Ian A. Reid

Chronic exercise reduces sympathetic nerve activity in rabbits with pacing-induced heart failure: A role for angiotensin II.

BackgroundChronic exercise (EX) improves the quality of life and increases the survival of patients with chronic heart failure (CHF). Because sympathetic nerve activity is elevated in the CHF state, it is possible that EX is beneficial in this disease due to a decrease in sympathetic outflow. Methods and ResultsWe evaluated arterial baroreflex function and resting renal sympathetic nerve activity (RSNA) in EX normal and CHF rabbits before and after angiotensin II type 1 (AT1) receptor blockade. Four groups of rabbits were studied: a normal non-EX group, a normal EX group, a CHF non-EX group, and a CHF EX group. EX lowered resting RSNA in rabbits with CHF but not in normal rabbits. In addition, EX increased arterial baroreflex sensitivity in the CHF group (heart rate slope: CHF 1.7±0.3 bpm/mm Hg, EX CHF 4.9±0.3 bpm/mm Hg;P <0.01; RSNA slope: CHF 2.2±0.2%max/mm Hg, EX CHF 5.7±0.4%max/mm Hg;P <0.01. AT1 receptor blockade enhanced baroreflex sensitivity in the non-EX CHF rabbits but had no effect in EX CHF rabbits. Concomitant with this effect, EX lowered the elevated plasma angiotensin II concentration in the CHF group. A significant positive correlation was observed between sympathetic nerve activity and plasma angiotensin II. ConclusionsThese data strongly suggest that EX reduces the sympathoexcitatory state in the setting of CHF. Enhanced arterial baroreflex sensitivity may contribute to this reduction. In addition, EX lowers plasma angiotensin II concentration in CHF. These data further suggest that the lowering of angiotensin II may contribute to the decrease in sympathetic nerve activity after EX in the CHF state.

Role of the area postrema in the modulation of the baroreflex control of heart rate by angiotensin II.

During angiotensin II (Ang II)-induced elevation of arterial pressure, there is an attenuation of the baroreflex control of heart rate (HR), but the site of this action of Ang II on the baroreflex is not known. To investigate the role of the area postrema, the effects of Ang II on arterial pressure and HR and on the baroreflex control of HR were compared in intact and area postrema-lesioned conscious rabbits. In intact rabbits, infusion of Ang II (2.5-100 ng/kg/min) produced dose-related increases in mean arterial pressure (MAP); the largest dose increased MAP by 32 +/- 3 mm Hg. HR decreased only at the highest dose of Ang II (21 +/- 6 beats/min). In lesioned rabbits, the increase in MAP was reduced (23 +/- 2 mm Hg, p less than 0.05) while the decrease in HR was enhanced (50 +/- 8 beats/min, p less than 0.01). The pressor and HR responses to infusion of phenylephrine (PE) (2-20 micrograms/kg/min) were not different between the two groups. In intact rabbits, the slope of the relation between HR and MAP during Ang II infusion was less than that during PE infusion; in lesioned rabbits, the slopes were not significantly different. Responses to bolus injections of Ang II and PE in intact and lesioned rabbits were similar to those obtained in the infusion study. In another series of experiments, cardiac baroreflex responses with or without background infusion of Ang II were obtained by increasing blood pressure with graded infusions of PE (2-20 micrograms/kg/min). In intact rabbits, infusion of Ang II at 10 ng/kg/min shifted the baroreflex to a higher pressure level (resetting) without changing its slope (sensitivity). Background infusion of PE caused comparable increases in blood pressure, but the subsequent baroreflex response was identical to the response without background PE. In lesioned rabbits, background infusion of Ang II did not change the slope, nor did it reset the baroreflex. The effects of Ang II on baroreflex responses during nitroprusside infusions (2-20 micrograms/kg/min) in intact and lesioned rabbits were the same as those observed during the PE infusions. These findings indicate that the attenuation of the baroreflex control of HR by Ang II results from resetting of the cardiac baroreflex and suggest that this effect is mediated via the area postrema.

Cardiovascular and Endocrine Effects of Acupuncture in Hypertensive Patients

It has been reported that acupuncture can decrease blood pressure in patients with hypertension, possibly by an endocrine mechanism. The aim of the present study was to investigate the effects of acupuncture on arterial blood pressure and the secretion of renin, vasopressin and cortisol in hypertensive patients. Acupuncture was performed in fifty untreated essential hypertensive patients resting in the supine position. Thirty min after acupuncture there were decreases in systolic pressure from 169 +/- 2 to 151 +/- 2 mm Hg, diastolic pressure from 107 +/- 1 to 96 +/- 1 mm Hg, and heart rate from 77 +/- 2 to 72 +/- 2 bpm (P < 0.01). Plasma renin activity decreased from 1.7 +/- 0.4 to 1.1 +/- 0.2 ng/ml/2h (P < 0.01), but there were no significant changes in plasma vasopressin or cortisol concentrations. These results confirm that acupuncture decreases blood pressure in hypertensive patients, and suggest that the decrease results, at least in part, from a decrease in renin secretion.

[Sar1, Ala8] angiotensin II in cerebrospinal fluid blocks the binding of blood-borne [125I]angiotensin II to the circumventricular organs

There is a specific, high affinity uptake of angiotensin II in the circumventricular organs when the peptide is injected systemically. The question of whether angiotensin II in cerebrospinal fluid can reach angiotensin receptors in the circumventricular organs was investigated in rats by determining the effect of intraventricular administration of the angiotensin II receptor blocking peptide [Sar,Ala]angiotensin II (saralasin) on the binding of blood-borne [125I]angiotensin II. Other rats received intraventricular saline, intraventricular ACTH as a peptide control, or intravenous saralasin. The brains of the rats were then sectioned and subjected to radioautography. ACTH had no effect on angiotensin II uptake. Intraventricular saralasin reduced the uptake of blood-borne angiotensin II in the median eminence and organum vasculosum of the lamina terminalis to the same degree as intravenous saralasin, and reduced uptake in the subfornical organ and area postrema to a lesser extent. Uptake was reduced 40% in the anterior lobe of the pituitary by intraventricular saralasin and 73% by intravenous saralasin, indicating that some saralasin entered the portal vessels. Uptake in the posterior lobe was unaffected by intraventricular saralasin, but reduced by intravenous saralasin. The data indicate that saralasin, and so presumably angiotensin II, in the cerebrospinal fluid can reach angiotensin II receptors in the circumventricular organs which bind blood-borne angiotensin II. Consequently, the effects of intraventricular angiotensin II that are also produced by intravenous angiotensin II can probably be explained by the peptide acting on the circumventricular organs.

Role of Vasopressin Deficiency in the Vasodilation of Septic Shock

Septic shock is a form of distributive shock most commonly caused by infection with gram-negative bacteria.1 2 The hallmark of septic shock is marked peripheral arteriolar vasodilation, which results in low systemic vascular resistance, high cardiac output, severe hypotension, and inadequate tissue perfusion. Therapy typically includes administration of fluids and vasopressor agents. The mechanism of the vasodilation of septic shock remains incompletely understood, but considerable evidence implicates abnormalities of vasodilator mechanisms. Much attention has been focused on bacterial lipopolysaccharide or endotoxin, the administration of which reproduces many of the cardiovascular alterations that occur in septic shock.3 Endotoxin stimulates the synthesis of tumor necrosis factor, interleukin 1, and other cytokines, and these substances in turn increase the generation of the vasodilator nitric oxide. Thus, inhibition of nitric oxide synthase reverses endotoxin- or cytokine-induced hypotension in experimental animals4 5 6 7 and increases systemic vascular resistance and blood pressure in patients with septic shock who have not responded to conventional therapy.8 In addition to increased generation of nitric oxide, there may also be activation of the vascular ATP-sensitive K+ channel in septic shock.9 Opening of this channel hyperpolarizes vascular smooth muscle and reduces Ca2+ entry through voltage-gated Ca2+ channels, thereby inducing vasodilation. There may also be abnormalities in vasoconstrictor mechanisms in septic shock. In this issue, Landry and associates10 present evidence that deficiency of vasopressin, now recognized as an important vasoconstrictor peptide, contributes to the hypotension of septic shock. Vasopressin is a peptide hormone that is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and transported to the posterior pituitary, where it is stored. It is released into the circulation upon stimulation by increased plasma osmolality or as a baroreflex response to decreases in blood volume or blood pressure.11 Release …

Role of the renin-angiotensin system in the control of vasopressin secretion in conscious dogs.

The present studies were designed to evaluate the physiological significance of angiotensin II in the control of vasopressin secretion in conscious dogs. They demonstrated that exogenous angiotensin II (10 ng/kg per min) increased vasopressin secretion more when the pressor effect of angiotensin II was abolished. The fact that endogenous angiotensin II levels are normally increased without an increase in arterial pressure suggests that angiotensin II may play a greater role in the control of vasopressin secretion than was previously thought. The present study also evaluated the role of endogenous angiotensin II in the control of vasopressin secretion during sodium depletion, a state in which angiotensin II levels are elevated. Intracarotid infusion of a low dose of the angiotensin II antagonist, saralasin, decreased plasma vasopressin concentration, suggesting that endogenous angiotensin II acts in an area of the brain perfused by the carotid arteries to stimulate vasopressin secretion in sodium-deprived dogs. Finally, the present experiments evaluated the role of angiotensin II in baroreceptor reflex control of vasopressin secretion. Baroreflex function was assessed by examining the relationship between the change in blood pressure and the log of the change in vasopressin secretion over a range of blood pressure levels. Exogenous angiotensin II (10 ng/kg per min) altered baroreflex function by causing a shift of this relationship to a higher pressure level in sodium-replete dogs. In sodium-depleted dogs, inhibition of the renin-angiotensin system with saralasin or captopril produced an opposite shift. These results suggest that endogenous angiotensin II may be necessary for the maintenance of normal baroreflex control of vasopressin secretion during sodium depletion. Collectively, these results support the hypothesis that endogenous angiotensin II plays a role in the control of vasopressin secretion.

Role of nitric oxide in the regulation of renin and vasopressin secretion.

Research during recent years has established nitric oxide as a unique signaling molecule that plays important roles in the regulation of the cardiovascular, nervous, immune, and other systems. Nitric oxide has also been implicated in the control of the secretion of hormones by the pancreas, hypothalamus, and anterior pituitary gland, and evidence is accumulating that it contributes to the regulation of the secretion of renin and vasopressin, hormones that play key roles in the control of sodium and water balance. Several lines of evidence have implicated nitric oxide in the control of renin secretion. The enzyme nitric oxide synthase is present in vascular and tubular elements of the kidney, particularly in cells of the macula densa, a structure that plays an important role in the control of renin secretion. Guanylyl cyclase, a major target for nitric oxide, is also present in the kidney. Drugs that inhibit nitric oxide synthesis generally suppress renin release in vivo and in vitro, suggesting a stimulatory role for the L-arginine/nitric oxide pathway in the control of renin secretion. Under some conditions, however, blockade of nitric oxide synthesis increases renin secretion. Recent studies indicate that nitric oxide not only contributes to the regulation of basal renin secretion, but also participates in the renin secretory responses to activation of the renal baroreceptor, macula densa, and beta adrenoceptor mechanisms that regulate renin secretion. Histochemical and immunocytochemical studies have revealed the presence of nitric oxide synthase in the supraoptic and paraventricular nuclei of the hypothalamus and in the posterior pituitary gland. Colocalization of nitric oxide synthase and vasopressin has been demonstrated in some hypothalamic neurons. Nitric oxide synthase activity in the hypothalamus and pituitary is increased by maneuvers known to stimulate vasopressin secretion, including salt loading and dehydration. Administration of L-arginine and nitric oxide donors in vitro and in vivo has variable effects on vasopressin secretion, but the most common one is inhibition. Blockade of nitric oxide synthesis has been reported to increase vasopressin secretion, but again variable results have been obtained. An attractive working hypothesis is that nitric oxide serves a neuromodulatory role as an inhibitor of vasopressin secretion.

Effect of Theophylline and Adrenergic Blocking Drugs on the Renin Response to Norepinephrine In Vitro

The effects of norepinephrine, theophylline, and adrenergic blocking drugs on renin release from rat kidney slices were studied in vitro. l-Norepinephrine increased renin release into the incubation medium; this increase was accompanied by an increase in the renin content of the slices. Statistically significant increases in renin release were produced by 10−5M and 2 × 10−5M l-norepinephrine. d-Norepinephrine in the same doses was ineffective. Theophylline (10−3M) had no effect by itself, but it potentiated the effect of l-norepinephrine on renin release. The response to l-norepinephrine was markedly suppressed by l-propranolol (10−4M) but not by d-propranolol (10−4M). The α-receptor blocking agents phentolamine (10−4M) and phenoxybenzamine (10−4M) increased rather than decreased the effect of l-norepinephrine. These results are consistent with a direct intrarenal effect of norepinephrine on renin release; this effect appears to be mediated by a β-adrenergic mechanism.

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.

Angiotensin II exerts differential actions on renal nerve activity and heart rate.

Angiotensin II (Ang II) exerts complex actions on sympathetic nerve activity and heart rate, but these actions are incompletely understood. We performed three series of experiments in conscious rabbits to analyze the actions of exogenous and endogenous Ang II on renal sympathetic nerve activity and heart rate. (1) Graded intravenous doses of phenylephrine and Ang II suppressed renal sympathetic nerve activity to the same degree, whereas Ang II decreased heart rate much less than phenylephrine. (2) Ang II infusion at 10 ng/kg per minute increased mean arterial pressure by 13 +/- 2 mm Hg (P < .01) and decreased renal sympathetic nerve activity by 67 +/- 13% (P < .01) but did not change heart rate. In the same rabbits, nitroprusside and phenylephrine infusions were used to generate baroreceptor reflex curves. Ang II shifted the heart rate-mean arterial pressure curve to the right but did not alter the renal nerve activity-mean arterial pressure curve. (3) The Ang II type 1 receptor antagonist losartan decreased mean arterial pressure by 8 +/- 3 mm Hg (P < .01) and increased renal sympathetic nerve activity by 63 +/- 15% (P < .05) but did not change heart rate. Losartan shifted the heart rate-mean arterial pressure curve to the left but did not alter the renal nerve activity-mean arterial pressure curve. These results demonstrate that whereas exogenous Ang II resets the baroreceptor reflex control of heart rate to a higher pressure, it does not increase resting renal sympathetic nerve activity or alter the baroreceptor reflex control of renal nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)