with primary aldosteronism.

Verapamil antagonizes forearm vasoconstriction mediated by selective alpha 1- and alpha 2-agonists in hypertensive patients.

Calcium channel blocking agents preferentially antagonize alpha 2-mediated pressor responses in various animal species. Whether the same happens in man is not clear. For this reason we studied the interference exerted by verapamil, a calcium entry blocker, on forearm vasoconstriction mediated by selective alpha 1- (methoxamine) and alpha 2- (B-HT 933) adrenergic agonists in untreated mild-to-moderately hypertensive patients (n = 22). Each patient underwent a single study. Forearm blood flow was recorded by strain gauge venous plethysmography; all drugs were infused into the brachial artery at systemically ineffective rates. Cumulative dose-response curves to intra-arterial methoxamine or B-HT 933 were obtained during saline or two different rates of verapamil infusion (0.9 and 3.1 micrograms/100 ml forearm tissue per min) which increased forearm blood flow dose-dependently without changing systemic blood pressure or heart rate. Either methoxamine or B-HT 933 decreased forearm blood flow during saline infusion, but their effect was blunted in a dose-dependent manner during verapamil. No evidence of preferential alpha 2-antagonism was present. At variance with animal data, calcium entry blockade by verapamil antagonizes either alpha 1- or alpha 2-mediated vasoconstriction in human forearm vessels.