Autonomic and baroreflex function after captopril in hypertension

Absent reflex tachycardia with captopril therapy suggests blunting of circulatory reflexes, perhaps contributing to antihypertensive efficacy, and angiotensin converting enzyme inhibition may alter sympathetic function. Captopril effects on autonomic function were investigated in five severe hypertensive patients. Mean blood pressure fell in all patients (from 141 +/- 6 to 119 +/- 7 mm Hg, p less than 0.02) without orthostatic blood pressure fall or increase in heart rate (both p greater than 0.1) on captopril. Captopril did not alter baroreflex sensitivity as tested by amyl nitrile hypotension or phenylephrine hypertension (both p greater than 0.1). Comparison of these severely hypertensive patients to age matched normotensive control subjects did reveal markedly blunted baroreflex sensitivity in both the amyl nitrite test (by 89%, p less than 0.01) and the phenylephrine test (by 83%, p less than 0.01), suggesting that baseline blunting of baroreflex function may in part account for absence of reflex tachycardia. Captopril diminished the cardioacceleration after cold stress (from 61 +/- 38 to 23 +/- 43 msec, p less than 0.05) as well as the blood pressure fall after alpha-adrenergic blockade (from 46 +/- 13 to 24 +/- 9 mm Hg, p less than 0.05), suggesting diminished sympathetic stimulation of resistance vessels and decreased sympathetic participation in blood pressure maintenance, possibly at the prejunctional synaptic level. Four biochemical indices of sympathetic activity did not change. Thus captopril-treated patients had blunted reflex tachycardia, commensurate with blunted baroreflex function at baseline, and physiologic and pharmacologic evidence of diminished sympathetic activity was obtained with captopril therapy. Whether diminished sympathetic activity is involved in captopril's antihypertensive effect has not been determined.     

Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine

In rats with large myocardial infarctions, we compared the effects of captopril, a presumed arterial and venous vasodilator, with hydralazine, which is thought primarily to be an arterial vasodilator. To determine if the effects of captopril were dependent on the pathophysiological consequences of heart failure, we also studied a group of noninfarcted rats treated with captopril. In noninfarcted rats treated with captopril, left ventricular (LV) systolic and mean aortic pressures decreased from 132 +/- 12 to 107 +/- 15 mm Hg and 122 +/- 1 to 100 +/- 2, respectively (p less than 0.01). In noninfarcted rats, captopril decreased LV weight, LV weight/body weight, and total heart weight/body weight but produced no effects on the peripheral venous circulation. Rats subjected to coronary artery ligation were selected by ECG criteria to have large myocardial infarctions and were treated for 4 weeks with captopril (n = 8), hydralazine (n = 5), or placebo (n = 9). In infarcted rats treated with captopril, LV systolic, mean aortic pressures and LV end-diastolic pressure (LVEDP) decreased (p less than 0.01) from 115 +/- 4 to 86 +/- 3 mm Hg, 106 +/- 4 to 74 +/- 3 mm Hg, and 23 +/- 2 to 11 +/- 2 mm Hg, respectively. Mean circulatory filling pressure decreased (p less than 0.05) from 11.2 +/- 0.6 to 8.7 +/- 0.8 mm Hg and venous compliance increased (p less than 0.05) from 2.04 +/- 0.07 to 2.70 +/- 0.20 ml/mm Hg/kg. Blood volume decreased (p less than 0.05) from 67.3 +/- 0.9 to 58.2 +/- 1.8 ml/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of heart failure on baroreflex control of sympathetic neural activity.

Baroreflex control of heart rate, vascular resistance and norepinephrine is impaired in patients with heart failure, but recent animal studies demonstrate preserved baroreflex control of sympathetic nerve activity in this disorder. Studies were therefore performed to compare baroreflex control of efferent sympathetic nerve activity to muscle in 10 normal subjects (age mean +/- SEM 21 +/- 1 years) and in 11 patients with moderate to severe heart failure (age 48 +/- 5 years, New York Heart Association class II to IV, left ventricular ejection fraction 19 +/- 2%, pulmonary capillary wedge pressure 27 +/- 2 mm Hg, cardiac index 2.04 +/- 0.22 liters/min/m2). Baroreflex activation was produced by intravenous infusion of phenylephrine (0.5 to 2.0 micrograms/kg/min) and deactivation by infusion of nitroprusside (0.4 to 2.5 micrograms/kg/min). During phenylephrine infusion, comparable increases in mean arterial pressure were produced in normal subjects (89 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01) and in patients with heart failure (90 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01). The patients with heart failure exhibited significantly attenuated (p less than 0.01 for normal vs heart failure) decreases in heart rate (93 +/- 5 to 90 +/- 6 beats/min, p = not significant [NS]) compared with normal subjects (67 +/- 3 to 58 +/- 4 beats/min, p less than 0.01) and tended to demonstrate attenuated sympathoinhibitory responses to this pressor stimulus. More strikingly, patients with heart failure demonstrated significant impairment of baroreflex responses during nitroprusside-induced baroreceptor deactivation. In normal subjects, nitroprusside produced a decrease in mean arterial (90 +/- 2 to 80 +/- 3 mm Hg, p less than 0.001) and right atrial (4 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01) pressures with a resultant reflex increase in heart rate (68 +/- 3 to 81 +/- 4 beats/min, p less than 0.001) and muscle sympathetic nerve activity (326 +/- 74 to 746 +/- 147 U/min, p less than 0.01). In patients with heart failure (n = 10), nitroprusside produced comparable (p = NS for normal vs heart failure) decreases in mean arterial (89 +/- 2 to 77 +/- 2 mm Hg, p less than 0.001) and right atrial (6 +/- 1 to 1 +/- 1 mm Hg, p less than 0.001) pressures, but did not significantly alter heart rate (91 +/- 6 to 97 +/- 4 beats/min, p = NS) or sympathetic nerve activity (936 +/- 155 to 1179 +/- 275 U/min, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)     

Central inhibition of sympathetic overdrive by clonidine in acute myocardial infarction with systolic hypertension. Haemodynamic study

Intravenous clonidine was used to treat systolic hypertension (systolic blood pressure greater than 160 mm Hg) in 15 patients with acute myocardial infarction and documented sympathetic overactivity (high plasma norepinephrine). Its effects on haemodynamics and blood gases were studied. After one hour, clonidine significantly reduced the systolic (195 +/- 7 to 137 +/- 7 mm Hg, p less than 0.01) and diastolic (81 +/- 4 to 60 +/- 3 mm Hg, p less than 0.01) blood pressures as well as the systemic vascular resistance (26 +/- 2 to 20 +/- 1 IU, p less than 0.01). The cardiac index was reduced from 2.8 +/- 0.2 to 2.4 +/- 0.2 l/min X m2, p less than 0.01. This change was related to a reduction of the heart rate (92 +/- 4 to 81 +/- 4 beats/min, p less than 0.01) as the stroke index was unchanged. Pulmonary wedge pressure (15 +/- 3 to 10 +/- 2 mm Hg, p less than 0.01) and rate pressure product (18.034 +/- 1.159 to 11.274 +/- 917 mm Hg, beats/min, p less than 0.01) were also significantly decreased. The arterial oxygen tension did not change significantly but there was a significant drop in the mixed venous oxygen saturation (63 +/- 2 to 61 +/- 2%, p less than 0.02) and oxygen transport (433 +/- 41 to 409 +/- 36, p less than 0.01). Clonidine is thus able to normalize blood pressure in acute myocardial infarction; this is accompanied by a reduction in myocardial oxygen requirements and pulmonary wedge pressure. Oxygen transport to the tissues, however, may be decreased.     

Acute hemodynamic and hormonal effects of CI-930, a new phosphodiesterase inhibitor, in severe congestive heart failure

The phosphodiesterase inhibitor CI-930 hydrochloride exerts a positive inotropic and vasodilator effect in experimental animals. The acute hemodynamic and hormonal effects of intravenous CI-930 were studied in 9 patients with severe congestive heart failure. At 60 minutes of drug infusion, there was an increase in cardiac index (2.7 +/- 0.9 vs 2.0 +/- 0.7 liters/min/m2, p less than 0.01) and positive dP/dt (1,390 +/- 470 vs 1,100 +/- 300 mm Hg/s, p less than 0.02). Additionally, there were decreases in mean systemic arterial (78 +/- 16 vs 86 +/- 15 mm Hg, p less than 0.01), mean right atrial (5 +/- 3 vs 9 +/- 4 mm Hg, p less than 0.02), mean pulmonary arterial (27 +/- 11 vs 37 +/- 9 mm Hg, p less than 0.01) and LV end-diastolic (19 +/- 8 vs 28 +/- 6 mm Hg, p less than 0.01) pressures. Heart rate did not change (97 +/- 17 vs 97 +/- 22 beats/min). The inotropic response correlated significantly (r = 0.70, p less than 0.05) with the dose of CI-930. Plasma renin activity did not change significantly (from 16 +/- 9 to 23 +/- 15 ng/ml/hour), nor did plasma norepinephrine or arginine vasopressin levels. The plasma atrial natriuretic peptide level decreased (from 153 +/- 97 to 83 +/- 35 pg/ml, p less than 0.02). These findings suggest that intravenous CI-930 hydrochloride is a useful therapeutic agent in congestive heart failure and that its use does not appear to further activate potentially deleterious hormonal systems.     

Importance of endogenous angiotensin II in the cardiovascular responses to sympathetic stimulation in conscious rabbits

Pharmacological evidence indicates that angiotensin (Ang II) converting enzyme inhibitors attenuate cardiovascular responses to sympathetic stimulation. To investigate the physiological significance of this attenuation, the pressor and heart rate responses to bilateral carotid occlusion (BCO) were studied before and after administration of captopril and again during Ang II replacement in conscious, aortic nerve-sectioned rabbits with chronically implanted carotid occluders. In the control period, BCO produced increases (p less than 0.05) in mean arterial pressure (MAP) and heart rate (HR) of 37.3 +/- 3.0 mm Hg and 21.7 +/- 5.4 beats/min from baseline values of 79.1 +/- 2.5 mm Hg and 255.4 +/- 16.7 beats/min. Captopril (5 mg/kg i.v.) markedly reduced (p less than 0.05) both the pressor (10.2 +/- 2.6 mm Hg) and HR (5.0 +/- 4.0 beats/min) responses to BCO, in parallel with a decrease in plasma Ang II of 75%. Infusion of a subpressor dose of Ang II (5-25 ng/kg/min i.v.) increased plasma Ang II to precaptopril levels and fully restored (p less than 0.05) the pressor (33.0 +/- 5.7 mm Hg) and HR (19.8 +/- 7.7 beats/min) responses to BCO. In two additional series of experiments, the mechanism of the effects of captopril and Ang II were investigated. In the first series, cardiac baroreflex curves (pulse interval versus MAP) were generated by increasing or decreasing blood pressure with phenylephrine or nitroprusside (5-20 micrograms/kg/min i.v.). The slope of the linear region of the curve (2.9 msec/mm Hg) was not changed significantly by captopril treatment (3.1 msec/mm Hg) or Ang II replacement (3.2 msec/mm Hg), indicating that cardiac baroreflex sensitivity was not altered by blockade of the renin-angiotensin system. In the second series, the effect of captopril on the pressor response to exogenous norepinephrine (0.1-2.5 micrograms/kg/min i.v.) was tested. The response was reduced by less than 40%, indicating only a modest postsynaptic component to the action of captopril. These results provide physiological evidence for an important action of endogenous Ang II in facilitating the cardiovascular responses to sympathetic stimulation in conscious rabbits. This facilitation is not due to an action upon the baroreflex per se but results, at least in part, from a presynaptic action of Ang II.     

Comparative effects of captopril and isosorbide dinitrate on pulmonary arteriolar resistance and right ventricular function in patients with severe left ventricular failure: results of a randomized crossover study

We compared the short-term hemodynamic effects of isosorbide dinitrate (40 mg orally) and captopril (25 mg orally) in 18 patients with severe chronic heart failure in a randomized, crossover study conducted on consecutive days. Captopril and isosorbide dinitrate produced similar decreases in systemic vascular resistance, but whereas nitrate therapy decreased pulmonary arteriolar resistance significantly, captopril did not; the difference between the two drugs was highly significant (-25% vs -5%, p less than 0.001). Left ventricular filling pressures declined similarly with both captopril (-10.5 mm Hg) and with isosorbide dinitrate (-9.3 mm Hg), but because pulmonary arteriolar resistance fell significantly with nitrate therapy, mean right atrial pressure decreased more with isosorbide dinitrate than with captopril (-5.4 vs -2.8 mm Hg, respectively; p less than 0.001). Although systemic resistance declined similarly with both drugs, cardiac index increased more with nitrate therapy than during converting-enzyme inhibition (+0.47 vs +0.23 L/min/m2) (p less than 0.01), and therefore mean arterial pressure fell less with isosorbide dinitrate than with captopril (-10.5 mm Hg vs -16.7 mm Hg); p less than 0.05); two patients developed symptomatic hypotension with captopril, whereas none did so with the nitrate. The difference in the effects of the two drugs on cardiac index was not due to differences in their effects on heart rate, since heart rate fell similarly with both drugs, and thus both drugs produced similar increases in stroke volume index. These data indicate that, in patients with severe chronic heart failure, nitrates exert favorable dilating effects on the pulmonary circulation not shared by captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic and regional hemodynamic effects of captopril and milrinone administered alone and concomitantly in patients with heart failure

The effects of milrinone and captopril on ventricular performance, renal blood flow, and femoral vein oxygen content were compared in 11 patients with severe chronic heart failure. The increase in stroke volume index was greater with milrinone than with captopril (28 +/- 7 vs 24 +/- 7 ml/m2; p less than .05), while pulmonary capillary wedge pressures fell similarly (19 +/- 10 vs 21 +/- 7 mm Hg). Mean systemic arterial pressure decreased significantly from 84 +/- 10 to 73 +/- 11 mm Hg (p less than .05) with captopril but did not with milrinone. Neither drug changed heart rate significantly. Although milrinone produced a greater improvement in ventricular performance than captopril, renal blood flow increased similarly with both drugs from 289 +/- 78 to 417 +/- 111 ml/min (p less than .05) and from 278 +/- 77 to 441 +/- 115 ml/min (p less than .05), respectively. Femoral vein oxygen content was increased by milrinone from 7.9 +/- 2.6 to 9.8 +/- 3.0 ml/100 ml (p less than .05) and was not changed by captopril. In seven additional patients, intravenous milrinone, administered at the peak effect of captopril, further augmented stroke volume index from 24 +/- 6 to 32 +/- 6 ml/m2 (p less than .05) and tended to reduce pulmonary capillary wedge pressure further from 20 +/- 8 to 18 +/- 9 mm Hg (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Baroreflex function in lifetime-captopril-treated spontaneously hypertensive rats

The effects of lifetime oral captopril treatment on baroreflex control of heart rate and lumbar sympathetic nerve activity were measured in 19-21-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The sensitivity of baroreflex control of heart rate and lumbar sympathetic nerve activity were determined by the slopes of the relation between the change in mean arterial pressure (MAP) (mm Hg) versus the change in pulse interval (msec/beat) and the change in MAP versus the percent change in nerve activity, respectively. Untreated SHR had significantly higher MAP than WKY (157 +/- 3 vs. 115 +/- 3 mm Hg, p less than 0.001) and exhibited a decreased baroreflex control of heart rate. Lifetime treatment with captopril prevented the development of hypertension in SHR (MAP = 110 +/- 5 mm Hg) and increased the sensitivity of baroreflex function. The gains of the baroreflex control of heart rate for captopril-treated SHR and control SHR when MAP was raised or lowered by phenylephrine or nitroprusside were 2.38 +/- 0.49 vs. 1.10 +/- 0.33 msec/mm Hg (p less than 0.05) and 0.74 +/- 0.20 vs. 0.54 +/- 0.09 (NS) msec/mm Hg, respectively. The sensitivity of the baroreflex control of lumbar sympathetic nerve activity was greater in captopril-treated SHR than in control SHR when MAP was increased or decreased (-1.03 +/- 0.26 vs. -0.38 +/- 0.11, p less than 0.05; -0.84 +/- 0.2 vs. -0.04 +/- 0.58 (NS) mm Hg-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme inhibition, catecholamines and hemodynamics in essential hypertension

Captopril was given to 15 unselected patients with essential hypertension (WHO II) at a dose range of 300 to 600 mg/day. Hemodynamic indexes (thermodilution) as well as levels of plasma norepinephrine, epinephrine, renin activity and aldosterone were determined simultaneously at the end of 2 weeks of placebo and after 8 weeks of captopril treatment. Systolic and diastolic arterial pressures were reduced significantly by treatment both supine (p less than 0.0025) and standing (p less than 0.0025). The diastolic arterial pressure was normalized (less than 95 mm Hg) in five patients and significantly reduced in four, whereas six patients were considered poor responders (mean arterial pressure decrease 10 mm Hg or less). The decrease in arterial pressure correlated significantly with the reduction in total peripheral resistance (r = 0.71), whereas cardiac index did not change and stroke index increased because of a slight decrease of heart rate. Plasma and urinary norepinephrine and epinephrine did not change during treatment. Moreover, the response of both heart rate and plasma catecholamines to upright posture was not altered by captopril treatment. Plasma renin activity increased and plasma aldosterone concentration decreased during treatment. These results suggest that inhibition of converting enzyme activity by captopril induces a reduction in arterial pressure through a reduction in total peripheral resistance. There was no evidence of an appreciable reduction in sympathetic nervous system activity during therapy.     

Chronic effects of direct vasodilation (pinacidil), alpha-adrenergic blockade (prazosin) and angiotensin-converting enzyme inhibition (captopril) in systemic hypertension

Chronic responses of systemic hemodynamics and blood pressure counterregulatory ("pseudo-tolerance") mechanisms were investigated in matched groups of patients with essential hypertension after 1 month of vasodilator therapy with pinacidil (a direct arterial dilator), prazosin (an alpha 1-adrenergic blocking drug) or captopril (an angiotensin-converting enzyme inhibitor). For equivalent decreases in mean arterial pressure compared with placebo baseline (approximately 8 mm Hg supine and 12 mm Hg upright), prazosin and captopril did not increase cardiac index or heart rate. In contrast, marked decreases in systemic vascular resistance with pinacidil (approximately 25%, p less than 0.05) were accompanied by reflex increases in cardiac index (approximately 20%, p less than 0.05). Activity of the sympathetic nervous system, measured by supine and upright plasma norepinephrine (NE), increased approximately 50% with pinacidil and prazosin (p less than 0.001 each), whereas captopril decreased supine plasma NE by 12% (p less than 0.05) and did not change upright plasma NE. All 3 drugs caused an expansion of height-adjusted blood volume (approximately 14%). Pinacidil and prazosin caused reversible weight gains of 0.9 and 0.7 kg, respectively, whereas captopril reversibly decreased body weight by 0.8 kg (p less than 0.05), suggesting differential effects of the 3 drugs on interstitial fluid volume. During chronic therapy, all 3 drugs may require concomitant diuretic therapy, whereas concomitant sympatholytic therapy may be required with the potent vasodilator pinacidil. Captopril may be associated with the lowest cardiac risk because of its lack of stimulatory effects on the sympathetic nervous system and cardiac index.     

The effects of captopril in stable angina pectoris]

Eighteen normotensive patients with coronary disease and stable effort-induced angina were selected. The effect of captopril was studied. A Bruce stress test was obtained before and after administration of conventional treatment with captopril or placebo. The captopril induced less systolic pressure elevation during maximal exercise without modification of heart rate. By decreasing myocardial oxygen consumption, increasing the time in which angina appears during exercise. Captopril may prove to be useful adjunct to the antianginal drug regimens of patients with stable angina and systolic arterial pressure greater than 110 mm Hg.     

Captopril in cardiac insufficiency. Immediate and long-term effects

Captopril was administered to 23 patients in cardiac failure refractory to digitalo-diuretic therapy. Four patients had a large fall in systolic blood pressure (less than 70 mmHg) with a single dose of 25 mg of captopril. In the other 19 patients a significant fall in mean pulmonary capillary pressure (16,8 +/- 6,1 mmHg vs 27,2 +/- 8,5 mmHg, p less than 0,001), mean pulmonary artery pressure (26,3 +/- 11,3 mmHg vs 38,3 +/- 12,4 mmHg, p less than 0,001), mean right atrial pressure (5 +/- 5 mmHg vs 8 +/- 6 mmHg, p less than 0,01) was observed: there was a moderate fall in mean systemic arterial pressure (13%, p less than 0,001). There was a significant fall in pulmonary resistance (27%, p less than 0,001). The cardiac index increased (2,8 +/- 0,5 l/min/m2, p less than 0,001) and systemic resistance fell by 25% (p less than 0,001). The heart rate decreased by an average of 7 beats/min (p less than 0,02). The treatment was stopped in one patient because of the inefficacy of captopril at 100 mg per dose. The average daily dose in the 18 patients on long-term treatment was 212,5 +/- 106,8 mg. At the second month, the haemodynamic parameters were remeasured before the morning dose of captopril. The effects observed after the single dose were maintained apart from the systemic blood pressure, heart rate and systemic resistances which had returned to the value observed before administration of captopril. The mean pulmonary capillary pressure was significantly lower than before treatment but was higher than after the single dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of perindopril versus captopril for treatment of acute myocardial infarction.

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with acute myocardial infarction (AMI), but these benefits might be limited by acute hemodynamic changes and difficulties in titrating to recommended doses. The objective of this study was to compare the hemodynamic changes and tolerability of perindopril with captopril after AMI. We randomized 212 patients to receive either captopril (n = 102) or perindopril (n = 110) within 72 hours of AMI. Captopril was given as an initial dose of 6.25 mg, and then 50 mg/day on day 1 and 100 mg/day thereafter. The corresponding doses of perindopril were 2, 4, and 8 mg/day. Acute hemodynamic changes, the percentage of patients who reached target doses, and in-hospital and 6-month cardiovascular events were monitored. Baseline clinical characteristics of the 2 groups were identical, but patients randomized to perindopril were in a higher Killip class (1.4 +/- 0.6 vs 1.2 +/- 0.5, p = 0.05). During the first 6 hours, treatment with perindopril resulted in higher minimal systolic (97 +/- 15 vs 91 +/- 14 mm Hg, p <0.01) and diastolic blood pressure (BP) (57 +/- 11 vs 54 +/- 10 mm Hg, p <0.02), later occurrence of minimal BP (3.6 +/- 0.2 vs 2.7 +/- 0.1 hour, p <0.001), and a lower incidence of persistent hypotension with systolic BP < 90 mm Hg for > or =1 hour (5% vs 16%; p < 0.01) compared with captopril. At initial administration, target doses of perindopril and captopril were attained in 97% and 82% of the patients, respectively (p < 0.01). After 6 months, there were no differences between patients treated with perindopril and captopril in mortality rates (6% vs 13%, p = 0.16) and need for revascularization (20% vs 21%, p = 0.9). Thus, in patients during AMI, perindopril treatment showed better short-term tolerance than treatment with captopril, with significantly less acute hemodynamic changes and fewer withdrawals.     

Effects of diltiazem on hormonal and hemodynamic responses to lower body negative pressure and tilt in patients with mild to moderate systemic hypertension

Mean arterial blood pressure, forearm vascular resistance, plasma norepinephrine, plasma renin activity and aldosterone responses to graded lower body negative pressure and tilt at 80 degrees were examined in 10 men with mild to moderate essential hypertension before and after 12 weeks of diltiazem (240 to 360 mg/day) therapy. Diltiazem therapy lowered basal supine systolic and diastolic blood pressures without affecting basal heart rate. Mean arterial blood pressure and forearm vascular resistance were decreased from 114 +/- 1.5 to 105 +/- 1 mm Hg, p less than 0.01 and from 29.3 +/- 3.5 to 18.9 +/- 2.1 units, p less than 0.01, respectively. Diltiazem therapy had no effect on basal supine levels of norepinephrine, plasma renin activity or aldosterone, nor on the responses of these hormones to lower body negative pressure. Diltiazem did decrease the forearm vascular resistance responses to lower body negative pressure and tilt. Diltiazem abolished an orthostatic increase (10 +/- 0.3 mm Hg) in mean arterial blood pressure and this was associated with a greater plasma norepinephrine response to tilt. These results suggest that diltiazem decreases vascular resistance through a reduction in the postjunctional effects of norepinephrine on vascular smooth muscle.     

Brain angiotensin II and baroreceptor reflex function in spontaneously hypertensive rats

We examined whether the increase in baroreceptor reflex function previously reported in lifetime - captopril-treated spontaneously hypertensive rats (SHR) was due to an inhibition of brain angiotensin II mechanisms. Pregnant and lactating SHR were given oral captopril (100 mg/kg/day). After weaning, pups were maintained on captopril (50 mg/kg/day) until the study (19-21 weeks). Control rats received tap water. One week before study captopril-treated and control SHR were given an intracerebroventricular infusion of angiotensin II (7.5 ng/hr, osmotic pump) or vehicle (artificial cerebrospinal fluid). Baroreceptor reflex control of heart rate was assessed by the slope of the relation between the change in mean arterial pressure (mm Hg) versus the change in pulse interval (msec beat-1). Arterial pressure was raised or lowered by intravenous bolus injections of phenylephrine or nitroprusside, respectively. Central infusion of angiotensin II had no significant effect on mean arterial pressure in captopril or control SHR (captopril-angiotensin II 125 +/- 4 vs. captopril-vehicle 121 +/- 2; control-angiotensin II 169 +/- 5 vs. control-vehicle 173 +/- 7 mm Hg), but it produced a significant rise in basal heart rate (captopril-angiotensin II 371 +/- 10 vs. captopril-vehicle 323 +/- 8, p less than 0.0002; control-angiotensin II 338 +/- 7 vs. control-vehicle 312 +/- 8 beats/min, p less than 0.0183) and in daily water intake (captopril-angiotensin II 20.7 +/- 2.2 vs. captopril-vehicle 9.8 +/- 0.7, p less than 0.0426; control-angiotensin II 33.1 +/- 3.8 vs. control-vehicle 9.0 +/- 0.6 ml/100 g body wt, p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Adenosine increases sympathetic nerve traffic in humans

BACKGROUND. Adenosine is an effective hypotensive agent in experimental animals and in anesthetized patients, producing little if any evidence of reflex sympathetic activation. In contrast, adenosine increases systolic blood pressure and heart rate in conscious subjects. To determine whether this response is related to sympathetic activation, we studied the cardiovascular and respiratory effects of adenosine in normal subjects while measuring muscle sympathetic nerve traffic through direct recordings from a peroneal nerve. METHODS AND RESULTS. Adenosine (80 micrograms/kg/min i.v.) increased heart rate (+32 +/- 3 beats/min), systolic blood pressure (+10 +/- 2 mm Hg), and minute ventilation (+7 +/- 1 l/min). This was accompanied by a dose-dependent increase in muscle sympathetic nerve activity (from 198 +/- 52 to 451 +/- 92 units/min). Adenosine also produced a small, but consistent, decrease in diastolic blood pressure (-6 +/- 3 mm Hg). Adenosine produced a greater increase in sympathetic nerve traffic (145 +/- 32% above baseline) than did nitroprusside (65 +/- 16%) at doses that resulted in equivalent decreased in diastolic blood pressure. Arterial baroreceptor unloading, therefore, could not totally explain the increase in sympathetic traffic produced by adenosine. CONCLUSIONS. Given the constellation of findings of increased ventilation and sympathetic activity, we, therefore, propose that adenosine increases sympathetic tone by activating afferent nerves, including arterial chemoreceptors. Contrary to the known inhibitory actions of adenosine on central and peripheral efferent systems, this and other reports suggest that adenosine-induced activation of afferent nerves, leading to sympathetic activation, may be a more widespread phenomenon than previously recognized.     

Renin dependency of blood pressure in isolated systolic hypertension

The role of the renin system in the maintenance of the elevated systolic blood pressure in isolated systolic hypertension was investigated in 31 patients who received long-term treatment with propranolol (120 mg daily) and in another group of 22 patients with isolated systolic hypertension who received a test dose of captopril (25 or 50 mg). The greatest systolic blood pressure decrease (35 +/- 5 mm Hg) by propranolol occurred in the high-renin group (n = 9), and the smallest decrease (3 +/- 2 mm Hg) in the low-renin group (n = 9), whereas in the normal-renin group (n = 13), systolic blood pressure was decreased by propranolol by 22 +/- 5 mm Hg. For all the propranolol-treated patients, the decrement in the systolic blood pressure by propranolol was related to the control plasma renin activity (r = 0.63, p less than 0.01) and to the concurrent change in plasma renin activity (r = 0.70, p less than 0.001). Captopril decreased the systolic blood pressure by 55 +/- 10 mm Hg in the high-renin group (n = 11) and by 17 +/- 5 mm Hg in the normal-renin group (n = 6), whereas the smallest decrease (12 +/- 5 mm Hg) in systolic blood pressure occurred in the low-renin group (n = 5). In all the captopril-tested patients (n = 22), the decrease in systolic blood pressure by captopril was related to the control plasma renin activity (r = 0.75, p less than 0.001). These results indicate that the plasma renin activity value indicates the participation of the renin-angiotensin system in the maintenance of the elevated systolic blood pressure in patients with isolated systolic hypertension.     

Comparative effects of volume loading, dobutamine, and nitroprusside in patients with predominant right ventricular infarction

To assess the value of volume loading and to determine the relative efficacy of dobutamine compared with nitroprusside therapy in acute right ventricular infarction (RVMI), 13 patients with clinical, hemodynamic, and radionuclide angiographic evidence of RVMI were evaluated. In 10 patients who had an initial pulmonary arterial wedge pressure less than 18 mm Hg, volume loading did not improve cardiac index (1.9 +/- 0.5 [SD] to 2.1 +/- 0.4 liters/min/m2), despite significant increases in mean right atrial pressure (11 +/- 2 to 15 +/- 2 mm Hg, p less than .001) and pulmonary arterial wedge pressure (10 +/- 4 to 15 +/- 2 mm Hg, p less than .001). Nine patients received dobutamine or nitroprusside in random order, while hemodynamic measurements and radionuclide angiograms were obtained simultaneously. Compared with nitroprusside, dobutamine produced a statistically significant increase in cardiac index (2.0 +/- 0.4 to 2.7 +/- 0.5 vs 2.1 +/- 0.4 to 2.3 +/- 0.5 liters/min/m2, p less than .001), stroke volume index (29 +/- 6 to 36 +/- 8 vs 29 +/- 6 to 30 +/- 6 ml/m2, p = .02), and right ventricular ejection fraction (30 +/- 8% to 42 +/- 7% vs 34 +/- 8% to 37 +/- 4%, p less than .01) by two-way analysis of variance. We conclude that volume loading does not improve cardiac index in patients with acute RVMI despite a rise in cardiac filling pressures and that infusion of dobutamine, after appropriate volume loading, produces a significant improvement in cardiac index and right ventricular ejection fraction over those after infusion of nitroprusside.