Significant Pressor Response Research Articles

Functional knockout of the TRPV1 channel has no effect on the exercise pressor reflex in rats.

The role played by the transient receptor potential vanilloid 1 (TRPV1) channel on the thin fibre afferents evoking the exercise pressor reflex is controversial. To shed light on this controversy, we compared the exercise pressor reflex between newly developed TRPV1+/+ , TRPV1+/- and TRPV1-/- rats. Carotid arterial injection of capsaicin (0.5μg), evoked significant pressor responses in TRPV1+/+ and TRPV1+/- rats, but not in TRPV1-/- rats. In acutely isolated dorsal root ganglion neurons innervating the gastrocnemius muscles, capsaicin evoked inward currents in neurons isolated from TRPV1+/+ and TRPV1+/- rats but not in neurons isolated from TRPV1-/- rats. The reflex was evoked by stimulating the tibial nerve in decerebrated rats whose femoral artery was either freely perfused or occluded. We found no difference between the reflex in the three groups of rats regardless of the patency of the femoral artery. For example, the peak pressor responses to contraction in TRPV1+/+ , TRPV1+/- and TRPV1-/- rats with patent femoral arteries averaged 17.1 ± 7.2, 18.9 ± 12.4 and 18.4 ± 8.6mmHg, respectively. Stimulation of the tibial nerve after paralysis with pancuronium had no effect on arterial pressure, findings which indicated that the pressor responses to contraction were not caused by electrical stimulation of afferent tibial nerve axons. We also found that expression levels of acid-sensing ion channel 1 and endoperoxide 4 receptor in the L4 and 5 dorsal root ganglia were not upregulated in the TRPV1-/- rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex in rats whose contracting muscles have either a patent or an occluded arterial blood supply. KEY POINTS: A reflex arising in contracting skeletal muscle contributes to the increases in arterial blood pressure, cardiac output and breathing evoked by exercise. The sensory arm of the reflex comprises both mechanoreceptors and metaboreceptors, of which the latter signals that blood flow to exercising muscle is not meeting its metabolic demand. The nature of the channel on the metaboreceptor sensing a mismatch between supply and demand is controversial; some believe that it is the transient receptor potential vanilloid 1 (TRPV1) channel. Using genetically engineered rats in which the TRPV1 channel is rendered non-functional, we have shown that it is not needed to evoke the metaboreflex.

TRPV1 on the endings of thin fiber muscle afferents is not needed to evoke the exercise pressor reflex

Laura Anselmi, Victor Ruiz-Velasco, Sean D. Stocker, Shannon P. Higgins, Guillaume P. Ducrocq and Marc P. Kaufman. The role played by the transient receptor potential vallinoid-1 (TRPV1) on the endings of thin fiber muscle afferents in evoking the exercise pressor reflex is controversial. To shed light on this controversy, we used TRPV1-/- rats that were made by a CRISPR-Cas9 deletion to introduce a 26-bp frameshift deletion in exon 3. We compared the magnitude of the reflex between TRPV1 +/+ wild-type rats (WT), TRPV1+/- heterozygous rats (HET), and TRPV1-/- knockout rats (KO). The exercise pressor reflex was evoked by stimulating the tibial nerve (40Hz, 0.01ms, 1.5 times motor threshold) in precollicular decerebrated unanesthetized rats whose femoral arteries were either freely perfused or were occluded for 30 sec before the start of contraction. We found that there was no difference between the magnitude of the reflex in the three groups of rats with freely perfused hindlimbs (p=0.61). Specifically, the exercise pressor reflex averaged 16.4 ± 2.2 mmHg in WT rats (n=9), 21.1 ± 5 mmHg in HET rats (n=9), and 17.7 ± 2.3 mmHg in KO rats (n=9). No difference was also observed among the three groups of rats that received acute femoral artery occlusion (p=0.79). Specifically, the peak exercise pressor reflex averaged 15.3 ± 2.2 mmHg in WT rats (n=4), 19.8 ± 4.7 mmHg in HET rats (n=6), and 19 ± 8 mmHg in KO rats (n=3). Stimulation of the tibial nerve after paralysis of the rats with pancuronium (iv) had trivial effects on arterial pressure indicating that the pressor responses to contraction were not caused by electrical stimulation within the axon of the tibial nerve. Intra-carotid arterial injection of the TRPV1 agonist, capsaicin (0.5 mg), evoked a significant pressor response in the WT rats (34.7 ± 9.2 mmHg) and in the HET rats (36.3 ± 7.2 mmHg), but not in the KO rats (3.2 ± 0.4 mmHg). In electrophysiological studies of dorsal root ganglion cells innervating the gastrocnemius muscles, capsaicin evoked inward currents in the WT and HET rats, but not in the KO rats. Moreover, immunofluorescence revealed the presence of TRPV1 in the DRG of WT, but not in the DRG of KO rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex either in rats whose femoral arteries were either freely perfused or were occluded. These results are consistent with our previous finding that pharmacological antagonism of TRPV1 had no effect on the exercise pressor reflex. Supported by HL156594 and HL 156513 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PS-B05-7: HYPERTENSION IN A MODEL OF PKD IS NOT DEPENDENT ON THE SHORT-TERM ACTIONS OF TUMOUR NECROSIS FACTOR-A IN THE SFO

Objective: The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by neuronal overactivity in the subfornical organ (SFO). Circulating proinflammatory cytokines, namely TNFα, are suggested to act in the central nervous system to produce an increase in neuronal excitability. As circulating cytokines are increased in kidney disease, we hypothesised that TNFα acts on the SFO to increase neuronal activity, therefore contributing to the development of hypertension in this animal model. Design and Methods: Urethane anaesthetised Lewis control (n = 23 total) and LPK (n = 18 total) animals were instrumented to record blood pressure and perform microinjections of TNFα (1–300pg/50nl), TNFα receptor 1 (TNFRI) neutralising antibody (1ng/50nl) or minocycline (0.5 μg/50nl), an inhibitor of microglial activation. Results: Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK animals (9 ± 2 mmHg vs -1 ± 3 mmHg, Lewis vs LPK peak change from baseline, P = 0.04). Acute inhibition of actions of local TNFα via administration of TNFRI neutralising antibody in the SFO did not reduce mean arterial blood pressure in Lewis control or LPK animals (1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.59). Acute blockade of the actions of all proinflammatory cytokines on microglia via microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK animals (-1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.11). Prior microinjection of TNFRI neutralising antibody into the SFO abolished the pressor response observed upon microinjection of TNFα in Lewis rats (9 ± 2 mmHg vs 1 ± 1 mmHg, TNFα vs TNFα after TNFRI Ab peak change from baseline, P = 0.01), whereas prior microinjection of minocycline into the SFO only attenuated the pressor response observed upon TNFα microinjection in Lewis rats (9 ± 2 mmHg vs 3 ± 1 mmHg, TNFα vs TNFα after Minocycline peak change from baseline, P = 0.04) Conclusions: Overall, these findings demonstrate that although hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of mean arterial blood pressure activity is not dependent on the actions of endogenous TNFα or generalised microglial activation by proinflammatory cytokines in the SFO.

Hypertension in an Animal Model of Kidney Disease is not Dependent on the Short‐Term Actions of Endogenous Tumour Necrosis Factor‐α in the SFO

Introduction The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by the overactivation of the subfornical organ (SFO). Circulating proinflammatory cytokines, namely tumour necrosis factor-α (TNFα), are suggested to act in the central nervous system to produce an increase in neuronal excitability. As circulating cytokines are increased in kidney disease, we hypothesised that TNFα acts on the SFO to increase neuronal activity, therefore contributing to the development of hypertension. Methods Urethane anaesthetised Lewis control (n=18 total) and LPK (n=18 total) rats were instrumented to record blood pressure and perform microinjections of TNFRI neutralising antibody (1ng/50nl) or minocycline (0.5µg/50nl), an inhibitor of microglial activation, followed by a GABAa agonist (10mM isoguvacine) into the SFO. Results Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK rats (9±2mmHg vs 3±4mmHg peak change from baseline, P=0.0004). Acute inhibition of local TNFα by microinjection of a TNFRI neutralising antibody into the SFO did not reduce mean arterial blood pressure in Lewis control or LPK rats (1±1mmHg vs -1±1mmHg change from baseline, P=0.78). Similarly, acute non-specific blockade of proinflammatory cytokines by microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK rats (-1±1mmHg vs -1±1mmHg change from baseline, P=0.98). Microinjection of a GABAa agonist into the SFO caused a significant depressor response that was not altered by the pre-treatment with a microinjection of TNFRI neutralising antibody in either strain (P>0.05), demonstrating that pre-treatment did alter the tonic activation of neurons within the SFO. Interestingly, pre-treatment with a microinjection of minocycline increased the tonic activation in the LPK (P=0.04), but not Lewis (P=0.15), as indicated by the increased depressor response to GABAa agonist microinjection. Conclusions Overall, these findings demonstrate that although the hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of blood pressure is not dependent on the actions of endogenous TNFα or generalised microglial and neuronal activation by proinflammatory cytokines in the SFO.

Inorganic phosphate and lactate potentiate the pressor response to acidic stimuli in rats.

What is the central question of this study? What is the contribution of the main acidic compounds accumulated during contractions, namely H+ , lactic acid and inorganic phosphate, to evoke the metabolic component of the exercise pressor reflex? What is the main finding and its importance? We found that the pressor response to acidic stimuli is driven by the concentration of hydrogen ions and that lactate and inorganic phosphate act as potentiating agents. H+ ions, lactate and inorganic phosphate are produced by contracting skeletal muscles and evoke, in part, the metabolic component of the exercise pressor reflex. Owing to their disparate dissociation constants (i.e. pKa ), the contribution of each acid to the muscle metaboreflex is unclear. This lack of information prompted us to determine the reflex pressor responses to injection of acidic saline, lactate (24mm)and inorganic phosphate(86mm)at various values of pH (from 2.66 to 7.5), alone or in combination, into the arterial supply of hindlimb skeletal muscle of decerebrate rats. In particular, we tested the hypothesis that the pressor response to an injection of a combination of lactate and phosphate at an acidic pH is greater than that evoked by injection of either phosphate or lactate alone at the same pH. We found that injection of acidic saline produced a pressor response only at a pH of 2.66 (7±4mmHg), an effect that was potentiated when the solution contained lactate (50±20mmHg). At a pH of 6.0, however, this effect was lost. At a pH of 6.0, only the injection of inorganic phosphate produced a significant pressor response (23±12mmHg). A large potentiating effect was found when lactate was added to the inorganic phosphate solution (39±18mmHg), an effect that was lost at a pH>7.0. Our findings led to the conclusion that the pressor response to injection of acidic solutions was driven by H+ ions and that inorganic phosphate and lactate functioned as sensitizing agents.

Corticotropin‐Releasing Hormone Receptor 2 in the Nucleus of the Solitary Tract Contributes to the Intermittent Hypoxia Induced Hypertension

Our previous study in rats suggested that Corticotropin‐Releasing Hormone (CRH) Receptor 2 (CRHR2) is the predominant CRH receptor in the nucleus of the solitary tract (NTS), a key nucleus that regulates autonomic and cardiovascular functions; exposure to intermittent hypoxia (IH), a model of the arterial hypoxemias that occur during sleep apnea, significantly decreased CRHR2 mRNA levels in the NTS. To study the CRHR2 signaling pathway in the NTS, we performed calcium imaging on NTS slice preparations using Fura‐2‐acetoxymethyl ester. CRH induced a transient increase of intracellular calcium level in NTS neurons that was abolished by the voltage‐dependent calcium channel blocker nifedipine. Calcium influx was attenuated by the CRHR2 antagonist K41498 but not by NBI‐35965, an antagonist for CRH receptor 1 (CRHR1). Calcium influx can be induced by the CRHR2 agonist Urocortin II but not by the CRHR1 agonist Stressin I. More importantly, consistent with the down‐regulation of CRHR2 mRNA after IH exposure, IH exposure also attenuated the CRH‐induced calcium influx in the NTS. Further in vivo pharmacological studies revealed that intra‐4th ventricle infusion of the CRHR2 agonist Urocortin II significantly increased basal blood pressure and exacerbated the IH‐induced hypertension in rats; intra‐4th ventricle infusion of the CRHR2 antagonist K41498 did not affect the basal blood pressure but significantly delayed the onset of IH‐induced hypertension. Considering that the NTS is the major CRHR2‐expressing nucleus in the brain stem that regulates sympathetic activity and blood pressure, these results indicate that activation of CRHR2 in the NTS contributes to the hypertension during IH. To study the source of CRH in the NTS that regulates blood pressure, we expressed Channelrhodopsin 2 (ChR2) specifically into the CRH‐producing neurons in the paraventricular nucleus of the hypothalamus (PVN) by injecting Cre‐inducible viral constructs expressing ChR2 into the PVN of CRH‐Cre mice. We observed significant pressor responses after optogenetic stimulation of CRH somas in the PVN (12.3 ± 1.13 mmHg) or CRH fibers in the NTS that originated from the PVN (3.54 ± 0.69 mmHg), suggesting that activation of CRH projections from the PVN to the NTS increases blood pressure. Collectively, these results suggest that CRH derived from the PVN activates CRHR2 in the NTS, which may contribute to the IH‐induced hypertension; down‐regulation of CRHR2 and CRHR2‐mediated calcium influx in the NTS may serve as compensatory responses to protect against the IH‐induced hypertension.Support or Funding InformationThis study was supported by National Institute of Health HL088052This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anti-diabetic drug metformin dilates retinal blood vessels through activation of AMP-activated protein kinase in rats

The aim of this study was to examine whether metformin, a biguanide anti-hyperglycemic drug, dilates retinal blood vessels in rats. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo and diameters of retinal blood vessels were measured. Both systemic blood pressure and heart rate were continuously recorded. Metformin (0.01–0.3mg/kg/min) increased diameters of retinal blood vessels in a dose-dependent manner. This retinal vasodilator effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase. Similar results were obtained with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR, 0.01–1mg/kg/min). Neither metformin nor AICAR exerted significant effect on mean blood pressure and heart rate. However, a significant pressor response to AICAR was observed upon inhibition of NO synthase. These results suggest that metformin dilates retinal blood vessels through activation of AMPK, and NO plays an important role in the retinal vasodilator response following AMPK activation.

Vasodilator Effects of Elcatonin, a Synthetic Eel Calcitonin, on Retinal Blood Vessels in Rats.

The aim of this study was to examine the effects of elcatonin, a synthetic derivative of eel calcitonin, on rat retinal blood vessels, and to determine how diabetes affects the retinal vascular responses. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate were continuously recorded. Elcatonin increased the diameter of retinal blood vessels but decreased mean blood pressure in a dose-dependent manner, whereas it had no significant effect on heart rate. A diminished retinal vasodilator response and significant pressor response to elcatonin were observed in rats injected intravenously with N(G)-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. Intravitreal injection of indomethacin, a non-selective cyclooxygenase (COX) inhibitor, and SQ22536, an adenylyl cyclase inhibitor, markedly attenuated the vasodilator effects of elcatonin on retinal blood vessels. The retinal vasodilator responses to elcatonin were unaffected 2 weeks after the induction of diabetes by a combination of streptozotocin treatment and D-glucose feeding. These results suggest that elcatonin dilates rat retinal blood vessels via NO- and COX-dependent mechanisms and that the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate system plays a major role in the vasodilator mechanisms. The retinal vasodilatory effects of elcatonin seem to be preserved at early stages of diabetes.

Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke

Pressor response after stroke commonly leads to early death or susceptibility to stroke recurrence, and detailed mechanisms are still lacking. We assessed the hypothesis that the renin–angiotensin system contributes to pressor response after stroke by differential modulation of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) in the rostral ventrolateral medulla (RVLM), a key brain stem site that maintains blood pressure. We also investigated the beneficial effects of a novel renin inhibitor, aliskiren, against stroke-elicited pressor response. Experiments were performed in male adult Sprague–Dawley rats. Stroke induced by middle cerebral artery occlusion elicited significant pressor response, accompanied by activation of angiotensin II (Ang II)/type I receptor (AT1R) and AT2R signaling, depression of Ang-(1–7)/MasR and Ang IV/AT4R cascade, alongside augmentation of MCP-1/C–C chemokine receptor 2 (CCR2) signaling and neuroinflammation in the RVLM. Stroke-elicited pressor response was significantly blunted by antagonism of AT1R, AT2R or MCP-1/CCR2 signaling, and eliminated by applying Ang-(1–7) or Ang IV into the RVLM. Furthermore, stroke-activated MCP-1/CCR2 signaling was enhanced by AT1R and AT2R activation, and depressed by Ang-(1–7)/MasR and Ang IV/AT4R cascade. Aliskiren inhibited stroke-elicited pressor response via downregulating MCP-1/CCR2 activity and reduced neuroinflammation in the RVLM; these effects were potentiated by Ang-(1–7) or Ang IV. We conclude that whereas Ang II/AT1R or Ang II/AT2R signaling in the brain stem enhances, Ang-(1–7)/MasR or Ang IV/AT4R antagonizes pressor response after stroke by differential modulations of MCP-1 in the RVLM. Furthermore, combined administration of aliskiren and Ang-(1–7) or Ang IV into the brain stem provides more effective amelioration of stroked-induced pressor response.

Abstract 235: Role of Angiotensin Converting Enzyme on the Production of Angiotensins From Angiotensin-(1-12) In Normotensive Wistar-kyoto Rats and Spontaneously Hypertensive Rats

We investigated the metabolic pathways contributing to angiotensin II (Ang II) formation from Ang-(1-12) in WKY and SHR. Intravenous infusion of Ang-(1-12) (2 nmol/kg/min) induced a significant pressor response (+ 48 ± 5 mm Hg). Pretreatment with lisinopril [angiotensin converting enzyme (ACE) inhibitor, 10mg/kg] abolished the pressor response by Ang-(1-12) while chymostatin (chymase inhibitor, 10mg/kg) had no effect on the blood pressure rise by Ang-(1-12). ACE inhibition increased plasma Ang-(1-12) from an average of 6,750 ± 2,871 to 23,345 ± 4,509 fmol/mL in vehicle and lisinopril-treated WKY (P < 0.01), respectively (Figure), whereas in SHR plasma Ang-(1-12) rose to 14,334 ± 5,971 in lisinopril-treated compared to 432 ± 142 fmol/mL in vehicle-treated SHR (P < 0.01). The degradation of Ang-(1-12) into Ang I following lisinopril treatment resulted in plasma Ang I averaging 4,762 ± 746 in WKY versus 2,724 ± 657 fmol/mL in SHR compared to plasma Ang I of 744 ± 149 and 580 ± 81 fmol/mL in vehicle-treated WKY and SHR (all P < 0.01). ACE inhibition suppressed Ang II formation from Ang-(1-12) to almost the detectable level of the assay. In contrast, chymostatin increased plasma Ang-(1-7) (138% of control, P<0.05) while having no effect on Ang-(1-12), Ang I or Ang II following Ang-(1-12) infusion compared to control in WKY but not SHR. The data shows that Ang-(1-12) metabolism or plasma clearance is significantly augmented in SHR compared to WKY and that in both strains ACE acts as the primary source for the direct circulatory conversion of Ang-(1-12) into Ang II. Furthermore, we now show for the first time a role of chymase in acting as an Ang-(1-7) degrading enzyme in WKY.

Stereospecific pharmacodynamics and chiral inversion of NG‐nitro‐arginine in the beagle dogs

In the present study, we analyzed the stereospecific pharmacodynamics and inversion of N(G)-nitro-arginine by an intravenous blous injection of L-N(G)-nitro-arginine (L-NNA) or D-N(G)-nitro-arginine (D-NNA) (10 mg/kg) in beagle dogs. Significant pressor responses were observed for both substances, though a similar maximum response induced by L-NNA was reached at 120 min slower as compared with D-NNA. The rise in mean arterial pressure (MAP) of D-NNA dogs was also shown to be slower than the L-NNA group. Our data showed that D-NNA had no impact on MAP within 60 min after its injection. Plasma L-NNA started to appear after 45 min posterior to the i.v. bolus injection of D-NNA. This chiral inversion is unidirectional because no D-NNA was not produced from L-NNA. The pressor response in the D-NNA-injected dogs was well parallel to the plasma L-NNA concentration. Similar disposition of N(G)-nitro-arginine enantiomers and 4% of chiral inversion ratio from D-NNA to L-NNA was found in the beagle dogs. Given that D-amino acid oxidase (DAAO) is the essential enzyme in chiral inversion of D-NNA, we further compared the enzymatic activity of the renal DAAO between dogs and rats. Our data showed that dogs had a significantly lower enzymatic activity than rats, thus supported a lower inversion ratio of D-NNA in dogs.

Pressor and tachycardic responses to intrathecal administration of neuropeptide FF in anesthetized rats

Neuropeptide FF (NPFF) belongs to a neuropeptide family including two precursors (pro-NPFF A and pro-NPFF B) and two receptors (NPFF 1 and NPFF 2). NPFF and NPFF receptor mRNAs have been reported to be highly expressed and localized in the rat and human spinal cord. In the present study, the i.t. action of NPFF system on blood pressure and heart rate were examined using NPFF and two related agonists, NPVF and dNPA, which exhibit highest selectivities for NPFF 1 and NPFF 2 receptors, respectively. In urethane-anesthetized rats, NPFF and related peptides (5–40 nmol, i.t.) produced significant pressor and tachycardic responses at the spinal cord level. These effects were dose-dependent and similar with respect to time-course for the three peptides. Furthermore, i.t. injection of RF9 (20 nmol), a selective NPFF antagonist, significantly antagonized the cardiovascular responses to 20 nmol NPFF and related peptides (i.t.). Moreover, pretreatment of the rats with α-adrenoceptor antagonist phentolamine (1 mg/kg, i.v.) significantly reduced the pressor effects of NPFF. Nevertheless, pretreatment with muscarinic receptor and adrenoceptor antagonists (i.v.) could block the tachycardic effects induced by NPFF. Collectively, our results suggested that i.t. administration of NPFF and related peptides increased MAP and HR which were possibly mediated by the activation of both NPFF 1 and NPFF 2 receptors in the rat spinal cord. In addition, our results showed that the muscarinic receptor and adrenoceptor participated in the tachycardic response to i.t. NPFF, while α-adrenoceptor played an important role in the regulation of pressor effect of NPFF.

Cytisine induces autonomic cardiovascular responses via activations of different nicotinic receptors

Nicotinic cholinergic receptors mediate autonomic transmission at ganglia. However, whether different subtypes of nicotinic cholinergic receptors expressed in autonomic ganglia elicit distinct roles in mediating sympathetic and parasympathetic regulations remain to be defined. In this study, we observed that different subtypes of nicotinic receptors were responsible for the sympathetic and parasympathetic cardiovascular responses. In urethane anesthetized mice, intravenous injection with cytisine, a non-selective nicotinic agonist, induced a brief but pronounced decrease in heart rate, followed by increases in heart rate and arterial blood pressure. The bradycardic response was blocked by atropine, and the pressor response was blocked by prazosin, confirming that these responses were parasympathetic and sympathetic activities, respectively. Hexamethonium, a ganglionic blocker, blocked both sympathetic and parasympathetic responses. Pretreatment with methyllycaconitine citrate, a selective α7 nicotinic receptor antagonist, significantly attenuated cytisine-induced sympathetic response with little effect on the parasympathetic response. In contrast, pretreatment with dihydro-β-erythroidine hydrobromide, a selective α4β2 nicotinic receptor antagonist, blocked cytisine-induced parasympathetic response but not the sympathetic response. Pretreatment with dihydro-β-erythroidine hydrobromide also blocked baroreflex associated parasympathetic bradycardic response. Moreover, treatment with nicotine induced a bradycardic response without a significant pressor response, which was also attenuated by dihydro-β-erythroidine hydrobromide. Collectively, these data suggest that different nicotinic receptors play distinct roles in sympathetic and parasympathetic ganglia. Specifically, activations of α7 and α4β2 nicotinic receptors are involved in cytisine-induced cardiovascular sympathetic and parasympathetic responses, respectively.

Pheromones Produced by the Intact Male Mouse causes a Hypertensive Response during Restrained and Free‐Roaming conditions

Pheromones regulate aggression in sexually mature male mice and castrated males no longer produce these pheromones. We tested the hypothesis that pheromones from the urine of sexually mature‐intact (SMI) males placed in a restrainer or in cage bedding would elicit a hypertensive response in male mice. Sexually mature male C57BL/6 mice were implanted with a biotelemetry device to measure mean arterial pressure (MAP), heart rate (HR) and locomotor activity. All groups were exposed to 200 μl of urine from SMI males, castrated mice and saline. Urine from SMI mice placed in the cages caused a peak change in MAP (24 + 5 mmHg), HR (151 + 25 bpm) and activity (11 + 3 counts). Urine from castrated mice caused a peak change in MAP (12 + 5 mmHg), HR (93 + 15 bpm), and activity (7 + 1 counts). Saline did not increase MAP, HR or activity in any group. During restraint, urine from SMI mice caused a peak change in MAP (19 + 3 mmHg), HR (159 + 27 bpm). Urine from castrated mice caused a peak change in MAP (9 + 2 mmHg), HR (75 + bpm). Saline elicited a peak change in MAP (4 + 1 mmHg) and HR (20 + 7 bpm). These results indicate that a significant pressor response occurs when male mice are exposed to urine from SMI males. Therefore, the SMI male pheromones excreted in the cage bedding and mouse restrainers are responsible for significant increases in the pressor response.

The pressor effect of water: mechanism and location of action

Water ingestion induces a robust, sustained pressor response in patients with baroreflex impairment and in mice with sinoaortic deafferentation (SAD). The mechanism of water's effect on blood pressure remains unknown. In order to isolate the location at which water acts, SAD mice were given water via intragastric or intraduodenal routes. In both cases a similar pressor response appeared. The presence of a pressor response following intraduodenal infusion indicates that the pharynx, esophagus, and stomach are not critical sites for water's pressor action. Administering an identical volume of physiological saline did not induce a significant pressor response. Osmolality of portal and systemic circulations was measured 15 minutes post intraduodenal water infusion and found to be 292.7 and 304.4 mOsm/kg, respectively. TRPV4 is an osmo‐sensitive cation channel found throughout the body, and has been reported to be activated under hypotonic conditions. To investigate the potential role of TRPV4 in water's pressor response, animals lacking TRPV4 were given water intraduodenally. Compared to wild type, TRPV4 ‐/‐ animals had a greatly diminished pressor response to water. We conclude that the pressor effect of water is not dependent on pharyngeal, esophageal, nor gastric mechanisms; portal osmolality is reduced following water administration; and that the TRPV4 channel is essential for water's effect.

Pressor responses to hyperventilation in elderly subjects differentiate essential from secondary hypertension

Abstract We evaluated pressor responses to the hyperventilation test in elderly normotensive (n=43, mean age 82 ± 5 years) and elderly hypertensive subjects (n=45 with essential hypertension, mean age 82 ± 2 years, and n=49 with secondary hypertension, mean age 82 ± 3 years). Hyperventilation did not change blood pressure (BP) in normotensive and secondary hypertensive subjects, whereas it decreased BP in essential hypertensives. Hierarchical cluster analysis based on BP responses to hyperventilation disclosed three groups of subjects in each population: group 1 exhibited a reduction in BP (essential hypertensives: 76%), group 2 no change (normotensives: 70%, secondary hypertensives: 76%), and group 3 an increase (normotensives: 19%, essential hypertensives: 13%, secondary hypertensives: 14%). Ambulatory BP monitoring found significant differences in pressor daytime profiles of hypertensive patients according to pressor responses to hyperventilation showing wide fluctuations in group 1 and 3 patients. Interestingly, the peak ambulatory SBP values correlated to the pre-hyperventilation SBP values in group 1, and to the hyperventilation peak SBP values in group 3. In conclusion: 1) Aging decreases reactivity to respiratory alkalosis in elderly normotensives; 2) hyperventilation induces significant pressor changes frequently in essential hypertension, but rarely in secondary hypertension; 3) the significant pressor responses to hyperventilation reflect the daytime pressor profiles predicting the highest daily fluctuations of BP values.

Developmental Programming Through Epigenetic Changes

See related article, pages 520–526 The last decade has seen an exponential number of scientific articles addressing the concept of fetal programming of adult onset diseases. Though it has long been known (as it is probably part of common knowledge in human history) that the environment and life events during the fetal period impact on the child’s development, the notion that intrauterine life can also impact on adult health and on the incidence of late onset diseases such as hypertension and type II diabetes is relatively more recent. In 1964, Rose reported the association of ischemic heart disease and infant mortality within the same families (reviewed by1). Then Forsdahl in 1977 showed that incidence of arteriosclerotic heart disease in a certain age group could be correlated with the infant mortality rate of that same population.1 Interest in these types of association rose dramatically following Professor Barker and collaborators’ extensive observations of a well documented population in England and Wales. The meticulous work of home health visitors in the early 20th century, which noted every child weight and length at birth and throughout the first year of life as well as other observations of the mother health and living milieu, generated data which clearly demonstrated an inverse relationship between birthweight and adult incidence of cardiovascular related mortality and morbidities as well as type II diabetes.1 We will focus here on hypertension and related complications. The association between birthweight and adult blood pressure was demonstrated in many parts of the world, in industrialized as well as in more developing countries, in both men and women.1 The association is first noted in early childhood (but not at birth) and seems to increase with age. Despite the significant number of studies published, which have examined to date tens …

Effects of Remifentanil and Alfentanil on Cardiovascular Responses to Laryngoscopy and Double-lumen Endobronchial Intubation

Background: This study examined the cardiovascular responses to double-lumen endobronchial intubation during rapid sequence induction of anesthesia, and compared the effect of remifentanil and alfentanil in a randomized, double-blind, placebo-controlled study in three groups of 20 elderly patients each. Methods: Anesthesia was induced with intravenous thiopental (4－6 mg/kg) immediately followed by either remifentanil 2 μg/kg, alfentanil 30μg/kg, or saline (placebo) given over 30 sec. Succinylcholine 1 .5 mg/kg was given for neuromuscular block. The laryngoscopy and intubation were performed 60 sec later. Results: The intubation significantly increased systolic arterial pressure (SAP) and heart rate (HR) in all groups. The maximum pressure changes in the remifentanil and alfentanil groups (36 ± 26 and 33 ± 30 mmHg, respectively) were significantly lower than the 83 ± 35 mmHg in the control group. The maximum HR in the remifentanil (77 ± 13 bpm) and alfentanil (80 ± 13 bpm) groups was lower when compared to controls (93 ± 11 bpm). The norepinephrine and epinephrine concentrations increased after intubation in the control group but remained unaltered in both the alfentanil and remifentanil groups. There were no significant differences between the remifentanil and alfentanil groups in HR, SAP or catecholamines at any time. Five patients in the remifentanil group and three in the alfentanil group received ephedrine for hypotension. Conclusions: Endobronchial intubation elicited a significant pressor response, and that both remifentanil and alfentanil similarly attenuated the pressor response. However, the incidence of hypotension confirms that both drugs should be used with caution in elderly patients. (Korean J Anesthesiol 2007; 52: S 14～20)

Aging and vascular responses to flavanol-rich cocoa

Strong evidence has secured aging as a powerful predictor of both cardiovascular risk and endothelial dysfunction, yet specific treatment is not available. We tested the hypothesis that vascular responsiveness to flavanol-rich cocoa increases with advancing age. We have previously shown that flavanol-rich cocoa induced peripheral vasodilation, improving endothelial function via a nitric oxide (NO)-dependent mechanism. We studied blood pressure and peripheral arterial responses to several days of cocoa in 15 young (< 50 years) and 19 older (> 50) healthy subjects. The nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine-methyl-ester (L-NAME) induced significant pressor responses following cocoa administration only among the older subjects: systolic blood pressure (SBP) rose 13 +/- 4 mmHg, diastolic blood pressure (DBP) 6 +/- 2 mmHg (P = 0.008 and 0.047, respectively); SBP was significantly higher in the older subjects (P < 0.05). Flow-mediated vasodilation, measured by tonometry in the finger, was enhanced with flavanol-rich cocoa in both groups, but significantly more so among the old (P = 0.01). Finally, basal pulse wave amplitude (PWA) followed a similar pattern. Four to six days of flavanol-rich cocoa caused a rise in PWA in both groups. At peak vasodilation following acute cocoa intake on the final day, both groups showed a further, significant rise in PWA. The response in the older subjects was more robust; P < 0.05. L-NAME significantly reversed dilation in both groups. Flavanol-rich cocoa enhanced several measures of endothelial function to a greater degree among older than younger healthy subjects. Our data suggest that the NO-dependent vascular effects of flavanol-rich cocoa may be greater among older people, in whom endothelial function is more disturbed.

Blood pressure and heart rate changes during fibreoptic orotracheal intubation: a comparison of children and adults

Autonomic circulatory regulation and airway anatomy in children are significantly different from those in adults. There is no available published data to compare whether there is a clinically relevant difference in the haemodynamic responses to fibreoptic orotracheal intubation (FOI) under the same conditions between children and adults. In this randomized clinical study, we compared the blood pressure (BP) and heart rate (HR) changes during FOI in 40 children aged 3.5-9 yr and 40 adults aged 21-57 yr, ASA 1 scheduled for elective plastic surgery under general anaesthesia requiring orotracheal intubation. Anaesthesia was induced with intravenous (i.v.) injection of fentanyl and propofol, and face mask inhalation of isoflurane before FOI. Noninvasive BP and HR were recorded before induction (baseline values), after induction (postinduction values), at intubation and for 5 min after intubation at 1-min intervals. The percentage changes of BP and HR at each time point were calculated. In children and adults, HR at intubation and 1-3 min after intubation were significantly higher than baseline and postinduction values. In adults, BP at intubation increased significantly compared to the postinduction values but did not exceed baseline values. In children, BP at intubation and 1 min after intubation were significantly higher than postinduction and baseline values. As compared to adults, FOI caused a more significant pressor response in children. The percentage changes of BP at intubation and 1 min after intubation were larger in children than in adults. However, there was no significant difference in the percentage change of HR during the observation between children and adults. Under general anaesthesia, FOI might cause a more significant pressor response in children than in adults.