Combined Arterial Hypertension and Ischemic Stroke Exaggerate Anesthesia-Related Hypotension and Cerebral Oxygenation Deficits: A Preclinical Study.

BACKGROUND: Intraoperative arterial hypotension (IOH) is a common side effect of general anesthesia (GA), associated with poor outcomes in ischemic stroke. While IOH is more prevalent with hypertension, it is unknown whether IOH may differ when GA is induced during ischemic stroke, versus other clinical settings. This is important given that many stroke patients receive GA for endovascular thrombectomy. METHODS: We evaluate the cardiovascular responses to volatile GA (isoflurane in 100% o2 ) before and during middle cerebral artery occlusion stroke in rats instrumented to record blood pressure (BP) and cerebral tissue oxygenation (p o2 ) in the projected penumbra, in clinically relevant cohorts of normotensive (Wistar rat, n = 10), treated hypertensive (spontaneously hypertensive [SH] + enalapril, n = 12), and untreated hypertensive (SH rat, n = 12). RESULTS: During baseline induction of GA, IOH was similar in normotensive, treated hypertensive, and untreated hypertensive rats during the induction phase (first 10 minutes) (-24 ± 15 vs -28 ± 22 vs -48 ± 24 mm Hg; P > .05) and across the procedure (-24 ± 13 vs -30 ± 35 vs -39 ± 27 mm Hg; P > .05). Despite the BP reduction, cerebral p o2 increased by ~50% in all groups during the procedure. When inducing GA after 2 hours, all stroke groups showed a greater magnitude IOH compared to baseline GA induction, with larger falls in treated (-79 ± 24 mm Hg; P = .0202) and untreated(-105 ± 43 mm Hg; P < .001) hypertensive rats versus normotensives (-49 ± 21 mm Hg). This was accompanied by smaller increases in cerebral p o2 in normotensive rats (19% ± 32%; P = .0144 versus no-stroke); but a decrease in cerebral p o2 in treated (-11% ± 19%; P = .0048) and untreated (-12% ± 15%; P = .0003) hypertensive rats. Sham animals (normotensive and hypertensive) showed similar magnitude and pattern of IOH when induced with GA before and after sham procedure. CONCLUSIONS: Our findings are the first demonstration that ischemic stroke per se increases the severity of IOH, particularly when combined with a prior history of hypertension; this combination appears to compromise penumbral perfusion.

Variable role of carotid bodies in cardiovascular responses to exercise, hypoxia and hypercapnia in spontaneously hypertensive rats.

KEY POINTS: Carotid bodies play a critical role in maintaining arterial pressure during hypoxia and this has important implications when considering resection therapy of the carotid body in disease states such as hypertension. Curbing hypertension in patients whether resting or under stress remains a major global health challenge. We demonstrated previously the benefits of removing carotid body afferent input into the brain for both alleviating sympathetic overdrive and reducing blood pressure in neurogenic hypertension. We describe a new approach in rats for selective ablation of the carotid bodies that spares the functional integrity of the carotid sinus baroreceptors, and demonstrate the importance of the carotid bodies in the haemodynamic response to forced exercise, hypoxia and hypercapnia in conditions of hypertension. Selective ablation reduced blood pressure in hypertensive rats and re-set baroreceptor reflex function accordingly; the increases in blood pressure seen during exercise, hypoxia and hypercapnia were unaffected, abolished and augmented, respectively, after selective carotid body removal. The data suggest that carotid body ablation may trigger potential cardiovascular risks particularly during hypoxia and hypercapnia and that suppression rather than obliteration of their activity may be a more effective and safer route to pursue. ABSTRACT: The carotid body has recently emerged as a promising therapeutic target for treating cardiovascular disease, but the potential impact of carotid body removal on the dynamic cardiovascular responses to acute stressors such as exercise, hypoxia and hypercapnia in hypertension is an important safety consideration that has not been studied. We first validated a novel surgical approach to selectively resect the carotid bodies bilaterally (CBR) sparing the carotid sinus baroreflex. Second, we evaluated the impact of CBR on the cardiovascular responses to exercise, hypoxia and hypercapnia in conscious, chronically instrumented spontaneously hypertensive (SH) rats. The results confirm that our CBR technique successfully and selectively abolished the chemoreflex, whilst preserving carotid baroreflex function. CBR produced a sustained fall in arterial pressure in the SH rat of ∼20 mmHg that persisted across both dark and light phases (P < 0.001), with baroreflex function curves resetting around lower arterial pressure levels. The cardiovascular and respiratory responses to moderate forced exercise were similar between CBR and Sham rats. In contrast, CBR abolished the pressor response to hypoxia seen in Sham animals, although the increases in heart rate and respiration were similar between Sham and CBR groups. Both the pressor and the respiratory responses to 7% hypercapnia were augmented after CBR (P < 0.05) compared to sham. Our finding that the carotid bodies play a critical role in maintaining arterial pressure during hypoxia has important implications when considering resection therapy of the carotid body in disease states such as hypertension as well as heart failure with sleep apnoea.

Intracranial pressure influences the level of sympathetic tone.

Sympathetic overdrive is associated with many diseases, but its origin remains an enigma. An emerging hypothesis in the development of cardiovascular disease is that the brain puts the utmost priority on maintaining its own blood supply; even if this comes at the "cost" of high blood pressure to the rest of the body. A critical step in making a causative link between reduced brain blood flow and cardiovascular disease is how changes in cerebral perfusion affect the sympathetic nervous system. A direct link between decreases in cerebral perfusion pressure and sympathetic tone generation in a conscious large animal has not been shown. We hypothesized that there is a novel control pathway between physiological levels of intracranial pressure (ICP) and blood pressure via the sympathetic nervous system. Intracerebroventricular infusion of saline produced a ramped increase in ICP of up to 20 mmHg over a 30-min infusion period (baseline 4.0 ± 1.1 mmHg). The ICP increase was matched by an increase in mean arterial pressure such that cerebral perfusion pressure remained constant. Direct recordings of renal sympathetic nerve activity indicated that sympathetic drive increased with increasing ICP. Ganglionic blockade, by hexamethonium, preventing sympathetic transmission, abolished the increase in arterial pressure in response to increased ICP and was associated with a significant decrease in cerebral perfusion pressure. This is the first study to show that physiological elevations in ICP regulate renal sympathetic activity in conscious animals. We have demonstrated a novel physiological mechanism linking ICP levels with sympathetic discharge via a possible novel intracranial baroreflex.

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats.

KEY POINTS: Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure. Possible mechanisms include improvements in baroreceptor reflex sensitivity and renal function, restoration of cardiac calcium signalling towards control levels, and reduced neural inflammation. Our data suggest that the peripheral chemoreflex may be a viable therapeutic target for renovascular hypertension. ABSTRACT: The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (two kidney one clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. In the present study, we show that CSD ameliorates 2K1C hypertension and reveal the potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, and then underwent CSD (n = 9) or sham CSD (n = 9) 5 weeks after renal artery clipping, in comparison with normal Wistar rats (n = 5). After 21 days, renal function was assessed, and tissue was collected to assess sympathetic postganglionic intracellular calcium transients ([Ca2+ ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98 ± 4 mmHg vs. 2K1C: 147 ± 8 mmHg; P < 0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuroinflammatory markers and enhanced [Ca2+ ]I in stellate neurons (P < 0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14 ± 2 mmHg by week 3 (P < 0.01), which was accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca2+ ]i evoked responses from stellate neurons, and also reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurons and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension.

Deep brain stimulation for the treatment of resistant hypertension.

Hypertension is a leading risk factor for the development of several cardiovascular diseases. As the global prevalence of hypertension increases, so too has the recognition of resistant hypertension. Whilst figures vary, the proportion of hypertensive patients that are resistant to multiple drug therapies have been reported to be as high as 16.4 %. Resistant hypertension is typically associated with elevated sympathetic activity and abnormal homeostatic reflex control and is termed neurogenic hypertension because of its presumed central autonomic nervous system origin. This resistance to conventional pharmacological treatment has stimulated a plethora of medical devices to be investigated for use in hypertension, with varying degrees of success. In this review, we discuss a new therapy for drug-resistant hypertension, deep brain stimulation. The utility of deep brain stimulation in resistant hypertension was first discovered in patients with concurrent neuropathic pain, where it lowered blood pressure and improved baroreflex sensitivity. The most promising central target for stimulation is the ventrolateral periaqueductal gray, which has been well characterised in animal studies as a control centre for autonomic outflow. In this review, we will discuss the promise and potential mechanisms of deep brain stimulation in the treatment of severe, resistant hypertension.

Forgotten Circulation: Reduced Mesenteric Venous Capacitance in Hypertensive Rats Is Improved by Decreasing Sympathetic Activity.

BACKGROUND: The mesenteric venous reservoir plays a vital role in mediating blood volume and pressure changes and is richly innervated by sympathetic nerves; however, the precise nature of venous sympathetic regulation and its role during hypertension remains unclear. We hypothesized that sympathetic drive to mesenteric veins in spontaneously hypertensive (SH) rats is raised, increasing mean circulatory filling pressure (MCFP), and impairing mesenteric capacitance. METHODS: Arterial pressure, central venous pressure, mesenteric arterial, and venous blood flow were measured simultaneously in conscious male Wistar and SH rats. MCFP was assessed using an intraatrial balloon. Hemodynamic responses to volume changes (±20%) were measured before and after ganglionic blockade and carotid body denervation. Sympathetic venoconstrictor activity was measured in situ. RESULTS: MCFP in vivo (10.8±1.6 versus 8.0±2.1 mm Hg; P=0.0005) and sympathetic venoconstrictor drive in situ (18±1 versus 10±2 µV; P<0.0001) were higher in SH rats; MCFP decreased in SH rats after hexamethonium and carotid body denervation (7.6±1.4; P<0.0001 and 8.5±1.0 mm Hg; P=0.0045). During volume changes, arterial pressure remained stable. With blood loss, net efflux of blood from the mesenteric bed was measured in both strains. However, during volume infusion, we observed net influx in Wistar (+2.3±2.6 mL/min) but efflux in SH rats (-1.0±1.0 mL/min; P=0.0032); this counterintuitive efflux was abolished by hexamethonium and carotid body denervation (+0.3±1.7 and 0.5±1.6 mL/min, respectively). CONCLUSIONS: In SH rats, excessive sympathetic venoconstriction elevates MCFP and reduces capacitance, impairing volume buffering by mesenteric veins. We propose selective targeting of mesenteric veins through sympathetic drive reduction as a novel therapeutic opportunity for hypertension.

Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat.

The peripheral chemoreflex is known to be enhanced in individuals with hypertension. In pre-hypertensive (PH) and adult spontaneously hypertensive rats (SHRs) carotid body type I (glomus) cells exhibit hypersensitivity to chemosensory stimuli and elevated sympathoexcitatory responses to peripheral chemoreceptor stimulation. Herein, we eliminated carotid body inputs in both PH-SHRs and SHRs to test the hypothesis that heightened peripheral chemoreceptor activity contributes to both the development and maintenance of hypertension. The carotid sinus nerves were surgically denervated under general anaesthesia in 4- and 12-week-old SHRs. Control groups comprised sham-operated SHRs and aged-matched sham-operated and carotid sinus nerve denervated Wistar rats. Arterial blood pressure was recorded chronically in conscious, freely moving animals. Successful carotid sinus nerve denervation (CSD) was confirmed by testing respiratory responses to hypoxia (10% O(2)) or cardiovascular responses to i.v. injection of sodium cyanide. In the SHR, CSD reduced both the development of hypertension and its maintenance (P<0.05) and was associated with a reduction in sympathetic vasomotor tone (as revealed by frequency domain analysis and reduced arterial pressure responses to administration of hexamethonium; P<0.05 vs. sham-operated SHR) and an improvement in baroreflex sensitivity. No effect on blood pressure was observed in sham-operated SHRs or Wistar rats. In conclusion, carotid sinus nerve inputs from the carotid body are, in part, responsible for elevated sympathetic tone and critical for the genesis of hypertension in the developing SHR and its maintenance in later life.

Cardiovascular and autonomic responses to sexual activity in the rabbit.

1. Sexual intercourse is associated with an increased risk of death from arrhythmia development, myocardial infarction or stroke. It is unclear whether this increased risk is due to physical exertion alone or whether it is an inherent aspect of sexual activity itself. 2. Using a telemetric approach, we show that sexual activity is associated with transient (8-14 s) but profound increases in renal sympathetic nerve activity (RSNA; up to 22-fold that of baseline) in both male and female rabbits. This increase was significantly greater than that observed during physical exertion (three- to sixfold increase in RSNA). 3. In addition, we observed rapid transitions in male rabbits from tachycardia (422 ± 21 b.p.m.; P < 0.01) to bradycardia (186 ± 28 b.p.m.; P < 0.05) during and immediately following coitus. This suggests simultaneous activation of both the sympathetic and parasympathetic nervous systems. 4. The present study provides the first real-time insight into the extreme variation in neural and cardiovascular function occurring during sexual activity in normal healthy rabbits. Little is known about how the physiological responses to sexual activity may change under disease or drug-treatment states, and these findings may prove of use to these areas in future.

Integrative cerebral blood flow regulation in ischemic stroke.

Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.

The inevitability of ATP as a transmitter in the carotid body.

Atmospheric oxygen concentrations rose markedly at several points in evolutionary history. Each of these increases was followed by an evolutionary leap in organismal complexity, and thus the cellular adaptions we see today have been shaped by the levels of oxygen within our atmosphere. In eukaryotic cells, oxygen is essential for the production of adenosine 5'-triphosphate (ATP) which is the 'Universal Energy Currency' of life. Aerobic organisms survived by evolving precise mechanisms for converting oxygen within the environment into energy. Higher mammals developed specialised organs for detecting and responding to changes in oxygen content to maintain gaseous homeostasis for survival. Hypoxia is sensed by the carotid bodies, the primary chemoreceptor organs which utilise multiple neurotransmitters one of which is ATP to evoke compensatory reflexes. Yet, a paradox is presented in oxygen sensing cells of the carotid body when during periods of low oxygen, ATP is seemingly released in abundance to transmit this signal although the synthesis of ATP is theoretically halted because of its dependence on oxygen. We propose potential mechanisms to maintain ATP production in hypoxia and summarise recent data revealing elevated sensitivity of purinergic signalling within the carotid body during conditions of sympathetic overactivity and hypertension. We propose the carotid body is hypoxic in numerous chronic cardiovascular and respiratory diseases and highlight the therapeutic potential for modulating purinergic transmission.

A method to evaluate dynamic cerebral pressure-flow relationships in the conscious rat.

The classic dogma of cerebral autoregulation is that cerebral blood flow is steadily maintained across a wide range of perfusion pressures. This has been challenged by recent studies suggesting little to no "autoregulatory plateau" in the relationship between cerebral blood flow and blood pressure (BP). Therefore, the mechanisms underlying the cerebral pressure-flow relationship still require further understanding. Here, we present a novel approach to examine dynamic cerebral autoregulation in conscious Wistar rats (n = 16) instrumented to measure BP and internal carotid blood flow (iCBF), as an indicator of cerebral blood flow. Transient reductions in BP were induced by occluding the vena cava via inflation of a chronically implanted intravascular silicone balloon. Falls in BP were paralleled by progressive decreases in iCBF, with no evidence of a steady-state plateau. No significant changes in internal carotid vascular resistance (iCVR) were observed. In contrast, intravenous infusions of the vasoactive drug sodium nitroprusside (SNP) produced a similar fall in BP but increases in iCBF and decreases in iCVR were observed. These data suggest a considerable confounding influence of vasodilatory drugs such as SNP on cerebrovascular tone in the rat, making them unsuitable to investigate cerebral autoregulation. We demonstrate that our technique of transient vena cava occlusion produced reliable and repeatable depressor responses, highlighting the potential for our approach to permit assessment of the dynamic cerebral pressure-flow relationship over time in conscious rats.NEW & NOTEWORTHY We present a novel technique to overcome the use of vasoactive agents when studying cerebrovascular dynamics in the conscious rat. Our method of vena cava occlusion to reduce BP was associated with decreased iCBF and no change in iCVR. In contrast, comparable BP falls with intravenous SNP increased iCBF and reduced iCVR. Thus, the dynamic cerebral pressure-flow relationship shows a narrower, less level autoregulatory plateau than conventionally thought. We confirm our method allows repeatable assessment of cerebrovascular dynamics in conscious rats.

Quantifying sympathetic nerve activity: problems, pitfalls and the need for standardization.

Since the first recording of sympathetic nerve activity (SNA) early last century, numerous methods for presentation of the resulting data have developed. In this paper, we discuss the common ways of describing SNA and their application to chronic recordings. Suggestions on assessing the quality of SNA are made, including the use of arterial pressure wave-triggered averages and nasopharyngeal stimuli. Calculation of the zero level of the SNA signal from recordings during ganglionic blockade, the average level between bursts and the minimum of arterial pressure wave-triggered averages are compared and shown to be equivalent. The use of normalization between zero and maximal SNA levels to allow comparison between groups is discussed. We recommend that measured microvolt levels of integrated SNA be presented (with the zero/noise level subtracted), along with burst amplitude and frequency information whenever possible. We propose that standardization of the quantifying/reporting of SNA will allow better comparison between disease models and between research groups and ultimately allow data to be more reflective of the human situation.

Role of the Carotid Body in an Ovine Model of Renovascular Hypertension.

The carotid body is implicated as an important mediator and potential treatment target for hypertension. The mechanisms driving increased carotid body tonicity in hypertension are incompletely understood. Using a large preclinical animal model, which is crucial for translation, we hypothesized that carotid sinus nerve denervation would chronically decrease blood pressure in a renovascular ovine model of hypertension in which hypertonicity of the carotid body is associated with reduced common carotid artery blood flow. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. Hypertension was accompanied by a significant reduction in common carotid blood flow but no change in renal blood flow. Carotid sinus nerve denervation significantly reduced blood pressure compared with sham. In both hypertensive and normotensive animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure and common carotid conductance but a reduction in renal vascular conductance. These responses were not different between the animal groups. Taken together, our findings indicate that (1) the carotid body is activated in renovascular hypertension, and this is associated with reduced blood flow (decreased vascular conductance) in the common carotid artery and (2) the carotid body can differentially regulate blood flow to the common carotid and renal arteries. We suggest that in the ovine renovascular model, carotid body hypertonicity may be a product of reduced common carotid artery blood flow and plays an amplifying role with the kidney in the development of hypertension.

Therapeutic Relevance of Elevated Blood Pressure After Ischemic Stroke in the Hypertensive Rats.

Over 80% of patients exhibit an acute increase in blood pressure (BP) following stroke. Current clinical guidelines make no distinction in BP management between patients with or without prior hypertension. Spontaneously hypertensive (SH) rats were preinstrumented with telemeters to record BP, intracranial pressure, and brain tissue oxygen in the predicted ischemic penumbra for 3 days before and 10 days after transient middle cerebral artery occlusion (n=8 per group) or sham (n=5). Before stroke, BP was either left untreated or chronically treated to a normotensive level (enalapril 10 mg/kg per day). Poststroke elevations in BP were either left uncontrolled, controlled (to the prestroke baseline level), or overcontrolled (to a normotensive level) via subcutaneous infusion of labetalol. Baseline values of intracranial pressure and brain tissue oxygen were similar between all groups, whereas BP was lower in treated SH rats (144±3 versus 115±5 mm Hg; P<0.001). Following middle cerebral artery occlusion, a similar rise in BP was observed in untreated (+16±2 mm Hg; P=0.005) and treated SH rats (+13±5 mm Hg; P=0.021). Intervening to prevent BP from increasing after stroke did not worsen outcome. However, reducing BP below prestroke baseline levels was associated with higher intracranial pressure (days 1-3; P<0.001), reduced cerebral perfusion pressure (days 2-4; P<0.001), higher mortality, slower functional recovery and larger infarct volumes. Although treating to maintain BP at the prestroke baseline level was not detrimental, our results suggest that when setting BP targets after stroke, consideration must be given to the potential negative impact of inadvertent excessive BP lowering in subjects with undiagnosed or poorly controlled hypertension.

A high-salt diet does not influence renal sympathetic nerve activity: a direct telemetric investigation.

The importance of dietary salt in the development of hypertension has long been a source of controversy. Recent studies suggest a combination of high-salt and ANG II infusion may increase sympathetic drive; however, the effect of a change in dietary salt alone is unclear. Using telemetry, we recorded renal sympathetic nerve activity (RSNA), arterial pressure (MAP), and heart rate (HR) in seven New Zealand white rabbits before and during a 6-day period of increased salt intake (normal NaCl 0.5 g x kg(-1) x day(-1), high NaCl 2.5 g x kg(-1) x day(-1)) and a second group of seven rabbits with normal salt intake throughout. The responses to stressful stimuli encountered in the laboratory were recorded and compared with rest in control and high-salt groups. Resting MAP, HR, and RSNA were not significantly altered with high salt intake [88 +/- 5 vs. 91 +/- 6 mmHg; 251 +/- 8 vs. 244 +/- 9 beats per minute (bpm); 9.7 +/- and 1.2 vs. 10.8 +/- 1.7 normalized units (nu)] despite significant reductions in plasma renin activity (1.88 +/- 0.18 vs. 1.27 +/- 0.15 nmol ANG I x l(-1) x h(-1); P < 0.05) and ANG II (7.5 +/- 1.2 vs. 4.3 +/- 0.8 pmol/l). Increasing levels of stressful stimuli (resting in home cage, containment in box, handling, and nasopharyngeal activation) in animals on a normal salt diet caused graded increases in MAP (89 +/- 2 mmHg, 95 +/- 2 mmHg, 107 +/- 4 mmHg, and 122 +/- 5 mmHg, respectively) and RSNA (9.7 +/- 0.9 nu; 11.8 +/- 2.7 nu; 31.4 +/- 3.7 nu; 100 nu) but not HR (245 +/- 8 bpm; 234 +/- 8 bpm; 262 +/- 9 bpm; 36 +/- 5 bpm). High dietary salt did not significantly alter the responses to stress. We conclude that a 6-day period of high salt intake does not alter the level of RSNA, with non-neural mechanisms primarily responsible for the observed renin-angiotensin system suppression.

Blockade of Rostral Ventrolateral Medulla Apelin Receptors Does Not Attenuate Arterial Pressure in SHR and L-NAME-Induced Hypertensive Rats.

Dysfunction of the apelinergic system, comprised of the neuropeptide apelin mediating its effects via the G protein-coupled apelin receptor (APJ), may underlie the onset of cardiovascular disease such as hypertension. Apelin expression is increased in the rostral ventrolateral medulla (RVLM) in spontaneously hypertensive rats (SHRs) compared to Wistar-Kyoto (WKY) normotensive rats, however, evidence that the apelinergic system chronically influences mean arterial blood pressure (MABP) under pathophysiological conditions remains to be established. In this study we investigated, in conscious unrestrained rats, whether APJ contributes to MABP and sympathetic vasomotor tone in the progression of two models of hypertension - SHR and L-NAME-treated rats - and whether APJ contributes to the development of hypertension in pre-hypertensive SHR. In SHR we showed that APJ gene (aplnr) expression was elevated in the RVLM, and there was a greater MABP increase following microinjection of [Pyr1]apelin-13 to the RVLM of SHR compared to WKY rats. Bilateral microinjection of a lentiviral APJ-specific-shRNA construct into the RVLM of WKY, SHR, and L-NAME-treated rats, chronically implanted with radiotelemeters to measure MABP, decreased aplnr expression in the RVLM and abolished acute [Pyr1]apelin-13-induced increases in MABP. However, chronic knockdown of aplnr in the RVLM did not affect MABP in either SHR or L-NAME-treated rats. Moreover, knockdown of aplnr in the RVLM of prehypertensive SHR did not protect against the development of hypertension. These results show that endogenous apelin, acting via APJ, is not involved in the genesis or maintenance of hypertension in either animal model used in this study.

Evaluating the carotid bodies and renal nerves as therapeutic targets for hypertension.

Despite the plethora of current treatment options, hypertension remains a difficult condition to adequately control, and there is a pressing need for novel therapeutic strategies. The carotid body has recently become the focus of considerable interest as a potential novel treatment target in essential hypertension. Herein, we appraise the current literature suggesting that the carotid body plays an important causative role to generate sympathetic overactivity and drive increases in arterial pressure, in animal models of hypertension. We also review evidence from human studies showing cardiovascular benefits to the transient inactivation, or surgical removal of carotid bodies, and evaluate the potential benefits of pre-screening to identify patients likely to respond to carotid body-targeted therapy. Finally, given that a high proportion of patients who have undergone renal nerve ablation procedures remain hypertensive, we examine whether the renal nerves are necessary for the drop in blood pressure seen with carotid body removal.

Purinergic receptors in the carotid body as a new drug target for controlling hypertension.

In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.

Recording of intracranial pressure in conscious rats via telemetry.

Although cerebral perfusion pressure (CPP) is known to be fundamental in the control of normal brain function, there have been no previous long-term measurements in animal models. The aim of this study was to explore the stability and viability of long-term recordings of intracranial pressure (ICP) in freely moving rats via a telemetry device. We also developed a repeatable surgical approach with a solid-state pressure sensor at the tip of the catheter placed under the dura and in combination with arterial pressure (AP) measurement to enable the calculation of CPP. Telemeters with dual pressure catheters were implanted in Wistar rats to measure ICP and AP. We found that the signals were stable throughout the 28-day recording period with an average ICP value of 6 ± 0.8 mmHg. Significant light-dark differences were found in AP (3.1 ± 2.7 mmHg, P = 0.02) and HR (58 ± 12 beats/min, P = 0.003), but not ICP (0.3 ± 0.2 mmHg, P >0.05) or CPP (2.6 ± 2.8 mmHg, P > 0.05). Use of kaolin to induce hydrocephalus in several rats demonstrates the ability to measure changes in ICP throughout disease progression, validating this new solution for chronic measurement of ICP, CPP, and AP in conscious rats.