Greater Fall In Mean Arterial Pressure Research Articles

Effects of intrathecal kynurenate on arterial pressure during chronic osmotic stress in conscious rats

Increased plasma osmolality elevates mean arterial pressure (MAP) through activation of the sympathetic nervous system, but the neurotransmitters released in the spinal cord to regulate MAP during osmotic stress remain unresolved. Glutamatergic neurons of the rostral ventrolateral medulla project to sympathetic preganglionic neurons in the spinal cord and are likely activated during conditions of osmotic stress; however, this has not been examined in conscious rats. This study investigated whether increased MAP during chronic osmotic stress depends on activation of spinal glutamate receptors. Rats were chronically instrumented with an indwelling intrathecal (i.t.) catheter for antagonist delivery to the spinal cord and a radiotelemetry transmitter for continuous monitoring of MAP and heart rate. Osmotic stress induced by 48 h of water deprivation (WD) increased MAP by ~15 mmHg. Intrathecal kynurenic acid, a nonspecific antagonist of ionotropic glutamate receptors, decreased MAP significantly more after 48 h of WD compared with the water-replete state. Water-deprived rats also showed a greater fall in MAP in response to i.t. 2-amino-5-phosphonovalerate. Finally, i.t. kynurenic acid also decreased MAP more in an osmotically driven model of neurogenic hypertension, the DOCA-salt rat, compared with normotensive controls. Our results suggest that spinally released glutamate mediates increased MAP during 48-h WD and DOCA-salt hypertension.

Lack of the serotonin transporter (SERT) reduces the ability of 5-hydroxytryptamine to lower blood pressure

Serotonin (5-hydroxytryptamine; 5-HT) is a potent constrictor of isolated blood vessels. However, recent studies demonstrate that chronic 5-HT infusion results in a prolonged fall in blood pressure in the rat. This finding highlights the need for further study of 5-HT in the cardiovascular system. We tested the hypothesis that a functional serotonin transporter (SERT) is critical to enabling a 5-HT-induced fall in blood pressure. Experiments were performed in male and female rats to determine whether gender significantly affected the ability of 5-HT to lower blood pressure and to determine whether SERT dependence was different in male vs. female rats. 5-HT (25 μg/kg/min; s.c.) was infused for 7 days to male and female, SERT wild-type (WT) and SERT knockout (KO) rats. Mean arterial pressure (MAP) and heart rate were monitored via radiotelemetry. 5-HT produced a significantly greater fall in MAP (at the nadir) in the male SERT WT rat (-20 ± 1 mmHg) compared to the male SERT KO rat (-10 ± 2 mmHg). Similarly, 5-HT also produced a significantly greater fall in MAP (at the nadir) in the female SERT WT rat (-19 ± 1 mmHg) compared to the female SERT KO rat (-15 ± 0.4 mmHg). While the lack of a functional SERT protein did not prevent a 5-HT-induced fall in blood pressure, it did reduce the ability of 5-HT to lower blood pressure in the male and female SERT rat, suggesting a potentially important role for SERT in producing a 5-HT-induced fall in blood pressure.

Effect of intravenous angiotensin II infusion on responses to hypothalamic PVN injection of bicuculline.

The hypothalamic paraventricular nucleus (PVN) plays an important role in the sympathoexcitatory response to elevated plasma angiotensin II (Ang II). However, the mechanism by which Ang II influences sympathetic activity is not fully understood. In this study, we tested the hypothesis that GABA(gamma-aminobutyric acid)-ergic function in the PVN is reduced by peripheral infusion of Ang II. To accomplish this, rats received either intravenous Ang II (12 ng/kg per minute) or vehicle (D5W) for 7 days, and renal sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR) responses were recorded after unilateral PVN microinjection of the GABA-A receptor antagonist bicuculline methiodide (BMI, 0.1 nmol). Results indicate that in contrast to a significant increase in renal SNA, MAP, and HR observed in vehicle-infused rats (P<0.05), BMI injection into the PVN of Ang II-infused animals was without effect on all recorded variables. In a separate groups of animals, ganglionic blockade produced a significantly greater fall in MAP (P<0.01) in Ang II-infused rats than in vehicle-infused control rats, indicating that the contribution of SNA to the maintenance of blood pressure was elevated in the Ang II-infused group. Overall, these data indicate that cardiovascular and sympathoexcitatory responses to acute GABA-A receptor antagonism in the PVN are significantly blunted in rats after 7 days of intravenous infusion of Ang II. We conclude that an Ang II-induced reduction in GABAergic inhibition within the PVN may contribute to elevated SNA observed in this study.

Central haemodynamics during morphine abstinence in anaesthetized rats.

Central haemodynamics were studied in one group of morphine-dependent rats, and in a non-dependent control group, before and after administration of repeated bolus doses of naloxone. Dependence was induced by s.c. morphine pellet implantations. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO) and mean transit time (MTT) were measured in the conscious state, after induction of chloralose anaesthesia and after the administration of naloxone (0.005, 0.05, 0.5 and 5 mg kg-1 i.v.). Total peripheral resistance (TPR), stroke volume (SV) and central blood volume (CBV) were subsequently calculated. The haemodynamic variables did not differ significantly in the conscious state, except for a lower SV, when compared with the non-dependent control group. However, in response to anaesthesia the dependent rats exhibited a greater fall in MAP, mainly due to a TPR decrease. Naloxone elicited a marked increase in MAP in the morphine-dependent group, which was mainly caused by an increase in TPR. Naloxone induced no significant change compared with the control group in CO and CBV, while SV increased concomitantly with a lowered HR after naloxone in the morphine-dependent group. These results suggest that the withdrawal hypertension during morphine abstinence was mainly explained by an increase in TPR, reflecting an augmented tone of the resistance vessels. The minor changes in CBV indicate that the tone of the venous capacitance vessels was largely unaffected by naloxone-induced morphine abstinence.

The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes.

We have previously shown that mice transgenic for both the human renin and human angiotensinogen genes (RA+) exhibit appropriate tissue- and cell-specific expression of both transgenes, have 4-fold higher plasma angiotensin II (AII) levels, and are chronically hypertensive. However, the relative contribution of circulating and tissue-derived AII in causing hypertension in these animals is not known. We hypothesized that the brain renin-angiotensin system contributes to the elevated blood pressure in this model. To address this hypothesis, mean arterial pressure (MAP) and heart rate were measured in conscious, unrestrained mice after they were instrumented with intracerebroventricular cannulae and carotid arterial and jugular vein catheters. Intracerebroventricular administration of the selective AII type 1 (AT-1) receptor antagonist losartan (10 microgram, 1 microL) caused a significantly greater peak fall in MAP in RA+ mice than in nontransgenic RA- controls (-29+/-4 versus -4+/-2 mm Hg, P<0.01). To explore the mechanism of a central renin-angiotensin system-dependent hypertension in RA+ mice, we determined the relative depressor responses to intravenous administration of the ganglionic blocking agent hexamethonium (5 mg/kg) or an arginine vasopressin (AVP) V1 receptor antagonist (AVPX, 10 microgram/kg). Hexamethonium caused equal lowering of MAP in RA+ mice and controls (-46+/-3 versus -52+/-3, P>0.05), whereas AVPX caused a significantly greater fall in MAP in RA+ compared with RA- mice (-24+/-2 versus -6+/-1, P<0.01). Consistent with this was the observation that circulating AVP was 3-fold higher in RA+ mice than in control mice. These results suggest that increased activation of central AT-1 receptors, perhaps those located at sites involved in AVP release from the posterior pituitary gland, plays a role in the hypertension in RA+ mice. Furthermore, our finding that both human transgenes are expressed in brain regions of RA+ mice known to be involved in cardiovascular regulation raises the possibility that augmented local production of AII and increased activation of AT-1 receptors at these sites is involved.

1014-99 The Hypotensive Effect of the Angiotensin II Antagonist EXP 3174 Depends upon the Renin-Angiotensin System Activation in Conscious Dogs with Heart Failure

Since the renin-angiotensin system exerts deleterious effects in heart failure, angiotensin II antagonists are considered as a potential therapy in heart failure. Therefore, the acute hemodynamic effects of the angiotensin II antagonist EXP 3174 (EXP, 0.1 mg/kg) were compared to those of the angiotensin converting enzyme inhibitor enalaprilat (E, 1 mg/kg) in 14 chronically instrumented conscious dogs with heart failure induced by right ventricular pacing (240 bpm, 3 weeks). When all dogs were considered as one group, E lowered mean arterial pressure (MAP) by 14 ± 2 mmHg while EXP lowered MAP by 8 ± 2 mmHg (p &lt; 0.05 vs E). The fall in MAP after EXP was correlated with the baseline plasma angiotensin II level (r = 0.731) When dogs were grouped according to their baseline plasma levels of the renin-angiotensin system activity, dogs with low activation of the renin-angiotensin system (n = 7) had a greater fall in MAP during E (14 ± 3 mmHg) than during EXP (2 ± 1mmHg). Additional doses of E or EXP did not produce further changes. However, in dogs with marked activation of the renin-angiotensin system (n = 7) falls in MAP were not significantly different following E or EXP (E:14 ± 3 vs EXP: 13 ± 3 mmHg). Thus, in this model of heart failure, the angiotensin II antagonist EXP 3174 exerts potent acute hemodynamic effects. However, in contrast to Enalaprilat, the hypotensive effect of EXP 3174 depends upon the activation level of the renin-angiotensin system.

Autonomic control of the diurnal variation in arterial blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats.

The relative influences of sympathetic and parasympathetic neural modulation on mean arterial pressure (MAP) and heart rate (HR), and their respective variabilities, were studied in young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and HR in unrestrained rats. In addition, the autonomic nervous control of MAP and HR was studied in ageing SHR and WKY. Both WKY and SHR showed diurnal rhythms with regard to MAP and HR. The MAP variability was higher in SHR than in WKY during both daytime (inactive) and night-time (active), and did not change in response to either beta 1-adrenoceptor- or cholinergic blockade. Structural vascular changes, with a resultant increase in reactivity, may explain the elevated MAP variability in SHR. HR variability was clearly reduced in SHR; this was not influenced by vagal blockade, whereas HR variability was significantly reduced in WKY. This pattern is suggested to be due to a reduced tonic vagal discharge in SHR, as part of a persistent, mild defence reaction. The initial reduction in vagal activity will in turn eliminate vagally mediated tachycardias. Furthermore, administration beta 1-blockade to SHR of different ages caused a greater fall in MAP and HR than in WKY, indicating an increased dependence upon the sympathetic nervous system in SHR with age.

Rapid haemodynamic response to adrenocorticotrophin and the role of peripheral resistance in adrenocorticotrophin-induced hypertension in conscious sheep*

The haemodynamic effects associated with the onset of hypertension induced by infusion of adrenocorticotrophin (ACTH) were investigated in sheep. Analysis of haemodynamic data collected over 24 h by a computer-based monitoring system revealed that mean arterial pressure (MAP) was significantly increased after 4 h. Cardiac output was significantly raised after 1 h. The increased cardiac output was initially offset by a fall in calculated total peripheral resistance (CTPR) and MAP did not begin to rise until CTPR had returned to control values. This suggested that the return of CTPR to control values was essential for the development of hypertension. The development of ACTH-induced hypertension was prevented by both nisoldipine, a calcium channel blocker, and minoxidil, a vascular smooth muscle relaxant. Nisoldipine administration was also found to reverse established ACTH hypertension. A greater fall in MAP and CTPR occurred in the onset and established phase of ACTH hypertension sheep compared with normotensive controls. These results indicate that constriction of the peripheral vasculature is essential for the onset and maintenance of ACTH-induced hypertension in the sheep, and that the vasoconstriction does not involve a specific Ca21+-dependent mechanism because minoxidil was as effective as nisoldipine in abolishing the pressor response to ACTH. The onset of ACTH-induced hypertension in sheep is characterized by very rapid haemodynamic changes with an increase in cardiac output and a relative increase in CTPR after an initial peripheral vasodilatation.

Central haemodynamics during morphine abstinence in anaesthetized rats

Central haemodynamics were studied in one group of morphine‐dependent rats, and in a non‐dependent control group, before and after administration of repeated bolus doses of naloxone. Dependence was induced by s.c. morphine pellet implantations. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO) and mean transit time (MTT) were measured in the conscious state, after induction of chloralose anaesthesia and after the administration of naloxone (0.005, 0.05&gt; 0.5 and 5 mg kg−1 i.v.). Total peripheral resistance (TPR), stroke volume (SV) and central blood volume (CBV) were subsequently calculated. The haemodynamic variables did not differ significantly in the conscious state, except for a lower SV, when compared with the non‐dependent control group. However, in response to anaesthesia the dependent rats exhibited a greater fall in MAP, mainly due to a TPR decrease. Naloxone elicited a marked increase in MAP in the morphine‐dependent group, which was mainly caused by an increase in TPR. Naloxone induced no significant change compared with the control group in CO and CBV, while SV increased concomitantly with a lowered HR after naloxone in the morphine‐dependent group. These results suggest that the withdrawal hypertension during morphine abstinence was mainly explained by an increase in TPR, reflecting an augmented tone of the resistance vessels. The minor changes in CBV indicate that the tone of the venous capacitance vessels was largely unaffected by naloxone‐induced morphine abstinence.

Sympathetic nerve activity and central haemodynamics during mechanical ventilation with positive end-expiratory pressure in rats.

The aim of this study was to examine the effects of mechanical ventilation with increasing levels of positive end-expiratory pressure (PEEP) on sympathetic nerve activity (SNA), cardiac output (CO), stroke volume (SV), heart rate (HR), central blood volume (CBV), total peripheral resistance (TPR), mean arterial pressure (MAP), pulse pressure (PP) and right and left atrial transmural pressure in chloralose anaesthetized rats before and after vagotomy. Changing ventilatory pattern from spontaneous breathing (SB) to artificial ventilation with 10 cm H2O PEEP in intact animals caused a significant fall in CO, SV and CBV (42, 48 and 17%, respectively) and an increase in SNA, HR and TPR (90, 13 and 83%, respectively). The MAP increased slightly but significantly from 103 +/- 4 to 107 +/- 4 mmHg while PP decreased from 48 +/- 2 to 37 +/- 3, from spontaneous breathing (SB) to 10 cm H2O PEEP. Transmural left atrial pressure decreased significantly from 4.5 +/- 0.3 to 3.0 +/- 0.4 mmHg. After vagotomy, MAP and CO were significantly lower at 10 cm H2O PEEP and PP and SV were significantly lower at all levels of positive end-expiratory pressure than the corresponding prevagotomy values. In spite of a greater fall in MAP and PP during PEEP after vagotomy, the absolute and relative increase of SNA was significantly lower compared to corresponding prevagotomy values. We conclude that reflex cardiovascular adjustments elicited by ventilation with PEEP are not solely due to unloading of arterial baroreceptors as has been claimed by others. Unloading of cardiac receptors with tonically active inhibitory afferents in the vagi is probably also of great importance for the excitation of the sympathetic nervous system during mechanical ventilation with PEEP.