Catherine C.Y. Pang

Autonomic control of the venous system in health and disease: effects of drugs

The venous system contains approximately 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an alpha1- or alpha2-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An alpha1- or alpha2-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several alpha-adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.

Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats

Apelin is an endogenous depressor peptide for the G protein-coupled APJ receptor. Our hypothesis is that apelin is a venodilator, and it reduces mean circulatory filling pressure (MCFP; index of venous tone). Dose-response curves of apelin (10, 20 and 40 nmol/kg) or vehicle (0.9% NaCl) were constructed in two groups each of conscious, unrestrained rats: unblocked rats and rats pretreated with mecamylamine (Mec; ganglionic blocker) and noradrenaline (NA; to restore vascular tone). The vehicle had no effects in the unblocked or ganglionic-blocked rats. Apelin decreased mean arterial pressure (MAP) and increased heart rate (HR), but it did not alter mean circulatory filling pressure in the unblocked rats. In the ganglionic-blocked rats, apelin did not alter heart rate but decreased mean arterial pressure and mean circulatory filling pressure. These results show that apelin is an arterial and venous dilator in vivo. The depressor effect of apelin is accompanied by tachycardia which is abolished by ganglion blockade.

Cardiovascular side-effects of antipsychotic drugs: the role of the autonomic nervous system.

Cardiovascular disease is the leading cause of death in people with severe mental disorders, and rates are proportionally greater than for other diseases such as cancer. Reports of sudden death in patients receiving antipsychotic treatment have raised concerns about the safety of antipsychotic drugs, leading to a number of recent changes in how such drugs are advertised and marketed. The majority of second generation antipsychotic drugs also have significant metabolic side-effects, such as weight gain, insulin resistance and hyperlipidemia, which may contribute indirectly to cardiovascular complications. As the use of antipsychotic drugs continues to expand into new indications and populations such as children and adolescents, a better understanding is needed of how antipsychotic drugs affect the cardiovascular system. Antipsychotic drugs interact with numerous receptors both centrally and peripherally, including monoamine receptors. The direct, non-specific pharmacological actions of antipsychotic drugs can lead to adverse cardiovascular effects, including orthostatic hypotension, tachycardia and ventricular arrhythmias. The mechanisms responsible for these antipsychotic-induced cardiovascular abnormalities have not been fully elucidated, but likely involve blockade of adrenergic or cholinergic receptors and hERG channels, in addition to impaired autonomic function. The direct and indirect effects of antipsychotic drugs on the cardiovascular system and their possible mechanisms of action are discussed in this review, where both preclinical and clinical findings are integrated.

Measurement of body venous tone.

The venous system contains about 70% of the blood volume, and approximately 75% of the venous volume is in the small veins and venules. Veins play an active role in the control of cardiac output (CO) and blood pressure. Drugs that interfere with venous tone have profound effects on CO and blood pressure due to the large venous capacity. Information on body venous tone cannot be obtained from studies using isolated venous preparations and perfused venous beds, which lack modulating cardiovascular reflex mechanisms. In vivo methods used for the assessment of venous function in experimental animals and humans are as follows: the mean circulatory filling pressure (MCFP) method for the determination of body venous tone, constant CO reservoir technique for measuring vascular compliance and unstressed volume, plethysmography or blood-pool scintigraphy along with venous occlusion for measuring the volume and compliance of an organ, linear variable differential transformer (LVDT) technique for estimating the diameter of a human dorsal hand vein, intravascular ultrasound (IVUS) imaging technique to monitor the cross-sectional area of a large vein, and ultrasonic crystals to estimate the dimension of an organ. These methods are described and critically evaluated to disclose their validity, merits and limitations.

Effects of calcitonin gene‐related peptide receptor antagonists on renal actions of adrenomedullin

1 Adrenomedullin is a novel vasoactive peptide which is produced in the lungs, ventricle, kidneys, heart and adrenal medulla. Adrenomedullin shows homology to calcitonin gene‐related peptide (CGRP) and has similar pharmacological actions to CGRP. 2 This study examined the dose‐response effects of adrenomedullin (rat, 11–50) on mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF), glomerular filtration rate (GFR) and renal tubular electrolyte excretion in Inactin‐anaesthetized Sprague Dawley rats. The possible involvement of CGRP receptors in actions of adrenomedullin was also examined via renal arterial injection of a CGRP receptor antagonist, CGRP (8–37) (1 or 10 nmol kg−1) or [Tyr0]CGRP(28–37) (3 or 30 nmol kg−1), starting 15 min prior to the administration of adrenomedullin. 3 Renal arterial infusion (0.001 to 1 nmol kg−1) of adrenomedullin did not alter MAP, HR and renal K+ excretion but dose‐dependently increased RBF and arterial conductance, GFR, urine flow and Na+ excretion. 4 The renal actions of adrenomedullin were not blocked by either the low or the high dose of CGRP(8–37) or [Tyr0]CGRP(28–37). 5 The results show that adrenomedullin causes renal vasodilatation, increments in GFR, diuresis and natriuresis. The renal actions of adrenomedullin are not mediated via the activation of CGRP1 receptors.

Increase by NG-nitro-L-arginine methyl ester (L-NAME) of resistance to venous return in rats

1 The effects of the nitric oxide (NO) synthase inhibitor, NG‐nitro‐L‐arginine methyl ester (L‐NAME), on mean circulatory filling pressure (MCFP), total peripheral resistance (TPR), cardiac output (CO) and resistance to venous return (Rv) were studied in rats.

The effects of noradrenaline, B-HT 920, methoxamine, angiotensin II and vasopressin on mean circulatory filling pressure in conscious rats.

1 The effects of vasoactive substances on mean circulatory filling pressure (MCFP), an index of total body venous tone, were determined in conscious rats. 2 Cumulative doses of saline (0.9% w/v NaCl solution), methoxamine (α1‐adrenoceptor agonist), B‐HT 920 (α2‐adrenoceptor agonist) noradrenaline and vasopressin, and individual doses of angiotensin II (AII), were infused into the rats. Mean arterial pressure (MAP), MCFP and heart rate (HR) were determined before and during the plateau responses to infusions of the vasoactive substances. 3 The infusions of all the agonists caused a dose‐dependent increase in MAP and a decrease in HR. The infusion of saline affected neither MAP nor HR. 4 The infusions of saline and methoxamine did not affect MCFP while the infusions of B‐HT 920, noradrenaline and AII increased MCFP. MCFP was slightly increased during the infusion of high doses of vasopressin. 5 It was concluded that receptors for the α2‐adrenoceptor agonist and AII are involved in the control of venous tone. Receptors for the α1‐adrenoceptor agonist and vasopressin are not important for the control of venous tone.

Effects of inhalation and intravenous anaesthetic agents on presser response to NG-nitro-L-arginine

The effects of anaesthetic agents on pressor effect of NG-nitro-L-arginine (L-NNA), a potent inhibitor of nitric oxide (NO) synthesis, were examined in rats. I.v. bolus of L-NNA (1-32 mg/kg) in conscious rats dose dependently increased mean arterial pressure (MAP) to a maximum value of 53 +/- 2 mmHg at 16 mg/kg with ED50 value of 4.7 +/- 0.9 mg/kg. The effects of a single i.v. bolus dose (32 mg/kg) of L-NNA were examined in conscious rats and rats anaesthetised with pentobarbital, chloralose, ketamine, althesin (mixture of alphaxalone and alphadolone), urethane, enflurane or halothane. In conscious rats, peak MAP (51 +/- 3 mmHg) was reached 10 min after i.v. injection and the effect lasted more than two hours. The magnitudes of peak MAP differed under the influence of anaesthetic agents with the following rank order: althesin greater than conscious = pentobarbital = chloralose = ketamine = urethane greater than enflurane much greater than halothane (in which there was negligible change in MAP). The onsets were delayed in rats anaesthetised with pentobarbital, althesin, chloralose and enflurane but not altered with ketamine and urethane compared to that in conscious rats. Therefore, L-NNA caused intense and prolonged pressor response in conscious rats and rats anaesthetised with the i.v. anaesthetic agents pentobarbital, chloralose, ketamine, althesin and urethane. MAP effect of L-NNA was markedly attenuated by the inhalation anaesthetics halothane and enflurane.

Pressor effect of NG-nitro-L-arginine in pentobarbital-anesthetized rats.

The pressor effect of NG-nitro-L-arginine (L-NNA), a potent inhibitor of nitric oxide (NO) synthesis, was studied in pentobarbital anesthetized rats. Iv injections of L-NNA from 0.25 to 8 mg/kg caused bradycardia and a dose-dependent increase in mean arterial pressure (MAP) with a maximal response of 43 +/- 5 mmHg and ED50 value of 1.3 +/- 0.2 mg/kg. The time course of the response to the injection of a single dose of L-NNA was also determined. Peak response was reached 60 min after the injection of a single dose (4 mg/kg, iv) and the effect lasted greater than 5 h. The rising phase of the pressor response was accompanied by slight bradycardia while the recovery phase was associated with significant tachycardia. Iv injections of L-arginine (12.5-200 mg/kg) caused transient dose-dependent reductions in MAP. The pressor effect of L-NNA (4 mg/kg, iv bolus) was dose-dependently attenuated by L-arginine. The results show that L-NNA is an efficacious and long-acting pressor agent and are consistent with the hypothesis that endogenous NO plays an important role in the regulation of blood pressure.

α1b‐Adrenoceptors mediate renal tubular sodium and water reabsorption in the rat

1 It is known that activation of α1‐adrenoceptors causes renal vasoconstriction and increased tubular Na+ and water reabsorption, with the α1a‐subtype mediating the constrictor effect. 2 This study examines which subtype of α1‐adrenoceptors mediates tubular Na+ and water reabsorption in pentobarbitone‐anaesthetized rats. In order to avoid systemic effects, phenylephrine (0.3 to 30 μg kg−1), methoxamine (0.1–10 μg kg−1) and vehicle were infused into the right renal artery (via the suprarenal artery) of three groups of rats. Two other groups of rats were continuously infused with the irreversible selective α1b‐adrenoceptor antagonist, chloroethylclonidine (3 mg kg−1 h−1) for 1 h, prior to the construction of dose‐response curves to phenylephrine or methoxamine. Another group was continuously infused with the irreversible selective α1a‐adrenoceptor antagonist, SZL‐49 (10 μg kg−1 h−1) for 1 h, prior to the construction of dose‐response curves to phenylephrine. Mean arterial pressure (MAP), heart rate (HR), urine flow, Na+ and K+ excretion, and urine osmolality were monitored. 3 Phenylephrine and methoxamine did not affect MAP or HR but dose‐dependently and significantly decreased urine flow, urine osmolality as well as Na+ excretion and, slightly increased K+ excretion, although this was significant only for phenylephrine. 4 The antidiuretic, antinatriuretic and kaliuretic effects of phenylephrine were abolished by pretreatment with chloroethylclonidine, but were not inhibited by SZL‐49. The inhibitory effects of methoxamine on urine flow and Na+ excretion were also almost totally abolished by chloroethylclonidine. 5 Our results show that α1b‐adrenoceptors mediate renal tubular Na+ and water reabsorption.